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Basement membranes in skin: unique matrix structures with diverse functions?

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Abstract

The view of extracellular matrix (ECM) has evolved from a merely scaffolding and space filling tissue element to an interface actively controlling cellular activities and tissue functions. A highly specialized form of ECM is the basement membrane (BM), an ubiquitous sheet-like polymeric structure composed of a set of distinct glycoproteins and proteoglycans. In this review we are largely focusing on function and assembly of BM in skin (1) at the dermo-epidermal interface and (2) in the resident micro-vasculature. The role of the non-polymeric components perlecan and particularly nidogen is exemplified by reviewing experiments based on genetic approaches and adequate experimental skin models in vivo and in vitro. While in mice total deficiency of one of these components is eventually developmentally lethal, the severity of the defects varies drastically between tissues and also the skin models recapitulating BM formation in vitro. There is accumulating evidence that this relies on the mechanical properties, the molecular composition of the BM, the adjacent ECM or connective tissue, the dynamics of molecular assembly, and ‘minor’ tissue-specific modifier or adapter components. Though the role of nidogen or perlecan is still remaining a controversial issue, the statements ‘being essential for BM/or not’ should be consequently referred to the developmental, tissue, and functional (e.g., repair) context.

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References

  • Arikawa-Hirasawa E, Watanabe H, Takami J, Hassell JR, Yamada Y (1999) Perlecan is essential for cartilage and cephalic development. Nat Genet 23:354–358

    Article  PubMed  CAS  Google Scholar 

  • Aumailley M, Battaglia C, Mayer U, Nischt R, Timpl R, Fox JW (1993) Nidogen mediates the formation of ternary complexes of basement membrane components. Kidney Int 43:7–12

    Article  PubMed  CAS  Google Scholar 

  • Aumailley M, Bruckner-Tuderman L, Carter WG, Deutzmann R, Edgar D, Ekblom P, Engel J, Engvall E, Hohenester E, Jones JC, Kleinman HK, Marinkovich MP, Martin GR, Mayer U, Meneguzzi G, Miner JH, Miyazaki K, Patarroyo M, Paulsson M, Quaranta V, Sanes JR, Sasaki T, Sekiguchi K, Sorokin LM, Talts JF, Tryggvason K, Uitto J, Virtanen I, von der Mark K, Wewer UM, Yamada Y, Yurchenco PD (2005) A simplified laminin nomenclature. Matrix Biol 24:326–332

    Article  PubMed  CAS  Google Scholar 

  • Aumailley M, Has C, Tunggal L, Bruckner-Tudermann L (2006) Molecular basis of inherited skin-blistering disorders, and therapeutic implications. Expert Rev Mol Med 8:1–21

    Article  PubMed  Google Scholar 

  • Bader B, Smyth N, Nedbal S, Miosge N, Baranowsky A, Mokkapati S, Murshed M, Nischt R (2005) Compound genetic ablation of nidogen 1 and 2 causes basement membrane defects and perinatal lethality in mice. Mol Cell Biol 25:6846–6856

    Article  PubMed  CAS  Google Scholar 

  • Battaglia C, Mayer U, Aumailley M, Timpl R (1992) Basement-membrane heparan sulfate proteoglycan binds to laminin by its heparan sulfate side chains and to nidogen by sites in the protein core. Eur J Biochem 208:359–366

    Article  PubMed  CAS  Google Scholar 

  • Boukamp P, Dzarlieva-Petrusevska RT, Breitkreutz D, Hornung J, Markham A, Fusenig NE (1988) Normal keratinization in a spontaneously immortalized aneuploid human keratinocyte cell line. J Cell Biol 106:761–771

    Article  PubMed  CAS  Google Scholar 

  • Breitkreutz D, Stark HJ, Plein P, Baur M, Fusenig NE (1993) Differential modulation of epidermal keratinization in immortalized (HaCaT) and tumorigenic human skin keratinocytes (HaCaT-ras) by retinoic acid and extracellular Ca2+. Differentiation 54:201–217

