Skip to main content
Intended for healthcare professionals
Free access
Research article
First published July 2000

Cellular Localization of Gene Expression for Progranulin

Rachael Daniel, Zhiheng He, K. Paige Carmichael, Jaroslava Halper, and Andrew Bateman [email protected]View all authors and affiliations
Volume 48, Issue 7
https://doi.org/10.1177/002215540004800713

Abstract

Granulins, also called epithelins, are 6-kD peptides with growth modulatory effects on a variety of cells. The granulin/epithelin precursor supports tumorigenesis in appropriate cell models and is the only growth factor able to overcome the cell cycle block that occurs in murine fibroblasts after deletion of a functional IGF-1 receptor. However, little is known of the role of granulin/epithelin gene products in vivo. To understand the physiological role of granulins it is essential to know the cell types and conditions in which it is expressed. We examined granulin/epithelin gene expression in adult rodents by in situ hybridization. The granulin/epithelin precursor is constitutively expressed in a number of epithelia, particularly in the skin, GI tract, and reproductive system. Other epithelia express the gene less strongly. Progranulin is expressed in immune cells in vivo and in specific neurons in the brain, including Purkinje cells, pyramidal cells of the hippocampus, and some cerebral cortical neurons. Little expression was detected in muscle cell, connective tissue, or endothelium. Cumulatively, these results define the basal gene expression of a new growth factor system and suggest that the progranulin/epithelin gene is multifunctional, with important constitutive roles in epithelial homeostasis, reproductive, immunological, and neuronal function.
Granulins (grns) (Bateman et al. 1990), also called epithelins (epis) (Shoyab et al. 1990), were initially identified as peptides of approximately 6-kD, some of which can modulate the growth of cells in tissue culture (reviewed in Bateman and Bennett 1998). They are rich in cystine and possess a unique structurally defined motif of six disulfide bonds (Hrabal et al. 1996). All known mammalian grns are generated from a common precursor, progranulin, which consists of 7.5 sequentially arranged grn/epi motifs arranged in tandem (Bhandari et al. 1992, 1993; Plowman et al. 1992; Baba et al. 1993) and which is potently mitogenic in cell culture (Zhou et al. 1993; Zhang and Serrero 1998; Xu et al 1998; He and Bateman 1999). Progranulin stimulates proliferation of many epithelial cells, promotes their anchorage-independent growth and, when overexpressed, confers epithelial tumorigenicity (He and Bateman 1999). In cell culture, the rate of epithelial proliferation is proportional to the level of progranulin gene expression (He and Bateman 1999). Consistent with these results, progranulin has recently been shown to modulate the normal development of early embryonic epithelia (Diaz–Cueto et al. 2000). Many epithelial tissues and carcinomas contain a 25-kD protein called epithelial transforming growth factor (TGFe), which has some structural similarities to progranulin (Parnell et al. 1992). Like progranulin, it is also a potent mitogen for many epithelial and mesenchymal cell lines (Halper and Moses 1983, 1987; Brown and Halper 1990; Parnell et al. 1990; Dunnington et al. 1990a, b) Nonepithelial cells also respond mitogenically to progranulin. PC cells, which are highly tumorigenic murine mesenchymal teratoma cells (Serrero et al. 1991), require progranulin (called PCDGF in this context) to sustain their growth (Zhou et al. 1993), and antisense targeting of progranulin/PCDGF dramatically lowers their tumorigenicity (Zhang and Serrero 1998). The growth of nontransformed embryo fibroblasts typically requires insulin-like growth factor (IGF)-I or IGF-II and at least one other growth factor, such as EGF, PDGF, or FGF (Baserga et al. 1997). The central role of the IGF-I receptor in this pathway has been demonstrated using embryonic fibroblasts from mice whose IGF-I receptor has been deleted (Coppola et al. 1994; Sell et al. 1994). These cells, called R−, no longer grow in response to IGFs. Less predictably, in the absence of a functional IGF-I receptor proliferation in response to all other classic growth factors is precluded (Coppola et al 1994; De Angelis et al. 1995), and several intracellular oncogenes are blocked in their ability to transform the cells (Sell et al. 1994). Progranulin, in contrast, potently stimulates cell cycle progression in R− embryo fibroblasts independently of an intact IGF-I signaling system and is the only growth factor yet shown to circumvent the mitotic block imposed on R− cells (Xu et al. 1998). Progranulin does this by activating the MAP Kinase and PI-3 Kinase pathways of R− cells independently of IGF-I receptors or the IRS-1 adaptor protein (Zanocco–Marani et al. 1999).
Although progranulin, progranulin-derived peptides, and related proteins such as TGFe are clearly capable of regulating cell growth, less is known of their roles in vivo. Most established cell lines of epithelial origin express the progranulin gene strongly (Bhandari et al. 1992; Plowman et al. 1992). It is also abundant in many cell lines of hematopoietic origin (Bhandari et al. 1992), in some fibroblastic cell lines (Bhandari et al. 1992; Plowman et al. 1992) and as a glycoprotein called acrogranin in guinea pig acrosomal granules (Anakwe and Gerton 1990; Baba et al. 1993). Northern analysis of tissues indicates that it is highly expressed in the spleen, placenta, ovaries, epididymis, and adrenal gland. Moderate expression was observed in the gastrointestinal tract, lung, and kidney. Expression was low in skeletal muscle, heart, and brain (Bhandari et al. 1993). In some instances, progranulin gene expression is regulated by sex steroids. In estrogen-responsive breast cell lines, progranulin gene expression was upregulated by estrogens (Lu and Serrero 1999). Androgens potently induced progranulin in the ventromedial and arcuate nuclei of newborn female mice, whereas progranulin expression was high and constitutive in the same regions of newborn male brains (Suzuki et al. 1998), suggesting a role for progranulin products in phenotypic sex determination of the hypothalamus. Given the proliferative effects of progranulin on diverse cells in vitro (Zhou et al. 1993; Xu et al. 1998; He and Bateman 1999) and its ability to activate mitogenic signal transduction cascades (Zanocco–Marani et al. 1999), it is essential to establish the cellular localization and conditions of progranulin gene expression in vivo so that the physiological context of progranulin action can be investigated. Here we report the cellular distribution of the grn/epi precursor mRNA in healthy adult rodent tissue.

Materials and Methods

Isolation of RNA and Northern Blotting Analysis

Around 2 × 106 cells were harvested and washed with ice-cold PBS, pH 7.4, Total cellular RNA was isolated by the guanidium thiocyanate method (Chomczynski and Sacchi 1987). Fifteen μg total RNA was denatured with glyoxal, separated in a 1% agarose gel (1% agarose in 10 mM NaHPO4, pH 7.0), transferred to nylon membrane, and hybridized with a 32P-labeled granulin cDNA probe as described (Bhandari et al. 1993). Unless stated otherwise, all cell lines were of human origin and were obtained from ATCC (Manassas, VA). The cell lines used were: A549 (lung carcinoma), A431 (vulval epidermoid carcinoma), CaSki-1 (cervical epidermoid carcinoma), Calu-6 (anaplastic carcinoma), CHO (Chinese hamster ovary), SW-13 (adrenal cortical adenocarcinoma), MDCK (canine kidney epithelia), HepG2 (hepatoma), NHEK (normal human epidermal keratinocytes; gift of Dr. R. Kremer, Calcium Laboratory, Royal Victoria Hospital), primary culture of bronchial epithelium (gift of Dr. A. Giad, Montreal General Hospital), L6 (rat skeletal myoblasts), SKUT-1 (uterine mixed mesodermal tumor), SK-LMS-1 (vulval leiomyosarcoma), Swei (B-lymphoma), CEM-CM3 (T-cell lymphoblastic leukemia), HL60 (promyelocytic leukemia), U937 (histiocytic lymphoma), K562 (erythroleukemia), AML (primary acute myelogenous leukemia; gift of Dr. C. Shustik, Royal Victoria Hospital), CML (primary cells from chronic myelogenous leukemia; gift of Dr. C. Shustik), NIH-3T3 (murine embryonic fibroblasts), COS-7 (transformed monkey kidney fibroblasts), Malme-3M (melanoma), PC-12 (rat adrenal gland pheochromocytoma), and SK-N-DZ (human brain neuroblastoma) cells.

Generation of Digoxigenin-UTP-labeled Progranulin RNA Probe

A 238-bp fragment corresponding to nucleotides 748–1002 of full-length rat progranulin cDNA was blunt end-ligated to an expression vector BlueScript KII (Invitrogen, Carlsbad, CA). The 5′ end of the fragment is adjacent to an Xba restriction site with an upstream T7 promoter; a Xho restriction site is located downstream of the 3′ end of the fragment with a T3 promoter further down on the line. Sense or anti-sense digoxigenin-UTP-labeled RNA probes were generated by reverse-transcribing the 238-bp progranulin cDNA fragment using either T7 (sense) or T3 (antisense) RNA polymerase after digestion with either Xho (sense) or Xba (anti-sense). The reverse-transcription was performed using a commercially available Dig-UTP labeling and detection kit (Boehringer–Mannheim; Indianapolis, IN) according to the manufacturer's instructions. The probe was checked by performing Northern blotting hybridization with mouse kidney total RNA. In brief, two identical membranes containing 15 μg mouse kidney total RNA were hybridized to 100 ng/ml sense or antisense probe and washed. Signals on the membranes were detected as described (Genius System User's guide for membrane hybridization, version 3.0; Boehringer–Mannheim).