    Article  PubMed  CAS  Google Scholar 

  • Breitkreutz D, Stark HJ, Mirancea N, Tomakidi P, Steinbauer H, Fusenig NE (1997) Integrin and basement membrane normalization in mouse grafts of human keratinocytes—implications for epidermal homeostasis. Differentiation 61:195–209

    Article  PubMed  CAS  Google Scholar 

  • Breitkreutz D, Schoop VM, Mirancea N, Baur M, Stark HJ, Fusenig NE (1998) Epidermal differentiation and basement membrane formation by HaCaT cells in surface transplants. Eur J Cell Biol 75:273–286

    PubMed  CAS  Google Scholar 

  • Breitkreutz D, Mirancea N, Schmidt C, Beck R, Werner U, Stark HJ, Gerl M, Fusenig NE (2004) Inhibition of basement membrane formation by a nidogen-binding laminin γ1-chain fragment in human skin-organotypic cocultures. J Cell Sci 117:2611–2622

    Article  PubMed  CAS  Google Scholar 

  • Breitkreutz D, Braimann-Wiksman L, Daum N, Denning MF, Tennenbaum T (2007) Protein kinase C family—on the crossroads of cell signaling in skin. J Cancer Res Clin Oncol 133:793–808

    Article  PubMed  CAS  Google Scholar 

  • Bruckner-Tuderman L (1999) Hereditary skin diseases of anchoring fibrils. J Dermatol Sci 20:122–133

    Article  PubMed  CAS  Google Scholar 

  • Chaudhari P, Marinkovich MP (2007) What’s new in blistering disorders. Curr Allergy Asthma Rep 7:222–263

    Article  Google Scholar 

  • Costell M, Gustafsson E, Aszódi A, Mörgelin M, Bloch W, Hunziker E, Addicks K, Timpl R, Fässler R (1999) Perlecan maintains the integrity of cartilage and some basement membranes. J Cell Biol 147:354–358

    Article  Google Scholar 

  • Dong L, Chen Y, Lewis M, Hsieh JC, Reing J, Chaillet JR, Howell CY, Melhem M, Inoue S, Kuszak JR, DeGeest K, Chung AE (2002) Neurological defects and selective disruption of basement membranes in mice lacking entactin-1/nidogen-1. Lab Invest 82:1617–1630

    PubMed  CAS  Google Scholar 

  • Eckert RL, Sturniolo MT, Broome AM, Ruse M, Rorke EA (2005) Transglutaminase function in epidermis. J Invest Dermatol 124:481–492

    Article  PubMed  CAS  Google Scholar 

  • Fleischmajer R, Schechter A, Bruns M, Perlish JS, Macdonald ED, Pan TC, Timpl R, Chu ML (1995) Skin fibroblasts are the only source of nidogen during early basal lamina formation. J Invest Dermatol 105:597–601

    Article  PubMed  CAS  Google Scholar 

  • Fox JW, Mayer U, Nischt R, Aumailley M, Reinhardt D, Wiedemann H, Mann K, Timpl R, Krieg T, Engel J (1991) Recombinant nidogen consists of three globular domains and mediates binding of laminin to collagen IV. EMBO J 10:3137–3146

    PubMed  CAS  Google Scholar 

  • Franzke CW, Bruckner P, Bruckner-Tuderman L (2005) Collagenous transmembrane proteins: recent insights into biology and pathology. J Biol Chem 280:4005–4008

    Article  PubMed  CAS  Google Scholar 

  • Fuchs E, Raghavan S (2002) Getting under the skin of epidermal morphogenesis. Nat Rev Genet 3:199–209

    Article  PubMed  CAS  Google Scholar 

  • Hohl D, Lichti U, Breitkreutz D, Steinert PM, Roop DR (1991) Transcription of the human loricrin gene in vitro is induced by calcium and cell density and repressed by retinoic acid. J Invest Dermatol 96:414–418