In Situ Hybridization

Paraffin-embedded sections were deparaffinized in xylene (Fisher; Montreal, PQ, Canada) for 4 min, then dehydrated in 100% ethanol followed by progressive hydration in 95%, 70%, and 50% ethanol. The sections were then postfixed in prechilled 4% paraformaldehyde (Fisher), pH 7.4, for 10 min, and washed in 0.5 × SSC for 5 min. Permeabilization of the tissues was achieved by incubating the sections with 3.5 μg/ml proteinase K in 100 mM Tris-HCl, 50 mM EDTA, pH 8.0, at 37C for 15 min. The slides were fixed again in 4% paraformaldehyde for 10 min and rinsed thoroughly in PBS (6 min) and 0.5 × SSC (10 min). The slides were then pre-hybridized in hybridization solution [5 × SSC, 5 × Denhardt's solution, 50% deionized formamide (Fisher), and 250 μg/ml tRNA] at 42C. Three hours later the sections were cleaned with a lint-free tissue and hybridized with 75 ng Dig-UTP labeled progranulin RNA probe in hybridization solution for 18 hr at 42C. After washing, the slides were incubated with conjugated Dig antibody (Boehringer–Mannheim) and the reaction products were visualized according to the manufacturer's instructions. All experiments were conducted using parallel antisense and sense probes, and in most cases no nonspecific hybridization was observed (this is shown only for the testis sections; see Figure 3). Any experiments showing significant nonspecific hybridization with the sense probe were discarded. Sections from two species, rat and mouse, were analyzed. The numbers of different animals used for each tissue were as follows: testis and epididymis; n = 4; female reproductive organs; n = 3; mammary gland; n = 4; skin; n = 4; gastrointestinal tract; n = 5; urinary system; n = 5; lung; n = 5; liver; n = 4; skeletal muscle; n = 4; heart; n = 5; spleen; n = 5; brain; n = 3. Each tissue was serially sectioned and at least three sections per sample were examined. The species shown in the figure is identified in the legends.

Purification of the Recombinant Progranulin

Recombinant progranulin was produced as described previously (He and Bateman 1999). Briefly, COS-7 cells were transiently transfected with a full-length progranulin construct in pcDNA3 or with the pcDNA3 vector alone (mock-transfected). [35S]-Cysteine was used to metabolically label protein production. After 48 hr the serum-free conditioned medium was collected and then concentrated using a Centricon-30 spin column (Millipore; Bedford, MA). The concentrated CM was then fractionated using C-4 reversed-phase HPLC as described (He and Bateman 1999). A single transfection-specific [35S]-cysteine-labeled component was detected (not shown) with an apparent molecular weight of 80 kD as assessed by SDS-PAGE and autoradiography (He and Bateman 1999). The purity of the progranulin was further confirmed by SDS-PAGE and silver staining (not shown). This protein exhibited colony-forming activity on SW-13 adrenal carcinoma cells, and no comparable activity was detected in the mock transfectants (not shown). N-terminal gas-phase microsequence analysis has confirmed the identity of this protein as intact human progranulin (He and Bateman 1999).

Cell Growth Assay

To compare the effect of progranulin on selected cell lines, 1.5 × 104 cells were seeded in 24-well plates (Corning Co-star; Cambridge, MA). After 24 hr the medium was replaced with serum-free DMEM for 24 hr. Before addition of the re combinant progranulin, the cells were washed twice in 1 × PBS (pH 7.4) and then incubated with increasing concentrations of recombinant progranulin for 2 days. The cells were trypsinized and counted in a hemocytometer.

Results

Northern Blot Analysis

Total RNAs from several cell lines of various origins were probed for the expression of the progranulin gene (Figure 1A). All epithelial cell lines except the hepatoma line HepG2 expressed the progranulin transcript at high levels. Progranulin transcripts were also abundant in primary cultures of human bronchiolar epithelia and normal human keratinocytes. Myeloid- and lymphoid-derived cell lines also expressed the progranulin transcript, as did leukocytes from patients with acute and chronic myelogenous leukemia. Progranulin transcripts were detected in two leiomyosarcoma-derived lines (SK-UT-1 and SK-LMS-1) but not in undifferentiated L6 rat myoblasts. Neither of the neuron-derived cells lines (PC-12 and SK-N-DZ) expressed progranulin mRNA (not shown). The anti-sense riboprobe used for in situ hybridization is specific for progranulin transcripts because on Northern blotting analysis of murine kidney mRNA it hybridized to only one mRNA, which had a size of 2.4 kb as predicted for the rodent progranulin transcript (Figure 1B). No hybridization was observed with the sense riboprobe.
Figure 1. (A) Northern blotting analysis of progranulin mRNA in cells from different origins in culture (the origin of the cells is given in Materials and Methods). Note that this is a summary of several experiments. (B) To evaluate the specificity of the riboprobe used for in situ hybridization, the antisense and sense probes were hybridized to murine kidney mRNA. No signals were detected for the sense probe.

Normal Tissue Distribution

Testis and Epididymis. In the seminiferous tubule, the cells that line the basement membrane (mainly primary spermatogonia) expressed progranulin mRNA, as did the cells between one to three layers deeper within the tubule (Figure 2A). More mature spermatocytes showed little or no expression of progranulin mRNA. In some tubules, Sertoli cells also expressed the progranulin gene. Leydig cells and other cells in the interstitium rarely expressed progranulin. No vascular elements in the testis expressed progranulin. The sense control probe detected no hybridization (Figure 2C). The epididymis showed intense expression of the progranulin gene, which was confined to the epithelial layer (Figure 2B).
Female Reproductive Organs. A section of uterus in the proliferative phase is shown. Glandular epithelium showed pronounced expression of the progranulin gene (Figure 2D). Stromal cells in the proliferative zone expressed the progranulin gene. There was a marked boundary in the basal endometrium which exhibited much lower levels of progranulin hybridization. The smooth muscle cells of the myometrium expressed elevated levels of progranulin mRNA. In the oviducts, only the epithelia lining the oviduct expressed the progranulin mRNA (Figure 2E). The oviductal smooth muscle and vasculature did not express the progranulin gene. In the ovary, hybridization for the progranulin riboprobes was highest in follicular epithelial cells. Hybridization was weak in the corpus luteum and negligible in thecal cells. Progranulin transcripts were also present in oocytes (Figure 2F).
Mammary Gland. Hybridization of the progranulin riboprobe in virginal rat mammary gland was detected exclusively in the glandular epithelium (Figure 2G).
Skin. Epidermal keratinocytes stained strongly for granulin mRNA (Figure 3A). The outer hair follicle hybridized with the progranulin antisense riboprobes (Figure 3B). Cross-sections of the hair follicle showed that the dermal papillae did not express progranulin mRNA. All the epithelial cells at the hair root strongly expressed the progranulin gene. The progranulin gene was expressed in exocrine glands (Figure 3C), although the staining was less intense than that seen in the keratinocytes. Apart from follicles and glandular structures, little if any granulin mRNA was detected in dermal layer fibroblasts or in blood vessels.
Gastrointestinal Tract. Progranulin mRNA appeared to be predominantly located in epithelial cells in the gastrointestinal tract. Squamous epithelium in the esophagus and esophageal/gastric junction stained strongly for progranulin mRNA (Figure 3D). In the small intestine, progranulin was expressed by enterocytes in the deep crypts, with the mRNA levels progressively fading higher in the villus (Figure 3E). A similar pattern was observed in the colon (not shown). Smooth muscle and vasculature showed no progranulin mRNA. However, neuronal ganglia were strongly positive for progranulin mRNA (Figure 3E and insert, white arrow). Lymphocytes in the gut-associated lymphoid tissue hybridized strongly for progranulin mRNA (Figure 3F).
Kidney. Progranulin mRNA was confined to epithelial cells in the kidney. There was weak hybridization in the proximal and distal convoluted tubules of the cortex and in some collecting ducts of the medulla (Figure 3G). No hybridization was observed in the glomerulus or any vascular elements. The strongest hybridization occurred in the transitional epithelium of the ureter, which approached that of skin and intestinal crypt epithelium in intensity.
Lung. Progranulin mRNA was localized in alveolar epithelium only after prolonged incubation with the color reagents, and was confined only to sporadic epithelial cells (Figure 3H). Higher levels of progranulin mRNA were observed in the bronchiolar epithelium (Figure 3I, black arrow), but the intensity of hybridization was considerably lower than in keratinocytes or enterocytes. In the lung, lymphoid cells exhibited the highest levels of progranulin transcript (Figure 3I, open arrow). Progranulin mRNA was absent from cells of the lung vasculature.
Figure 2. Progranulin gene expression in the male (A–C) and female (D–F) reproductive system and the virginal rat mammary gland (G). Seminiferous tubules of the murine testis (A, × 175). In the epididymis (B, × 175), the epithelia stained strongly. Negative staining of the testis after hybridization with the sense progranulin probe (C, × 175). In the murine uterus (D, × 175) progranulin gene expression was observed in the glandular epithelium (black arrow), stroma (open arrow), and weakly in the myometrial smooth muscle (∗). In rat oviduct, only epithelial cells exhibit progranulin expression (E, × 175). In rat ovary (F, × 340), some follicular cells and oocytes have progranulin expression. In the virginal rat mammary gland (G, × 175), progranulin expression is seen in the glandular epithelium (black arrow).
Liver. The liver was essentially devoid of cells expressing the progranulin mRNA (not shown).
Skeletal Muscle and Heart. Neither skeletal muscle nor cardiac muscle expressed the progranulin gene (not shown).
Spleen. In the spleen (Figure 4A and 4B), expression of progranulin mRNA occurred predominantly in lymphoid cells on the outer edges of the periarteriolar lymphoid sheaths (white pulp). Cells in the red pulp stained sporadically.
Brain. Progranulin transcripts were prominent in neurons within the superficial lamina of the cerebral cortex (Figure 5A). Expression was high in the Purkinje cells of the cerebellum (Figure 5B), and in scattered cells in the molecular layer, but less strongly. Expression was absent from granule cells of the internal granular layer. Neurons of the cerebellar roof nuclei showed intense hybridization with the progranulin probe, which was comparable to that of the Purkinje cells (not shown). Progranulin gene expression was high in the hippocampus and was localized to the pyramidal cells and the granule cells. In the posterior portion of the hippocampus, all the granule cells stained evenly (not shown). However, in the mid-hippocampus (Figure 5C and 5D), the granule cells stained more intensely in the Ammon's horn (black arrow) than those in the dentate gyrus (open arrow). Nonneuronal components of the brain, such as ependymal cells and glia, did not express progranulin transcripts.

Cell Proliferation

Eight cell lines were selected and tested for their proliferative response to progranulin (Figure 6). Two epithelial lines previously shown to respond to progranulin (He and Bateman 1999) were included for comparative purposes (A549, human lung adenocarcinoma; MDCK, a nontransformed canine renal epithelial cell type). To test for the proliferative effects of progranulin in hematopoietic-derived cells, we used U937 (histiocytic lymphoma), and HL-60 (promyelocytic leukemia). To test for the effects of progranulin in proliferative smooth muscle-like cells, we used SK-UT-1 (a uterine leiomyosarcoma) and SK-LMS-1 (a vulval leiomyosarcoma). To test for the proliferative effects of progranulin in neuron-derived cells, we used PC-12 (rat adrenal gland pheochromocytoma) and SK-N-DZ (human brain neuroblastoma). Both epithelial cell lines proliferated in response to progranulin, as did the mesen-chyme-derived leiomyosarcoma SK-LMS-1 and neuronal PC-12 cells, but not SK-UT-1, SK-N-DZ, HL-60, and U937.

Discussion

Progranulin gene products promote tumorigenesis in experimental models (Zhou et al. 1993; Zhang and Serrero 1998; He and Bateman 1999) and are uniquely able to circumvent the requirement for a functional IGF-I receptor in the proliferation of untransformed murine embryonic fibroblasts (Xu et al. 1998), but their significance and roles in physiological systems are not well understood. It has recently been shown that progranulin is needed for epithelial development in early embryos (Diaz–Cueto et al. 2000). Here we have defined the basal gene expression of progranulin in adult rats and mice and find that it is prominent in certain epithelial, immune and neuronal cells in vivo. Comparable expression patterns were observed both between species and between individuals of the same species. If, as proposed elsewhere from cell culture studies (He and Bateman 1999), the level of epithelial expression of the progranulin transcript regulates epithelial mitogenesis, we would predict that highly proliferative epithelia should express elevated levels of the progranulin gene in vivo. In general, this is observed, because rapidly cycling epithelium, such as that in the skin and gastrointestinal tract, exhibits greater hybridization with the progranulin riboprobes than mitotically less active epithelia, such as the pulmonary alveolar cells or the renal tubules. In this regard, the small intestine and colon are particularly instructive because proliferating enterocytes are located deep within the crypt and are segregated from terminally differentiating cells at higher levels within the villus (Figure 3E). In the small intestine and colon, the most intense progranulin-gene expression occurs in the deep crypts, roughly coincident with the zone of less well-differentiated but highly proliferative cells. Progranulin expression declines rapidly at higher levels within the villus as the cells differentiate and cease to divide. Although progranulin expression in epithelial cells appears highly regulated in vivo, progranulin mRNA was abundant in all tranformed or immortal epithelial cell lines examined except for the HepG2 hepatoma cells, even in cells such as A549 (lung) and MDCK (kidney) that originate from tissues that express the progranulin gene relatively weakly (Figure 1A). This suggests that high progranulin expression in epithelia is associated with a rapidly proliferative phenotype regardless of tissue origin. Clearly, however, some epithelial cells, such as the epididymis and urothelium, that are less mitotically active than the skin or gastrointestinal tract retain high levels of progranulin expression.
Figure 3. Progranulin gene expression in the skin (A–C), GI tract (D–F), kidney (G), and lung (H, I). In the rat epidermis, extensive staining was observed only in the keratinocytes (A, black arrow, × 340), hair follicles (B, black arrow, × 340) and outer cells of the shaft (B, open arrow, × 340). Exocrine sweat glands in the dermis express progranulin (C, × 340). In the rat GI tract, epithelial cells express progranulin in the esophageal gastric junction (D, × 170) and in the ileum (E, open arrow). Inset in E shows progranulin expression in the enteric ganglia (black arrow, × 680). Progranulin expression was observed in lymph node follicles adjacent to the large intestine (F, × 340). In the rat kidney (G, × 340), the strongest hybridization is in the transitional epithelium of the beginning of the ureter (∗), and is weak in the collecting ducts of the medulla (open arrow). Tubules of the cortex stained with the same intensity as the collecting tubules (not shown). In the rat lung parenchyma, only sporadic epithelial cells showed progranulin expression (H, × 340, black arrow). The bronchial epithelium (I, × 340, black arrow) and lymphoid tissues (I, open arrow) beneath the bronchial mucosa have the strongest progranulin expression in the lung.
Figure 4. (A, B) Progranulin gene expression in rat spleen. Progranulin expression is noted in lymphoid cells in the outer margin of the white pulp (black arrow); cells in the red pulp stained sporadically. Original magnifications: A × 175; B × 340.
Figure 5. Progranulin expression in mouse brain. Progranulin expression was detected in neuronal cells, but not glial cells in several brain regions. Cortex (A, × 680); in the cerebellum, expression was strong in Purkinje cells (arrow) (B, × 680); In the mid-hippocampus, granule cell neurons stain throughout the mid-hippocampal region, but more intensely in Ammon's horn (black arrow) than the dentate gyrus (open arrow) (C, × 40); D, × 175.
Figure 6. Cell lines of epithelial, neuronal, smooth muscle, and myelogenic origin as described in Materials and Methods were incubated with increasing concentrations of purified recombinant progranulin in serum-free medium. Cell growth was determined and expressed as percentage of unstimulated cells (n = 4).
The results reported here support an important role for progranulin gene expression in both male and female reproductive tissues. In the adult testes, the highest levels of progranulin mRNA are associated with immature spermatocytes and spermatogonia but not with more mature spermatozoa (Figure 2A). This is presumably correlated with the synthesis of acrogranin, a high molecular weight progranulin product found within acrosomes (Anakwe and Gerton 1990). The expression is also high in the epididymal epithelium (Figure 2B), but whether the progranulin products act on the epididymal cells or on maturation of intralumenal sperm (Moore and Akhondi 1996) is unknown. In ovaries, a subset of follicles show high levels of expression in the epithelial cells but not in thecal cells (Figure 2F). The expression in the corpus luteum is uniformly low. Because luteal cells and mature spermatocytes are highly differentiated epithelial cells, this result is consistent with a model in which less well-differentiated or highly proliferative, or potentially proliferative, epithelia express elevated levels of the progranulin gene, and fully differentiated but less mitotically active epithelial cells express lower or negligible levels of progranulin mRNA.
Progranulin is a potent mitogen for fibroblasts (Zhou et al. 1993; Xu et al. 1998) and other mesenchymal cell lines such as SK-LMS-1 (Figure 6). These cells also express the progranulin gene (Figure 1).
However, the progranulin transcript was undetectable in most mesenchymal tissues in vivo, such as the connective tissue, adipose cells, skeletal muscle, smooth muscle, cardiac muscle, or vascular elements. Therefore, despite the mitotic responsiveness of mesenchyme to progranulin, intrinsic progranulin gene expression by these cells is not required for their survival and constitutive activity in vivo. The major exception is the female reproductive tract. In the female reproductive system, the epithelial cells of the uterine glands are strongly positive for progranulin gene expression. However, the primitive mesenchyme in the proliferating layer surrounding the glands also expresses the progranulin gene. The connective tissue beneath the proliferating layers shows little progranulin gene expression, but the smooth muscle of the myometrium expresses the progranulin mRNA (Figure 2D). In contrast, the smooth muscle of the oviduct does not express progranulin (Figure 2E). The myometrial smooth muscle is highly proliferative during pregnancy, whereas oviductal and gastrointestinal smooth muscle cells, which do not express appreciable levels of progranulin mRNA, are in general mitotically quiescent. The leiomysarcoma cell lines SK-UT-1 and SK-LMS-1 show relatively high level of expression of the progranulin gene (Figure 1), and progranulin stimulated proliferation in one of two leiomyosarcoma cell lines to the same extent as in the epithelial cell lines A549 and MDCK (Figure 6), supporting a potential mitotic role for progranulin in transformed or proliferating smooth muscle. These results suggest that some nonepithelial somatic cells with an intrinsically high capacity to proliferate may express the progranulin mRNA at levels substantially higher than quiescent mesenchymal cells.
The peripheral immune system shows very strong expression of the progranulin gene in lymphoid tissue of the lung, gut, and spleen. The distribution of progranulin mRNA in immune tissues does not correspond to the expected patterns of immune cell proliferation, implying a nonmitogenic function for progranulin products in the immune system. In the spleen, the progranulin transcript is confined mainly to marginal cells of the periarteriolar lymphoid sheath (PALS) (Figure 4A and 4B). These cells are largely T-lymphocytes. The B-lymphocytic population within the interior of the PALS shows less extensive progranulin staining. Lymphoid aggregates in the lung and gut express progranulin mRNA at high levels (Figure 3I and 3F). Cell lines derived from both B- and T-lymphomas express the progranulin gene in culture (Figure 1A). The cellular specificity of progranulin expression in the peripheral immune system, which is particularly apparent in the spleen, reflects stringent regulation of the progranulin gene in the immune system. Granulins were initially detected in activated inflammatory cells (Bate-man et al. 1990), and the gene is highly expressed in myelogenous leukemic cell lines (HL-60, U937) and in leukocytes from the blood of leukemic patients (Figure 1). Neither HL-60 nor U937 responded mitotically to progranulin. Expression in myelogenous cells and lymphocytes indicates a probable role for progranulin or granulin in the defense system.
In earlier studies we reported that the levels of progranulin mRNA in the brain were very low compared to those in other tissues (Bhandari et al. 1993). This was probably misleading, because although the levels are low overall, we show here that the progranulin gene is highly expressed in specific subsets of neuronal cells, notably cortical neurons (Figure 5A), Purkinje cells of the cerebellum (Figure 5B), and granule cells of the hippocampus (Figure 5C and 5D). It is known that the hippocampus is crucial for memory formation and the transformation of short-term to long-term memory (reviewed by Squire 1992; Parkin 1996). Given that progranulin is expressed in the hippocampus, it will be interesting to determine whether progranulin gene products contribute to this process. Nerve cells in the intestinal myenteric and submucosal plexi also express progranulin transcripts (Figure 3E), indicating that the progranulin gene is expressed in both the peripheral and the central nervous system. PC-12 cells, which are often used to study neuron development, show enhanced growth in response to progranulin (Figure 6). This is the first demonstration of a direct biological response to progranulin in a neuron-related cell line. PC-12 cells grow poorly or not at all in response to most growth factors, including epidermal growth factor, platelet-derived growth factor, nerve growth factor, and bombesin (Nielsen and Gammeltoft 1988), but they respond mitotically to IGF-I and IGF-II. Interestingly, progranulin and IGFs activate comparable signal transduction pathways in embryonic fibroblasts (Zarocco-Marani et al. 1999), which may underlie the shared ability of progranulin and IGFs to activate mitosis in PC-12 cells. Progranulin is induced by androgens in ventromedial and arcuate nuclei of the newborn female mouse hypothalamus but are expressed constitutively in these regions of the male brain (Suzuki et al. 1998). In addition to the progranulin gene, several other somatic growth factors are expressed in brain neurons, including PDGF-A chain (Yeh et al. 1991), PDGF-B chain (Sasahara et al. 1991), EGF (Fallon et al. 1984), TGFα (Wilcox and Derynck 1988), IGF-I (Bondy et al. 1992), acidic FGF (Kresse et al. 1995), and basic FGF (Matsuyama et al. 1992). The functional significance of somatic growth factor expression in CNS neurons, including that of progranulin, is not well understood. The highly localized neuronal expression of the progranulin gene reported here, and its inducibility in response to hormones (Suzuki et al. 1998), demonstrate stringent neuron-specific gene regulation. This, together with the progranulin's ability to promote the growth of PC-12 cells, implies possible regulatory functions within the nervous system.
In conclusion, progranulin gene expression is closely associated with epithelial cells in somatic tissues. Progranulin gene expression is prominent in rapidly self-renewing epithelia, such as the skin and gut. In the gut, the expression is greatest in the highly proliferative cells of the deep crypts and becomes negligible in the terminally differentiated cells higher in the villus. Chronically nonproliferating highly differentiated epithelia, such as the lung alveolae and kidney tubules, show much lower levels of progranulin expression, although immortalized or neoplastic cell lines from low progranulin-expressing tissues, such as the kidney (MDCK) or the lung (A549), express the gene highly and respond to the recombinant protein. This is consistent with results showing that overexpression of progranulin in some epithelial cell lines leads to a more proliferative phenotype (He and Bateman 1999). The gene is expressed in a cell-specific manner in both developing spermatocytes and in ovarian follicles, indicating that progranulin is likely to play an important role in reproductive physiology in both sexes. Unstimulated connective tissues, muscle, and endothelia show little or no expression of the gene in the healthy adult animal in vivo. The major exceptions are the endometrial mesenchyme and the smooth muscle of the myometrium. The immune system and the brain provide strong evidence for additional functions for progranulin and its products. In both cases, gene expression is regional, implying stringent mechanisms of gene regulation in these systems. The results presented here therefore provide evidence that progranulin gene expression is tightly regulated in vivo and plays a role in the biology at least of highly proliferative somatic epithelia, the male and female gonads, the immune system, and nerve cells in several regions of the brain.