    Article  PubMed  CAS  Google Scholar 

  • Huber M, Siegenthaler G, Mirancea N, Marenholz I, Nizetic D, Breitkreutz D, Mischke D, Hohl D (2005) Isolation and characterization of human repetin, a member of the fused gene family of the epidermal differentiation complex. J Invest Dermatol 124:998–1007

    Article  PubMed  CAS  Google Scholar 

  • Iozzo RV (2005) Basement membrane proteoglycans: from cellular to ceiling. Nat Rev Mol Cell Biol 6:646–656

    Article  PubMed  CAS  Google Scholar 

  • Ito M, Cotsarelis G (2008) Is the hair follicle necessary for normal wound healing? J Invest Dermatol 128:1059–1061

    Article  PubMed  CAS  Google Scholar 

  • Kaur P (2006) Interfollicular epidermal stem cells: identification, challenges, potential. J Invest Dermatol 126:1450–1458

    Article  PubMed  CAS  Google Scholar 

  • Kohfeldt E, Sasaki T, Göhring W, Timpl R (1998) Nidogen-2: a new basement membrane protein with diverse binding properties. J Mol Biol 282:99–109

    Article  PubMed  CAS  Google Scholar 

  • Köhling R, Nischt R, Vasudevan A, Ho M, Weiergräber M, Schneider T, Smyth N (2006) Nidogen and nidogen-associated basement membrane proteins and neuronal plasticity. Neurodegener Dis 3:56–61

    Article  PubMed  Google Scholar 

  • Lareu RR, Arsianti I, Subramhanya HK, Yanxian P, Raghunath M (2007) In vitro enhancement of collagen matrix formation and crosslinking for applications in tissue engineering: a preliminary study. Tissue Eng 13:385–391

    Article  PubMed  CAS  Google Scholar 

  • LeBleu VS, Macdonald B, Kalluri R (2007) Structure and function of basement membranes. Exp Biol Med 232:1121–1129

    Article  CAS  Google Scholar 

  • Limat A, Breitkreutz D, Thiekoetter G, Klein CE, Braathen LR, Hunziker T, Fusenig NE (1995) Formation of a regular neo-epidermis by cultured human outer root sheath cells grafted on nude mice. Transplantation 59:1032–1038

    Article  PubMed  CAS  Google Scholar 

  • Limat A, Stockhammer E, Breitkreutz D, Schaffner T, Egelrud T, Salomon D, Fusenig NE, Braathen LR, Hunziker T (1996) Endogenously regulated site-specific differentiation of human palmar skin keratinocytes in organotypic cocultures and in nude mouse transplants. Eur J Cell Biol 69:245–258

    PubMed  CAS  Google Scholar 

  • Litjens SH, de Pereda JM, Sonnenberg A (2006) Current insight into the formation and breakdown of hemidesmosomes. Trends Cell Biol 16:376–383

    Article  PubMed  CAS  Google Scholar 

  • Marinkovich MP (2007) Tumor microenvironment: laminin-322 in squamous cell carcinoma. Nat Rev Cancer 7:370–380

    Article  PubMed  CAS  Google Scholar 

  • Marionnet C, Pierrard C, Vioux-Chagnoleau C, Sok J, Asselineau D, Bernerd F (2006) Interactions between fibroblasts and keratinocytes in morphogenesis of dermal epidermal junction in a model of reconstructed skin. J Invest Dermatol 126:971–979

    Article  PubMed  CAS  Google Scholar 

  • Mayer U, Nischt R, Pöschl E, Mann K, Fukuda K, Gerl M, Yamada Y, Timpl R (1993a) A single EGF-like motif of laminins is responsible for high affinity nidogen binding. EMBO J 12:1879–1885

    PubMed  CAS  Google Scholar 

  • Mayer U, Mann K, Timpl R, Murphy G (1993b) Sites of nidogen cleavage by proteases involved in tissue homeostasis and remodeling. Eur J Biochem 217:877–884

    Article  PubMed  CAS  Google Scholar 

  • Mayer U, Zimmermann K, Mann K, Reinhardt D, Timpl R, Nischt R (1995) Binding properties and protease stability of recombinant human nidogen. Eur J Biochem 227:681–686