Acknowledgments

Supported in part by MRC of Canada grant MT11288 (AB) and NIH grant CA71023 (JH). AB is a Senior Chercheur Boursier of the Fonds de la Recherche en Santé du Québec. ZH is the recipient of a studentship from the Research Institute of the Royal Victoria Hospital, Montréal.

Literature Cited

Anakwe OO, Gerton GL (1990) Acrosome biosynthesis begins during meiosis: evidence from the synthesis and distribution of the acrosomal glycoprotein, acrogranin, during guinea pig spermatogenesis. Biol Reprod 42: 317–328
Crossref
PubMed
Google Scholar
Baba T, Hoff HB III, Nemoto H, Orth J, Arai Y, Gerton GL (1993) Acrogranin, an acrosomal cysteine-rich glycoprotein, is the precursor of the growth-modulating peptides, granulins and epithelins, and is expressed in somatic as well as male germ cells. Mol Reprod Dev 34: 233–243
Crossref
PubMed
Google Scholar
Baserga R, Hongo A, Rubini M, Prisco M, Valentinis B (1997) The IGF-I receptor in cell growth, transformation and apoptosis. Biochim Biophys Acta 1332: 105–126
Google Scholar
Bateman A, Belcourt D, Bennett HPJ, Lazure C, Solomon S (1990) Granulins, a novel class of peptides from leukocytes. Biochem Biophys Res Commun 173: 1161–1168
Crossref
PubMed
Google Scholar
Bateman A, Bennett HPJ (1998) Granulins: the structure and function of an emerging family of growth factors. J Endocrinol 158: 145–151
Crossref
PubMed
Google Scholar
Bhandari V, Giad A, Bateman A (1993) The cDNA structure, tissue distribution and cellular localization of the rat granulin precursor; a novel growth factor-like protein. Endocrinology 133: 2682–2689
Crossref
PubMed
Google Scholar
Bhandari V, Palfree RGE, Bateman A (1992) Isolation and sequence of the granulin precursor cDNA from human bone marrow reveals tandem cysteine-rich granulin domains. Proc Natl Acad Sci USA 89: 1715–1719
Crossref
PubMed
Google Scholar
Bondy C, Werner H, Roberts CT, LeRoith D (1992) Cellular pattern of type-I insulin-like growth factor receptor gene expression during maturation of the rat brain: comparison with insulin-like growth factors I and II. Neuroscience 46: 909–923
Crossref
PubMed
Google Scholar
Brown C, Halper J (1990) Mitogenic effects of transforming growth factor type e on epithelial and fibroblastic cells—comparison with other growth factors. Exp Cell Res 190: 233–242
Crossref
PubMed
Google Scholar
Chomczynski P, Sacchi N (1987) Single-step method of RNA isolation by guanidium-thioicyanate-phenol-chloroform extraction. Anal Biochem 162: 156–159
Crossref
PubMed
Google Scholar
Coppola D, Ferber A, Miura M, Sell C, D'Ambrosio C, Rubin R, Baserga R (1994) A functional insulin-like growth factor I receptor is required for the mitogenic and transforming activities of the epidermal growth factor receptor. Mol Cell Biol 14: 4588–4595
Crossref
PubMed
Google Scholar
De Angelis T, Ferber A, Baserga R (1995) The insulin-like growth factor I receptor is required for the mitogenic and transforming activities of the platelet-derived growth factor receptor. J Cell Physiol 164: 214–221
Crossref
PubMed
Google Scholar
Diaz–Cueto L, Stein P, Jacobs A, Schultz RM, Gerton GL (2000) Modulation of mouse preimplantation embryo development by acrogranin (epithelin/granulin precursor). Dev Biol 217: 406–418
Crossref
PubMed
Google Scholar
Dunnington DJ, Pritchett W, Moyer M, Greig R (1990a) Identification of a low molecular weight form of epithelial transforming growth factor. Life Sci 47: 2059–2063
Crossref
PubMed
Google Scholar
Dunnington DJ, Scott RJ, Anzano MA, Greig R (1990b) Characterization and partial purification of human epithelial transforming growth factor. J Cell Biochem 44: 229–239
Crossref
PubMed
Google Scholar
Fallon JH, Seroogy KB, Loughlin SE, Morrison RS, Bradshaw RA, Knaver DJ, Cunningham DD (1984) Epidermal growth factor immunoreactive material in the central nervous system: location and development. Science 224: 1107–1109
Crossref
PubMed
Google Scholar
Halper J, Moses HL (1983) Epithelial tissue-derived growth factorlike polypeptides. Cancer Res 43: 1972–1979
PubMed
Google Scholar
Halper J, Moses HL (1987) Purification and characterization of a novel transforming growth factor. Cancer Res 47: 4552–4559
PubMed
Google Scholar
He Z, Bateman A (1999) Progranulin gene expression regulates epithelial cell growth and promotes tumor growth in vivo. Cancer Res 59: 3222–3229
PubMed
Google Scholar
Hrabal R, Chen Z, James S, Bennett HPJ, Ni F (1996) The hairpin stack fold, a novel protein architecture for a new family of protein growth factors. Nature Struct Biol 3: 747–752
Crossref
PubMed
Google Scholar
Kresse A, Pettersson R, Hökfelt T (1995) Distribution of acidic fibroblast growth factor mRNA-expressing neurons in the adult mouse central nervous system. Comp Neurol 359: 323–339
Crossref
PubMed
Google Scholar
Lu R, Serrero G (1999) Stimulation of PC cell-derived growth factor (epithelin/granulin precursor) expression by estradiol in human breast cancer cells. Biochem Biophys Res Comm 256: 204–207
Crossref
PubMed
Google Scholar
Matsuyama A, Iwata H, Okumura N, Yoshida S, Imaizumi K, Lee Y, Siraishi S, Shiosaka S (1992) Localization of basic fibroblast growth factor-like immunoreactivity in the rat brain. Brain Res 587: 49–65
Crossref
PubMed
Google Scholar
Moore HD, Akhondi MA (1996) In vitro maturation of mammalian spermatozoa. Rev Reprod 1: 54–60
Crossref
PubMed
Google Scholar
Nielsen FC, Gammeltoft S (1988) Insulin-like growth factors are mitogens for rat pheochromocytoma PC-12 cells. Biochem Biophys Res Commun 154: 1018–1023
Crossref
PubMed
Google Scholar
Parkin AJ (1996) Human memory: the hippocampus is the key. Cur Biol 6: 1583–1585
Crossref
PubMed
Google Scholar
Parnell PG, Wunderlich J, Carter B, Halper J (1990) Purification of transforming growth factor e. J Cell Biochem 42: 111–116
Crossref
PubMed
Google Scholar
Parnell PG, Wunderlich J, Carter B, Halper J (1992) Transforming growth factor e: amino acid analysis and partial amino acid sequence. Growth Factors 7: 65–72
Crossref
PubMed
Google Scholar
Plowman GD, Green JM, Neubauer MG, Buckley SD, McDonald V, Todaro GJ, Shoyab M (1992) The epithelin precursor encodes two proteins with opposing activities on epithelial cell growth. J Biol Chem 267: 13073–13078
Crossref
PubMed
Google Scholar
Sasahara M, Fries JWU, Raines EW, Gown AM, Westrum LE, Frosch MP, Bonthron DT, Ross R, Collins T (1991) PDGF B-chain in neurons of the central nervous system, posterior pituitary, and in a transgenic model. Cell 64: 217–227
Crossref
PubMed
Google Scholar
Sell C, Dumenil G, Devaud C, Miura M, Coppola D, De Angelis T, Rubin R, Efstratiadis A, Baserga R (1994) Effect of a null mutation of the insulin-like growth factor I receptor gene on growth and transformation of mouse embryo fibroblasts. Mol Cell Biol 14: 3604–3612
Crossref
PubMed
Google Scholar
Serrero G, Zhou J, Mills D, Lepak N (1991) Decreased transforming growth factor-beta response and binding in insulin-independent teratoma-derived cell lines with increased tumorigenic properties. J Cell Physiol 149: 503–511
Crossref
PubMed
Google Scholar
Shoyab M, McDonald VL, Byles C, Todaro GJ, Plowman GD (1990) Epithelins 1 and 2: isolation and characterization of two cysteine-rich growth-modulating peptides. Proc Natl Acad Sci USA 87: 7912–7916
Crossref
PubMed
Google Scholar
Squire LR (1992) Memory and the hippocampus: a synthesis from findings with rats, monkeys, and humans. Psychol Rev 99: 195–231
Crossref
PubMed
Google Scholar
Suzuki M, Yoshida S, Nishihara M, Takahashi M (1998) Identification of a sex steriod-inducible gene in the neonatal rat hypothalamus. Neurosci Lett 242: 127–130
Crossref
PubMed
Google Scholar
Wilcox JN, Derynck R (1988) Localization of cells synthesizing transforming growth factor alpha mRNA in the mouse brain. J Neurosci 8: 1901–1904
PubMed
Google Scholar
Xu SQ, Tang D, Chamberlain S, Pronk G, Masiarz FR, Kaur S, Prisco M, Zanocco–Marani T, Baserga R (1998) The granulin/epithelin precursor abrogates the requirement for the insulin-like growth factor 1 receptor for growth in vitro. J Biol Chem 273: 20078–20083
Crossref
PubMed
Google Scholar
Yeh HJ, Ruit KG, Wang YX, Parks WC, Snider WD (1991) PDGF A-chain gene is expressed by mammalian neurons during development and in maturity. Cell 64: 209–216
Crossref
PubMed
Google Scholar
Zanocco–Marani T, Bateman A, Romano G, Valentinis B, He ZH, Baserga R (1999) Biological activities and signaling pathways of the granulin/epithelin precursor. Cancer Res 59: 5331–5340
PubMed
Google Scholar
Zhang H, Serrero G (1998) Inhibition of the tumorigenicity of the teratoma PC cell line by transfection with antisense cDNA for PC cell-derived growth actor (PCDGF, epithelin/granulin precursor). Proc Natl Acad Sci USA 93: 14202–14207
Crossref
Google Scholar
Zhou J, Gao G, Crabb JW, Serrero G (1993) Purification of an autocrine growth factor homologous with mouse epithelin precursor from a highly tumorigenic cell line. J Biol Chem 268: 10863–10869
Crossref
PubMed
Google Scholar

Cite article

Cite article

Cite article

OR

Download to reference manager

If you have citation software installed, you can download article citation data to the citation manager of your choice

Share options

Share

Share this article

Share with email
EMAIL ARTICLE LINK
Share on social media

Share access to this article

Sharing links are not relevant where the article is open access and not available if you do not have a subscription.

For more information view the Sage Journals article sharing page.

Information, rights and permissions

Information

Published In

Volume 48, Issue 7
Pages: 999 - 1009
Article first published: July 2000
Issue published: July 2000

Keywords

  1. progranulin
  2. epithelin
  3. acrogranin
  4. PCDGF
  5. TGFe
  6. growth factor

Rights and permissions

© 2000 Authors.
Request permissions for this article.
PubMed: 10858277

Authors

Affiliations

Rachael Daniel
Endocrine Laboratory, Royal Victoria Hospital and Division of Experimental Medicine, McGill University, Montréal, Québec, Canada, (RD, ZH, AB) Department of Pathology, College of Veterinary Medicine, University of Georgia, Athens, Georgia (KPC, JH)
View all articles by this author
Zhiheng He
Endocrine Laboratory, Royal Victoria Hospital and Division of Experimental Medicine, McGill University, Montréal, Québec, Canada, (RD, ZH, AB) Department of Pathology, College of Veterinary Medicine, University of Georgia, Athens, Georgia (KPC, JH)
View all articles by this author
K. Paige Carmichael
Endocrine Laboratory, Royal Victoria Hospital and Division of Experimental Medicine, McGill University, Montréal, Québec, Canada, (RD, ZH, AB) Department of Pathology, College of Veterinary Medicine, University of Georgia, Athens, Georgia (KPC, JH)
View all articles by this author
Jaroslava Halper
Endocrine Laboratory, Royal Victoria Hospital and Division of Experimental Medicine, McGill University, Montréal, Québec, Canada, (RD, ZH, AB) Department of Pathology, College of Veterinary Medicine, University of Georgia, Athens, Georgia (KPC, JH)
View all articles by this author
Andrew Bateman
Endocrine Laboratory, Royal Victoria Hospital and Division of Experimental Medicine, McGill University, Montréal, Québec, Canada, (RD, ZH, AB) Department of Pathology, College of Veterinary Medicine, University of Georgia, Athens, Georgia (KPC, JH)
[email protected]
View all articles by this author

Notes

Correspondence to: Andrew Bateman, Room L.2.05, Endocrine Laboratory, Royal Victoria Hospital, 687 Pine Ave West, Montréal, Québec H3A 1A1, Canada. E-mail: [email protected]
1
These authors contributed equally to this work.

Metrics and citations

Metrics

Journals metrics

This article was published in Journal of Histochemistry & Cytochemistry.