    Article  PubMed  CAS  Google Scholar 

  • McMillan JR, Akiyama M, Shimizu H (2003) Epidermal basement membrane zone components: ultrastructural distribution and molecular interactions. J Dermatol Sci 31:169–177

    Article  PubMed  CAS  Google Scholar 

  • Miner JH (2008) Laminins and their role in development. Microsc Res Tech 71:349–356

    Article  PubMed  CAS  Google Scholar 

  • Miner JH, Yurchenco PD (2004) Laminin function in tissue morphogenesis. Annu Rev Cell Dev Biol 20:255–284

    Article  PubMed  CAS  Google Scholar 

  • Miner JH, Li C, Mudd JL, Go G, Sutherland AE (2004) Compositional and structural requirements for laminin and basement membranes during mouse embryo implantation and gastrulation. Development 131:2247–2256

    Article  PubMed  CAS  Google Scholar 

  • Miosge N, Sasaki T, Timpl R (2002) Evidence for nidogen-2 compensation for nidogen-1 deficiency in transgenic mice. Matrix Biol 21:611–621

    Article  PubMed  CAS  Google Scholar 

  • Mirancea N, Schmidt C, Daum N, Tomakidi P, Stark HJ, Fusenig NE, Breitkreutz D (2002) Basement membrane defects in xeno-grafts of malignant human cells. In: Witz IP (ed) Proceedings of the 2nd international conference tumor microenvironment. Monduzzi, Bologna, pp 55–58

    Google Scholar 

  • Mirancea N, Hausser I, Beck R, Metze D, Fusenig NE, Breitkreutz D (2006) Vascular anomalies in lipoid proteinosis (hyalinosis cutis et mucosae): basement membrane components and ultrastructure. J Dermatol Sci 42:231–239

    Article  PubMed  CAS  Google Scholar 

  • Mirancea N, Hausser I, Metze D, Stark HJ, Boukamp P, Breitkreutz D (2007) Junctional basement membrane anomalies of skin and mucosa in lipoid proteinosis (hyalinosis cutis et mucosae): components and ultrastructure. J Dermatol Sci 45:175–185

    Article  PubMed  CAS  Google Scholar 

  • Mokkapati S, Baranowsky A, Mirancea N, Smyth N, Breitkreutz D, Nischt R (2008) Basement membranes are differently affected by lack of nidogen 1 and 2. J Invest Dermatol 128:2259–2267

    Article  PubMed  CAS  Google Scholar 

  • Morrison SJ, Spradling AC (2008) Stem cells and niches: mechanisms that promote stem cell maintenance throughout life. Cell 132:598–611

    Article  PubMed  CAS  Google Scholar 

  • Muffler S, Stark HJ, Amoros M, Falkowska-Hansen B, Boehnke K, Bühring HJ, Marme A, Bickenbach JR, Boukamp P (2008) A stable niche supports long-term maintenance of human epidermal stem cells in organotypic cultures. Stem Cells 26:2506–2515

    Article  PubMed  CAS  Google Scholar 

  • Müller MM, Fusenig NE (2004) Friends or foes—bipolar effects of the tumour stroma in cancer. Nat Rev Cancer 42:735–744

    Google Scholar 

  • Murshed M, Smyth N, Miosge N, Karolat J, Krieg T, Paulsson M, Nischt R (2000) The absence of nidogen-1 does not affect murine basement membrane formation. Mol Cell Biol 20:7007–7012

    Article  PubMed  CAS  Google Scholar 

  • Niessen CM (2007) Tight junctions/adherens junctions: basic structure and function. J Invest Dermatol 127:2525–2532

    Article  PubMed  CAS  Google Scholar 

  • Nischt R, Schmidt C, Mirancea N, Baranowsky A, Mokkapati S, Smyth N, Woenne EC, Stark HJ, Boukamp P, Breitkreutz D (2007) Lack of nidogen-1 and -2 prevents basement membrane assembly in skin-organotypic co-culture. J Invest Dermatol 127:545–554