VIEW ALL JOURNAL METRICS

Article usage*

Total views and downloads: 2453

*Article usage tracking started in December 2016

Articles citing this one

Receive email alerts when this article is cited

Web of Science: 289 view articles Opens in new tab

Crossref: 268

  1. The adipokines progranulin and omentin – novel regulators of basic ova...
    Go to citation Crossref Google Scholar
  2. Progranulin promotes regulatory T cells plasticity by mitochondrial me...
    Go to citation Crossref Google Scholar
  3. Granulin in renal tubular epithelia is associated with interstitial in...
    Go to citation Crossref Google ScholarPub Med
  4. Animal granulins: In the GRN scheme of things
    Go to citation Crossref Google Scholar
  5. Genetic Factors Associated with the Development of Neuropathy in Type ...
    Go to citation Crossref Google Scholar
  6. Structure and function analyses of the SRC gene in Pacific white shrim...
    Go to citation Crossref Google Scholar
  7. The uterine secretory cycle: recurring physiology of endometrial outpu...
    Go to citation Crossref Google Scholar
  8. The Role of Progranulin (PGRN) in the Pathogenesis of Glioblastoma Mul...
    Go to citation Crossref Google Scholar
  9. Elevated serum level of progranulin is associated with increased morta...
    Go to citation Crossref Google Scholar
  10. The brain reacting to COVID-19: analysis of the cerebrospinal fluid pr...
    Go to citation Crossref Google Scholar
  11. Progranulin and GPNMB: interactions in endo-lysosome function and infl...
    Go to citation Crossref Google Scholar
  12. Targeting Progranulin as an Immuno-Neurology Therapeutic Approach
    Go to citation Crossref Google Scholar
  13. The involvement of Purkinje cells in progressive myoclonic epilepsy: F...
    Go to citation Crossref Google Scholar
  14. Matrine From Sophora Flavescens Attenuates on Collagen-Induced Osteoar...
    Go to citation Crossref Google Scholar
  15. Research advances in endometriosis-related signaling pathways: A revie...
    Go to citation Crossref Google Scholar
  16. Serum Progranulin Levels and Disease Activity in Patients with Axial ...
    Go to citation Crossref Google Scholar
  17. Identification of potential ferroptosis-associated biomarkers in rheum...
    Go to citation Crossref Google Scholar
  18. Progranulin Protects against Hyperglycemia-Induced Neuronal Dysfunctio...
    Go to citation Crossref Google Scholar
  19. Implications of MMP-12 in the pathophysiology of ischaemic stroke
    Go to citation Crossref Google Scholar
  20. Serum Progranulin Level Might Differentiate Non-IPF ILD from IPF
    Go to citation Crossref Google Scholar
  21. Neurodevelopmental effects of genetic frontotemporal dementia in young...
    Go to citation Crossref Google Scholar
  22. Role of Coxsackievirus B3-Induced Immune Responses in the Transition f...
    Go to citation Crossref Google Scholar
  23. Rare GRN mutation in a patient diagnosed with primary progressive aph...
    Go to citation Crossref Google Scholar
  24. Progranulin promotes proliferation, migration and invasion via the PI3...
    Go to citation Crossref Google Scholar
  25. Crucial Regulatory Role of Organokines in Relation to Metabolic Change...
    Go to citation Crossref Google Scholar
  26. Progranulin is an FMRP target that influences macroorchidism but not b...
    Go to citation Crossref Google Scholar
  27. Progranulin improves neural development via the PI3K/Akt/GSK-3β pathwa...
    Go to citation Crossref Google Scholar
  28. Granulin as an important immune molecule involved in lamprey tissue re...
    Go to citation Crossref Google Scholar
  29. Progranulin from different gliocytes in the nucleus accumbens exerts d...
    Go to citation Crossref Google Scholar
  30. Progranulin in Musculoskeletal Inflammatory and Degenerative Disorders...
    Go to citation Crossref Google Scholar
  31. Progranulin is essential for bone homeostasis and immunology
    Go to citation Crossref Google Scholar
  32. Therapeutic efficacy of matrix metalloproteinase-12 suppression on neu...
    Go to citation Crossref Google Scholar
  33. Progranulin regulates the development and function of NKT2 cells throu...
    Go to citation Crossref Google Scholar
  34. Progranulin and Its Receptor Predict Kidney Function Decline in Patien...
    Go to citation Crossref Google Scholar
  35. Determination of Serum Progranulin in Patients with Untreated Familial...
    Go to citation Crossref Google Scholar
  36. Defects of Nutrient Signaling and Autophagy in Neurodegeneration
    Go to citation Crossref Google Scholar
  37. Involvement of progranulin (PGRN) in the pathogenesis and prognosis of...
    Go to citation Crossref Google Scholar
  38. The Role of VCP Mutations in the Spectrum of Amyotrophic Lateral Scler...
    Go to citation Crossref Google Scholar
  39. Effect of Progranulin on Proliferation and Differentiation of Neural S...
    Go to citation Crossref Google Scholar
  40. Potential Value of Cerebrospinal Fluid Progranulin in the Identificati...
    Go to citation Crossref Google Scholar
  41. Downregulation of LncRNA OIP5-AS1 Induced by IL-1β Aggravates Osteoart...
    Go to citation Crossref Google ScholarPub Med
  42. AZP2006, a new promising treatment for Alzheimer’s and related disease...
    Go to citation Crossref Google Scholar
  43. Abnormal spatiotemporal expression pattern of progranulin and neurodev...
    Go to citation Crossref Google Scholar
  44. Tweaking Progranulin Expression: Therapeutic Avenues and Opportunities
    Go to citation Crossref Google Scholar
  45. Progranulin in neurodegenerative dementia
    Go to citation Crossref Google Scholar
  46. Lysosome dysfunction as a cause of neurodegenerative diseases: Lessons...
    Go to citation Crossref Google Scholar
  47. Effects of alpha-lipoic acid treatment on serum progranulin levels and...
    Go to citation Crossref Google ScholarPub Med
  48. A GRN Autocrine-Dependent FAM135B/AKT/mTOR Feedforward Loop Promotes E...
    Go to citation Crossref Google Scholar
  49. A zebrafish model of granulin deficiency reveals essential roles in my...
    Go to citation Crossref Google Scholar
  50. Lysosomal Dysfunction and Other Pathomechanisms in FTLD: Evidence from...
    Go to citation Crossref Google Scholar
  51. Experimental Disease-Modifying Agents for Frontotemporal Lobar Degener...
    Go to citation Crossref Google Scholar
  52. Progranulin Protects Against Airway Remodeling Through the Modulation ...
    Go to citation Crossref Google Scholar
  53. Progranulin as a Potential Therapeutic Target in Immune-Mediated Disea...
    Go to citation Crossref Google Scholar
  54. Unravelling Genetic Factors Underlying Corticobasal Syndrome: A System...
    Go to citation Crossref Google Scholar
  55. Effects of progranulin on the pathological conditions in experimental ...
    Go to citation Crossref Google Scholar
  56. Secreted Chaperones in Neurodegeneration
    Go to citation Crossref Google Scholar
  57. Osteocytes control myeloid cell proliferation and differentiation thro...
    Go to citation Crossref Google Scholar
  58. Progranulin Regulates Inflammation and Tumor
    Go to citation Crossref Google Scholar
  59. Progranulin promotes osteogenic differentiation of human periodontal l...
    Go to citation Crossref Google Scholar
  60. Prognostic significance of serum progranulin level in de novo adult ac...
    Go to citation Crossref Google Scholar
  61. Elevated progranulin as a novel biomarker to predict poor prognosis in...
    Go to citation Crossref Google Scholar
  62. RETRACTED: Progranulin suppresses the age-dependent enhancement of neu...
    Go to citation Crossref Google Scholar
  63. Adenoviral mediated expression of anti-inflammatory progranulin by pla...
    Go to citation Crossref Google Scholar
  64. Progranulin Mediates Proinflammatory Responses in Systemic Lupus Eryth...
    Go to citation Crossref Google Scholar
  65. Suppression of Progranulin Expression Leads to Formation of Intranucle...
    Go to citation Crossref Google Scholar
  66. Characterization of lysosomal proteins Progranulin and Prosaposin and ...
    Go to citation Crossref Google Scholar
  67. Progranulin and beta‐catenin in psoriasis: An immunohistochemical stud...
    Go to citation Crossref Google Scholar
  68. Involvement of Progranulin and Granulin Expression in Inflammatory Res...
    Go to citation Crossref Google Scholar
  69. Progranulin deficiency leads to reduced glucocerebrosidase activity
    Go to citation Crossref Google Scholar
  70. Dissecting the Prognostic Significance and Functional Role of Progranu...
    Go to citation Crossref Google Scholar
  71. Increased serum levels of progranulin (PGRN) in patients with haemophi...
    Go to citation Crossref Google Scholar
  72. Microglial Progranulin: Involvement in Alzheimer’s Disease and Neurode...
    Go to citation Crossref Google Scholar
  73. Pleiotropic Protective Effects of Progranulin in the Treatment of Isch...
    Go to citation Crossref Google Scholar
  74. Progranulin in Sexual Differentiation of the Developing Brain
    Go to citation Crossref Google Scholar
  75. Granulin 1 Promotes Retinal Regeneration in Zebrafish
    Go to citation Crossref Google Scholar
  76. Innate Anti-microbial and Anti-chemotaxis Properties of Progranulin in...
    Go to citation Crossref Google Scholar
  77. CSF progranulin increases in the course of Alzheimer's d...
    Go to citation Crossref Google Scholar
  78. Biomarkers of Neurodegeneration in Autoimmune-Mediated Encephalitis
    Go to citation Crossref Google Scholar
  79. The lysosomal function of progranulin, a guardian against neurodegener...
    Go to citation Crossref Google Scholar
  80. Meta-analytic Review of Memory Impairment in Behavioral Variant Fronto...
    Go to citation Crossref Google Scholar
  81. Progranulin ameliorates coxsackievirus-B3-induced viral myocarditis by...
    Go to citation Crossref Google Scholar
  82. Role of clusterin/progranulin in toluene diisocyanate-induced occupati...
    Go to citation Crossref Google Scholar
  83. A potent tilapia secreted granulin peptide enhances the survival of tr...
    Go to citation Crossref Google Scholar
  84. Progranulin facilitates the increase of platelet count in immune throm...
    Go to citation Crossref Google Scholar
  85. Peripheral nerve atrophy together with higher cerebrospinal fluid prog...
    Go to citation Crossref Google Scholar
  86. Progranulin
    Go to citation Crossref Google Scholar
  87. Serum C-Peptide, Visfatin, Resistin, and Ghrelin are Altered in Sporad...
    Go to citation Crossref Google Scholar
  88. B Cell-Attracting Chemokine-1 and Progranulin in Bronchoalveolar Lavag...
    Go to citation Crossref Google Scholar
  89. A Brief Overview of Progranulin in Health and Disease
    Go to citation Crossref Google Scholar
  90. The Use of Caenorhabditis elegans to Study Progranulin in the Regulati...
    Go to citation Crossref Google Scholar
  91. Methods to Investigate the Roles of Progranulin in Angiogenesis Using ...
    Go to citation Crossref Google Scholar
  92. Intranasal administration of recombinant progranulin inhibits bronchia...
    Go to citation Crossref Google Scholar
  93. Progranulin and its biological effects in cancer
    Go to citation Crossref Google Scholar
  94. Progranulin deficiency causes the retinal ganglion cell loss during de...
    Go to citation Crossref Google Scholar
  95. Progranulin: a new avenue towards the understanding and treatment of n...
    Go to citation Crossref Google Scholar
  96. Loss of Neuroprotective Factors in Neurodegenerative Dementias: The En...
    Go to citation Crossref Google Scholar
  97. Disease and Region Specificity of Granulin Immunopositivities in Alzhe...
    Go to citation Crossref Google Scholar
  98. Progranulin as a biomarker and potential therapeutic agent
    Go to citation Crossref Google Scholar
  99. Progranulin protects lung epithelial cells from cigarette smoking‐indu...
    Go to citation Crossref Google Scholar
  100. Potential skin involvement in ALS: revisiting Charcot’s observation – ...
    Go to citation Crossref Google Scholar
  101. Progranulin Protects Hippocampal Neurogenesis via Suppression of Neuro...
    Go to citation Crossref Google Scholar
  102. Progranulin, lysosomal regulation and neurodegenerative disease
    Go to citation Crossref Google Scholar
  103. Restoring neuronal progranulin reverses deficits in a mouse model of f...
    Go to citation Crossref Google Scholar
  104. Foxo4‐ and Stat3‐dependent IL‐10 production by progranulin in regulato...
    Go to citation Crossref Google Scholar
  105. Progranulin and Its Related MicroRNAs after Status Epilepticus: Possib...
    Go to citation Crossref Google Scholar
  106. The Receptor-interacting Serine/Threonine Protein Kinase 1 (RIPK1) Reg...
    Go to citation Crossref Google Scholar
  107. Progranulin regulates neurogenesis in the developing vertebrate retina
    Go to citation Crossref Google Scholar
  108. Serum Progranulin Levels in Type 2 Diabetic Patients with Metabolic Sy...
    Go to citation Crossref Google Scholar
  109. Progranulin Controls Sepsis via C/EBPα-Regulated Il10 ...
    Go to citation Crossref Google Scholar
  110. Prosaposin is a regulator of progranulin levels and oligomerization
    Go to citation Crossref Google Scholar
  111. PGRN Suppresses Inflammation and Promotes Autophagy in Keratinocytes T...
    Go to citation Crossref Google Scholar
  112. Fully reduced granulin-B is intrinsically disordered and displays conc...
    Go to citation Crossref Google Scholar
  113. Progranulin Stimulates Proliferation of Mouse Pancreatic Islet Cells a...
    Go to citation Crossref Google Scholar
  114. Molecular Pathways Bridging Frontotemporal Lobar Degeneration and Psyc...
    Go to citation Crossref Google Scholar
  115. Lack of estrogen receptor α in astrocytes of progranulin-deficient mic...
    Go to citation Crossref Google Scholar
  116. Moxibustion upregulates hippocampal progranulin expression
    Go to citation Crossref Google Scholar
  117. Progranulin Deficiency Reduces CDK4/6/pRb Activation and Survival of H...
    Go to citation Crossref Google Scholar
  118. The role of progranulin in diabetes and kidney disease
    Go to citation Crossref Google Scholar
  119. Cell biology of the NCL proteins: What they do and don't do
    Go to citation Crossref Google Scholar
  120. The Evolution of the Secreted Regulatory Protein Progranulin
    Go to citation Crossref Google Scholar
  121. Multiple therapeutic effects of progranulin on experimental acute isch...
    Go to citation Crossref Google Scholar
  122. Evaluation of maternal serum progranulin levels in normotensive pregna...
    Go to citation Crossref Google Scholar
  123. Progranulin is preferentially expressed in patients with psoriasis vul...
    Go to citation Crossref Google Scholar
  124. A network of RNA and protein interactions in Fronto Temporal Dementia
    Go to citation Crossref Google Scholar
  125. Granulin Knock Out Zebrafish Lack Frontotemporal Lobar Degeneration an...
    Go to citation Crossref Google Scholar
  126. Genetics of Frontotemporal Dementia
    Go to citation Crossref Google Scholar
  127. Progranulin Is Associated with Disease Activity in Patients with Rheum...
    Go to citation Crossref Google Scholar
  128. Serum progranulin levels are elevated in dermatomyositis patients with...
    Go to citation Crossref Google Scholar
  129. Progressive retinal degeneration and accumulation of autofluorescent l...
    Go to citation Crossref Google Scholar
  130. Upregulated expression level of the growth factor, progranulin, is ass...
    Go to citation Crossref Google Scholar
  131. Increased Serum GP88 (Progranulin) Concentrations in Rheumatoid Arthri...
    Go to citation Crossref Google Scholar
  132. Progranulin protects against amyloid β deposition and toxicity in Alzh...
    Go to citation Crossref Google Scholar
  133. Dual cell protective mechanisms activated by differing levels of oxida...
    Go to citation Crossref Google Scholar
  134. Proinflammatory Progranulin Antibodies in Inflammatory Bowel Diseases
    Go to citation Crossref Google Scholar
  135. Progranulin is required for proper ER stress response and inhibits ER ...
    Go to citation Crossref Google Scholar
  136. XBP 1S, a BMP 2‐inducible tr...
    Go to citation Crossref Google Scholar
  137. Evidence of the Innate Antiviral and Neuroprotective Properties of Pro...
    Go to citation Crossref Google Scholar
  138. Progranulin protein levels are differently regulated in plasma and CSF
    Go to citation Crossref Google Scholar
  139. Effects of hypoxia on progranulin expression in HT22 mouse hippocampal...
    Go to citation Crossref Google Scholar
  140. Potential Roles of Microglial Cell Progranulin in HIV-Associated CNS P...
    Go to citation Crossref Google Scholar
  141. A Solid-Phase Assay for Studying Direct Binding of Progranulin to TNFR...
    Go to citation Crossref Google Scholar
  142. Progranulin is a substrate for neutrophil-elastase and proteinase-3 in...
    Go to citation Crossref Google Scholar
  143. Progranulin Peripheral Levels as a Screening Tool for the Identificati...
    Go to citation Crossref Google Scholar
  144. The anti-adipogenic effect of PGRN on porcine preadipocytes involves E...
    Go to citation Crossref Google Scholar
  145. The growth factor progranulin attenuates neuronal injury induced by ce...
    Go to citation Crossref Google Scholar
  146. Expression level of the growth factor progranulin is related with deve...
    Go to citation Crossref Google Scholar
  147. Cell biology and function of neuronal ceroid lipofuscinosis-related pr...
    Go to citation Crossref Google Scholar
  148. Progranulin expression in neural stem cells and their differentiated c...
    Go to citation Crossref Google Scholar
  149. Increased lysosomal biogenesis in activated microglia and exacerbated ...
    Go to citation Crossref Google Scholar
  150. Genetic factors in frontotemporal dementia: A review
    Go to citation Crossref Google Scholar
  151. Progranulin Is a Novel Independent Predictor of Disease Progression an...
    Go to citation Crossref Google Scholar
  152. Granulin Exacerbates Lupus Nephritis via Enhancing Macrophage M2b Pola...
    Go to citation Crossref Google Scholar
  153. Expression of the Growth Factor Progranulin in Endothelial Cells Influ...
    Go to citation Crossref Google Scholar
  154. Molecular Genetics of Frontotemporal Dementia
    Go to citation Crossref Google Scholar
  155. Seminal plasma adipokine levels are correlated with functional charact...
    Go to citation Crossref Google Scholar
  156. Mechanisms of Granulin Deficiency: Lessons from Cellular and Animal Mo...
    Go to citation Crossref Google Scholar
  157. Exacerbated inflammatory responses related to activated microglia afte...
    Go to citation Crossref Google Scholar
  158. Insights into the role of progranulin in immunity, infection, and infl...
    Go to citation Crossref Google Scholar
  159. Identification of multiple genes and their expression profiles in four...
    Go to citation Crossref Google Scholar
  160. Progranulin deficiency promotes neuroinflammation and neuron loss foll...
    Go to citation Crossref Google Scholar
  161. Progranulin compensates for blocked IGF‐1 signaling to promote myotube...
    Go to citation Crossref Google Scholar
  162. Progranulin: A Proteolytically Processed Protein at the Crossroads of ...
    Go to citation Crossref Google Scholar
  163. Cellular ageing, increased mortality and FTLD‐TDP‐associated neuropath...
    Go to citation Crossref Google Scholar
  164. CSF markers in amyotrophic lateral sclerosis
    Go to citation Crossref Google Scholar
  165. Neonatal Phytoestrogen Exposure Alters Oviduct Mucosal Immune Response...
    Go to citation Crossref Google Scholar
  166. GEP constitutes a negative feedback loop with MyoD and acts as a novel...
    Go to citation Crossref Google Scholar
  167. Inactivation of CDK/pRb Pathway Normalizes Survival Pattern of Lymphob...
    Go to citation Crossref Google Scholar
  168. Novel Urinary Protein Biomarkers Predicting the Development of Microal...
    Go to citation Crossref Google Scholar
  169. Progranulin: A growth factor, a novel TNFR ligand and a drug target
    Go to citation Crossref Google Scholar
  170. Prevention of LPS-Induced Acute Lung Injury in Mice by Progranulin
    Go to citation Crossref Google Scholar
  171. Progranulin axis and recent developments in frontotemporal lobar degen...
    Go to citation Crossref Google Scholar
  172. Serum progranulin levels are elevated in patients with systemic lupus ...
    Go to citation Crossref Google Scholar
  173. Extracellular progranulin protects cortical neurons from toxic insults...
    Go to citation Crossref Google Scholar
  174. Involvement of Progranulin in Hypothalamic Glucose Sensing and Feeding...
    Go to citation Crossref Google Scholar
  175. Progranulin: A promising therapeutic target for rheumatoid arthritis
    Go to citation Crossref Google Scholar
  176. Cellular Effects of Progranulin in Health and Disease
    Go to citation Crossref Google Scholar
  177. Human Genetics as a Tool to Identify Progranulin Regulators
    Go to citation Crossref Google Scholar
  178. Structure, Function, and Mechanism of Progranulin; the Brain and Beyon...
    Go to citation Crossref Google Scholar
  179. Progranulin and TDP-43: Mechanistic Links and Future Directions
    Go to citation Crossref Google Scholar
  180. Frontotemporal Dementia: From Mendelian Genetics Towards Genome Wide A...
    Go to citation Crossref Google Scholar
  181. Heterosexual Pedophilia in a Frontotemporal Dementia Patient with a Mu...
    Go to citation Crossref Google Scholar
  182. Upregulation of progranulin by Helicobacter pylori ...
    Go to citation Crossref Google Scholar