    Article  PubMed  CAS  Google Scholar 

  • Ortega N, Werb Z (2002) New functional roles for non-collagenous domains of basement membrane collagens. J Cell Sci 115:4201–4214

    Article  PubMed  CAS  Google Scholar 

  • Ortiz-Urda S, Garcia J, Green CL, Chen L, Lin Q, Veitch DP, Sakai LY, Lee H, Marinkovich MP, Khavari PA (2005) Type VII collagen is required for RAS-driven human epidermal carcinogensis. Science 307:1773–1776

    Article  PubMed  CAS  Google Scholar 

  • Pöschl E, Fox JW, Block D, Mayer U, Timpl R (1994) Two non-contiguous regions contribute to nidogen binding to a single EGF-like motif of the laminin gamma1 chain. EMBO J 13:3741–3747

    PubMed  Google Scholar 

  • Pöschl E, Schlötzer-Schrehardt U, Brachvogel B, Saito K, Ninomiya Y, Mayer U (2004) Collagen IV is essential for basement membrane stability but dispensable for initiation of its assembly during early development. Development 131:1619–1621

    Article  PubMed  Google Scholar 

  • Rodeck U, Uitto J (2007) Recessive dystrophic epidermolysis bullosa-associated squamous-cell carcinoma: an enigmatic entity with complex pathogenesis. J Invest Dermatol 127:2295–2296

    Article  PubMed  CAS  Google Scholar 

  • Ryle CM, Breitkreutz D, Stark HJ, Leigh IM, Steinert PM, Roop D, Fusenig NE (1989) Density-dependent modulation of synthesis of keratins l and 10 in the human keratinocyte line HaCaT and in ras-transfected tumorigenic clones. Differentiation 40:42–54

    Article  PubMed  CAS  Google Scholar 

  • Sadagurski M, Yakar S, Weingarten G, Holzenberger M, Rhodes CJ, Breitkreutz D, Leroith D, Wertheimer E (2006) Insulin-like growth factor 1 receptor signaling regulates skin development and inhibits skin keratinocyte differentiation. Mol Cell Biol 7:2675–2687

    Article  Google Scholar 

  • Salmivirta K, Talts J, Olsson M, Sasaki T, Timpl R, Ekblom P (2002) Binding of mouse nidogen-2 to basement membrane components and cells in embryonic and adult tissues suggest complementary functions of the two nidogens. Exp Cell Res 279:188–201

    Article  PubMed  CAS  Google Scholar 

  • Schneider H, Mühle C, Pacho F (2007) Biological function of laminin-5 and pathogenic impact of its deficiency. Eur J Cell Biol 86:701–717

    Article  PubMed  CAS  Google Scholar 

  • Schymeinsky J, Nedbal S, Miosge N, Pöschl E, Rao C, Beier DR, Skarnes WC, Timpl R, Bader BL (2002) Gene structure and functional analysis of the mouse nidogen-2 gene: nidogen-2 is not essential for basement membrane formation in mice. Mol Cell Biol 22:6820–6830

    Article  PubMed  CAS  Google Scholar 

  • Sevilla LM, Nachat R, Groot KR, Klement JF, Uitto J, Djian P, Määttä A, Watt FM (2007) Mice deficient in involucrin, envoplakin, and periplakin have a defective epidermal barrier. J Cell Biol 179:1599–1612

    Article  PubMed  CAS  Google Scholar 

  • Sher I, Zisman-Rozen S, Eliahu L, Whitelock JM, Maas-Szabowski N, Yamada Y, Breitkreutz D, Fusenig NE, Arikawa-Hirasawa E, Iozzo RV, Bergman R, Ron D (2006) Targeting perlecan in human keratinocytes reveals novel roles for perlecan in epidermis formation. J Biol Chem 281:5178–5187

    Article  PubMed  CAS  Google Scholar 

  • Smola H, Stark HJ, Thiekötter G, Mirancea N, Krieg T, Fusenig NE (1998) Dynamics of Basement membrane formation by keratinocyte-fibroblast interactions in organotypic skin cultures. Exp Cell Res 239:399–410