  183. Functional Genomic Analyses Identify Pathways Dysregulated by Progranu...
    Go to citation Crossref Google Scholar
  184. Progranulin Deficiency Decreases Gross Neural Connectivity But Enhance...
    Go to citation Crossref Google Scholar
  185. Progranulin enhances neural progenitor cell proliferation through glyc...
    Go to citation Crossref Google Scholar
  186. Domain-Specific Monoclonal Antibodies Produced Against Human PGRN
    Go to citation Crossref Google Scholar
  187. The Growth Factor Progranulin Binds to TNF Receptors and Is Therapeuti...
    Go to citation Crossref Google Scholar
  188. A neurodegenerative disease mutation that accelerates the clearance of...
    Go to citation Crossref Google Scholar
  189. MALDI Imaging of Formalin-Fixed Paraffin-Embedded Tissues: Application...
    Go to citation Crossref Google Scholar
  190. rs5848 polymorphism and serum progranulin level
    Go to citation Crossref Google Scholar
  191. Low plasma progranulin levels in children with autism
    Go to citation Crossref Google Scholar
  192. Expression Pattern of Progranulin in the Human Placenta and Its Effect...
    Go to citation Crossref Google Scholar
  193. Age-Dependent Changes in Progranulin Expression in the Mouse Brain
    Go to citation Crossref Google Scholar
  194. Progranulin Is a Chemoattractant for Microglia and Stimulates Their En...
    Go to citation Crossref Google Scholar
  195. Progranulin deficiency leads to enhanced cell vulnerability and TDP-43...
    Go to citation Crossref Google Scholar
  196. Microglial Upregulation of Progranulin as a Marker of Motor Neuron Deg...
    Go to citation Crossref Google Scholar
  197. Progranulin modulates zebrafish motoneuron development in vivoand resc...
    Go to citation Crossref Google Scholar
  198. Progranulin expression in the developing and adult murine brain
    Go to citation Crossref Google Scholar
  199. Accelerated Lipofuscinosis and Ubiquitination in Granulin Knockout Mic...
    Go to citation Crossref Google Scholar
  200. Progranulin promotes neurite outgrowth and neuronal differentiation by...
    Go to citation Crossref Google Scholar
  201. Granulin epithelin precursor: a bone morphogenic protein 2‐inducible g...
    Go to citation Crossref Google Scholar
  202. Molecular Pathways of Frontotemporal Lobar Degeneration
    Go to citation Crossref Google Scholar
  203. Expression of Progranulin (Acrogranin/PCDGF/Granulin-Epithelin Precurs...
    Go to citation Crossref Google Scholar
  204. Progranulin (granulin/epithelin precursor) and its constituent granuli...
    Go to citation Crossref Google Scholar
  205. Role of progranulin as a biomarker for Alzheimer’s disease
    Go to citation Crossref Google Scholar
  206. Exaggerated inflammation, impaired host defense, and neuropathology in...
    Go to citation Crossref Google Scholar
  207. Growth Factors as Active Participants in Carcinogenesis: A Perspective
    Go to citation Crossref Google ScholarPub Med
  208. Brain progranulin expression in GRN-associated frontotemporal lobar de...
    Go to citation Crossref Google Scholar
  209. Progranulin expression is upregulated after spinal contusion in mice
    Go to citation Crossref Google Scholar
  210. Progranulin is expressed within motor neurons and promotes neuronal ce...
    Go to citation Crossref Google Scholar
  211. Modulation of extracellular matrix by nutritional hepatotrophic factor...
    Go to citation Crossref Google Scholar
  212. The granulin gene family: from cancer to dementia
    Go to citation Crossref Google Scholar
  213. ADAMTS-7, a Direct Target of PTHrP, Adversely Regulates Endochondral B...
    Go to citation Crossref Google Scholar
  214. Development of macrophages of cyprinid fish
    Go to citation Crossref Google Scholar
  215. Progranulin, a secreted tumorigenesis and dementia-related factor, reg...
    Go to citation Crossref Google Scholar
  216. Progranulin (PGRN) expression in ALS: An immunohistochemical study
    Go to citation Crossref Google Scholar
  217. Alteration in Anxiety with Relation to the Volume of the Locus Ceruleu...
    Go to citation Crossref Google Scholar
  218. Roles of Progranulin in Sexual Differentiation of the Developing Brain...
    Go to citation Crossref Google Scholar
  219. Granulin mutations associated with frontotemporal lobar degeneration a...
    Go to citation Crossref Google Scholar
  220. Challenges and new opportunities in the investigation of new drug ther...
    Go to citation Crossref Google Scholar
  221. Mutations in progranulin (GRN) within the spectrum of clinical and pat...
    Go to citation Crossref Google Scholar
  222. Novel exon 1 progranulin gene variant in Alzheimer’s disease
    Go to citation Crossref Google Scholar
  223. Spatiotemporal expression pattern of progranulin in embryo implantatio...
    Go to citation Crossref Google Scholar
  224. Progranulin genetic variability contributes to amyotroph...
    Go to citation Crossref Google Scholar
  225. Update on Recent Molecular and Genetic Advances in Frontotemporal Loba...
    Go to citation Crossref Google Scholar
  226. Progranulin functions as a neurotrophic factor to regulate neurite out...
    Go to citation Crossref Google Scholar
  227. Molecular characterization of novel progranulin ( GRN ...
    Go to citation Crossref Google Scholar
  228. Loss of progranulin function in frontotemporal lobar degeneration
    Go to citation Crossref Google Scholar
  229. Structure dissection of human progranulin identifies well‐folded granu...
    Go to citation Crossref Google Scholar
  230. Phenotype variability in progranulin mutation carriers: a clinical, ne...
    Go to citation Crossref Google Scholar
  231. Missense Mutations in the Progranulin Gene Linked to Frontotemporal Lo...
    Go to citation Crossref Google Scholar
  232. Progranulin: normal function and role in neurodegeneration
    Go to citation Crossref Google Scholar
  233. Alteration of behavioural phenotype in mice by targeted disruption of ...
    Go to citation Crossref Google Scholar
  234. The genetics of frontotemporal lobar degeneration
    Go to citation Crossref Google Scholar
  235. Inhibition of PC cell-derived growth factor (PCDGF)/granulin-epithelin...
    Go to citation Crossref Google Scholar
  236. Progranulin in frontotemporal lobar degeneration and neuroinflammation
    Go to citation Crossref Google Scholar
  237. The molecular genetics and neuropathology of frontotemporal lobar dege...
    Go to citation Crossref Google Scholar
  238. Progranulin Mediates Caspase-Dependent Cleavage of TAR DNA Binding Pro...
    Go to citation Crossref Google Scholar
  239. Progranulin null mutations in both sporadic and familial frontotempora...
    Go to citation Crossref Google Scholar
  240. The genetics of frontotemporal lobar degeneration
    Go to citation Crossref Google Scholar
  241. The neuropathology and clinical phenotype of FTD with progranulin muta...
    Go to citation Crossref Google Scholar
  242. Progranulin and frontotemporal lobar degeneration
    Go to citation Crossref Google Scholar
  243. Cartilage Oligomeric Matrix Protein Associates with Granulin-Epithelin...
    Go to citation Crossref Google Scholar
  244. Progranulin is a stress-response factor in fibroblasts subjected to hy...
    Go to citation Crossref Google Scholar
  245. PC cell-derived growth factor overexpression promotes proliferation an...
    Go to citation Crossref Google Scholar
  246. Involvement of Granulin in Estrogen-Induced Neurogenesis in the Adult ...
    Go to citation Crossref Google Scholar
  247. Frontotemporal Lobar Degeneration: Current Concepts in the Light of Re...
    Go to citation Crossref Google Scholar
  248. Regulation of progranulin expression in myeloid cells
    Go to citation Crossref Google Scholar
  249. Gene expression in cortex and hippocampus during acute pneumococcal me...
    Go to citation Crossref Google Scholar
  250. HDDD2 is a familial frontotemporal lobar degeneration with ubiquitin‐p...
    Go to citation Crossref Google Scholar
  251. Mutations in progranulin cause tau-negative frontotemporal dementia li...
    Go to citation Crossref Google Scholar
  252. Null mutations in progranulin cause ubiquitin-positive frontotemporal ...
    Go to citation Crossref Google Scholar
  253. Comprehensive analysis of monoclonal antibodies against detergent-inso...
    Go to citation Crossref Google Scholar
  254. A Novel Hematopoietic Granulin Induces Proliferation of Goldfish (Cara...
    Go to citation Crossref Google Scholar
  255. Oncogenic Property of Acrogranin in Human Uterine Leiomyosarcoma: Dire...
    Go to citation Crossref Google Scholar
  256. The zebrafish progranulin gene family and antisense transcripts
    Go to citation Crossref Google Scholar
  257. Granulin and Granulin Repeats Interact with the Tat·P-TEFb Complex and...
    Go to citation Crossref Google Scholar
  258. Granulin‐epithelin precursor is a novel prognostic marker in epithelia...
    Go to citation Crossref Google Scholar
  259. Mesothelial Differentiation as Reflected by Differential Gene Expressi...
    Go to citation Crossref Google Scholar
  260. PC Cell-Derived Growth Factor Expression in Prostatic Intraepithelial ...
    Go to citation Crossref Google Scholar
  261. A Novel Interaction between Perlecan Protein Core and Progranulin
    Go to citation Crossref Google Scholar
  262. Autocrine growth factor revisited: PC-cell-derived growth factor (prog...
    Go to citation Crossref Google Scholar
  263. Progranulin (acrogranin/PC cell‐derived growth factor/granulin‐epithel...
    Go to citation Crossref Google Scholar
  264. The Growth Factor Granulin Interacts with Cyclin T1 and Modulates P-TE...
    Go to citation Crossref Google Scholar
  265. Progranulin is a mediator of the wound response
    Go to citation Crossref Google Scholar
  266. Conversion of Proepithelin to Epithelins
    Go to citation Crossref Google Scholar
  267. High‐density microarray analysis of hippocampal gene expression follow...
    Go to citation Crossref Google Scholar
  268. Granulin Precursor Gene: A Sex Steroid-Inducible Gene Involved in Sexu...
    Go to citation Crossref Google Scholar

Figures and tables

Figures & Media

Tables

View Options

View options

PDF/ePub

View PDF/ePub

Get access

Access options

If you have access to journal content via a personal subscription, university, library, employer or society, select from the options below:

JHC members can access this journal content using society membership credentials.

MEMBERSHIP LOGIN

JHC members can access this journal content using society membership credentials.

MEMBERSHIP LOGIN

Alternatively, view purchase options below:

Purchase 24 hour online access to view and download content.

Subscribe to this journal

Access journal content via a DeepDyve subscription or find out more about this option.

Start 2 week free trial
Need help?

Also from Sage