    Article  PubMed  CAS  Google Scholar 

  • Smyth N, Vatansever HS, Murray P, Meyer M, Frie C, Paulsson M, Edgar D (1999) Absence of basement membrane after targeting the LAMC1 gene results in embryonic lethality due to failure of endoderm differentiation. J Cell Biol 144:151–160

    Article  PubMed  CAS  Google Scholar 

  • Stark HJ, Baur M, Breitkreutz D, Mirancea N, Fusenig NE (1999) Organotypic keratinocyte cocultures in defined medium with regular epidermal morphogenesis and differentiation. J Invest Dermatol 112:681–691

    Article  PubMed  CAS  Google Scholar 

  • Stark HJ, Willhauck MJ, Mirancea N, Boehnke K, Nord I, Breitkreutz D, Pavesio A, Boukamp P, Fusenig NE (2004) Authentic fibroblast matrix in dermal equivalents normalizes epidermal histogenesis and dermo-epidermal junction in organotypic co-culture. Eur J Cell Biol 83:631–645

    Article  PubMed  Google Scholar 

  • Sugawara K, Tsuruta D, Ishii M, Jones JC, Kobayashi H (2008) Laminin-332 and laminin-511 in skin. Exp Dermatol 17:473–480

    Article  PubMed  CAS  Google Scholar 

  • Tennenbaum T, Weiner AK, Belanger AJ, Glick AB, Hennings H, Yuspa SH (1993) The suprabasal expression of alpha 6 beta 4 integrin is associated with a high risk for malignant progression in mouse skin carcinogenesis. Cancer Res 53:4803–4810

    PubMed  CAS  Google Scholar 

  • Timpl R, Brown JC (1996) Supramolecular assembly of basement membranes. Bioessays 18:123–132

    Article  PubMed  CAS  Google Scholar 

  • Tomakidi P, Mirancea N, Fusenig NE, Herold-Mende C, Bosch FX, Breitkreutz D (1999) Defects of basement membrane and hemidesmosome structure correlate with malignant phenotype and stromal interactions in HaCaT-ras transplants. Differentiation 64:263–275

    Article  PubMed  CAS  Google Scholar 

  • Tomakidi P, Stark HJ, Herold-Mende C, Bosch FX, Steinbauer H, Fusenig NE, Breitkreutz D (2003) Discriminating expression of differentiation markers evolving in transplants of benign and malignant human skin keratinocytes through stromal interactions. J Pathol 200:298–307

    Article  PubMed  Google Scholar 

  • Villone D, Fritsch A, Koch M, Bruckner-Tuderman L, Hansen U, Bruckner P (2008) Supramolecular interactions in the dermo-epidermal junction zone: anchoring fibril-collagen VII tightly binds to banded collagen fibrils. J Biol Chem 283:24506–24513

    Article  PubMed  CAS  Google Scholar 

  • Watt FM (2002) Role of integrins in regulating epidermal adhesion, growth, and differentiation. EMBO J 21:3919–3926

    Article  PubMed  CAS  Google Scholar 

  • Wilhelmsen K, Litjens SH, Sonnenberg A (2006) Multiple functions of the integrin alpha6beta4 in epidermal homeostasis and tumorigenesis. Mol Cell Biol 26:2877–2886

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

The work was in part supported by the Deutsche Forschungsgemeinschaft through the Sonderforschungsbereich (SFB) 589 at the University of Cologne, the grants NI-304/11-1 (Roswitha Nischt), BR-530/8-1 (Dirk Breitkreutz), and industrial grants (Sanofi-Aventis); furthermore we like to thank all students and colleagues involved or contributing to these studies at any stage, also by many fruitful discussions. We apologize to the many scientists whose paper we were unable to cite owing to space constraints.

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Breitkreutz, D., Mirancea, N. & Nischt, R. Basement membranes in skin: unique matrix structures with diverse functions?. Histochem Cell Biol 132, 1–10 (2009). https://doi.org/10.1007/s00418-009-0586-0

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