Versican A-subdomain is required for its adequate function in dermal development

ABSTRACT Versican, a large chondroitin sulfate (CS) proteoglycan, serves as a structural macromolecule of the extracellular matrix (ECM) and regulates cell behavior. We determined the function of versican in dermal development using VcanΔ3/Δ3 mutant mice expressing versican with deleted A-subdomain of the N-terminal G1 domain. The mutant versican showed a decreased hyaluronan (HA)-binding ability and failed to accumulate in the ECM. In the early developmental stage, VcanΔ3/Δ3 dermis showed a decrease in versican expression as compared with WT. As development proceeded, versican expression further decreased to a barely detectable level, and VcanΔ3/Δ3 mice died at the neonatal period (P0). At P0, VcanΔ3/Δ3 dermis exhibited an impaired ECM structure and decreased cell density. While the level of collagen deposition was similar in both genotypes, collagen biosynthesis significantly decreased in VcanΔ3/Δ3 fibroblasts as compared with that in wild type (WT). Transforming growth factor β (TGFβ) signaling mediated through the Smad2/3-dependent pathway was down-regulated in VcanΔ3/Δ3 fibroblasts and a reduced TGFβ storage in the ECM was observed. Microarray analysis revealed a decrease in the expression levels of transcription factors, early growth response (Egr) 2 and 4, which act downstream of TGFβ signaling. Thus, our results suggest that A-subdomain is necessary for adequate versican expression in dermis and that versican is involved in the formation of the ECM and regulation of TGFβ signaling.

[1]  E. Maytin.  Hyaluronan: More than just a wrinkle filler. , 2016, Glycobiology.

[2]  N. Nagai,et al.  Host stromal versican is essential for cancer‐associated fibroblast function to inhibit cancer growth , 2016, International journal of cancer.

[3]  B. McManus,et al.  Versican localizes to the nucleus in proliferating mesenchymal cells. , 2015, Cardiovascular pathology : the official journal of the Society for Cardiovascular Pathology.

[4]  T. Quan,et al.  Role of Age-Associated Alterations of the Dermal Extracellular Matrix Microenvironment in Human Skin Aging: A Mini-Review , 2015, Gerontology.

[5]  A. Terskikh,et al.  Derivation of Hair-Inducing Cell from Human Pluripotent Stem Cells , 2015, PloS one.

[6]  I. Kang,et al.  Versican and the control of inflammation. , 2014, Matrix biology : journal of the International Society for Matrix Biology.

[7]  D. Ingber,et al.  How Changes in Extracellular Matrix Mechanics and Gene Expression Variability Might Combine to Drive Cancer Progression , 2013, PloS one.

[8]  W. Tourtellotte,et al.  Egr‐1: new conductor for the tissue repair orchestra directs harmony (regeneration) or cacophony (fibrosis) , 2013, The Journal of pathology.

[9]  J. Vranka,et al.  Inhibition of Hyaluronan Synthesis Reduces Versican and Fibronectin Levels in Trabecular Meshwork Cells , 2012, PloS one.

[10]  N. Hiraiwa,et al.  Versican/PG-M is essential for ventricular septal formation subsequent to cardiac atrioventricular cushion development. , 2012, Glycobiology.

[11]  J. Fischer,et al.  Estradiol Protects Dermal Hyaluronan/Versican Matrix during Photoaging by Release of Epidermal Growth Factor from Keratinocytes* , 2012, The Journal of Biological Chemistry.

[12]  H. Kerstjens,et al.  β-Catenin signaling is required for TGF-β1-induced extracellular matrix production by airway smooth muscle cells. , 2011, American journal of physiology. Lung cellular and molecular physiology.

[13]  A. Vasanji,et al.  Pericellular Versican Regulates the Fibroblast-Myofibroblast Transition , 2011, The Journal of Biological Chemistry.

[14]  W. Tourtellotte,et al.  Early growth response transcription factors: key mediators of fibrosis and novel targets for anti-fibrotic therapy. , 2011, Matrix biology : journal of the International Society for Matrix Biology.

[15]  M. Feng,et al.  Versican targeting by RNA interference suppresses aggregative growth of dermal papilla cells , 2011, Clinical and experimental dermatology.

[16]  P. Kongtawelert,et al.  Versican Facilitates Chondrocyte Differentiation and Regulates Joint Morphogenesis* , 2010, The Journal of Biological Chemistry.

[17]  S. Lovell,et al.  Quantitative analysis and prediction of curvature in leucine‐rich repeat proteins , 2009, Proteins.

[18]  Robert H. Jenkins,et al.  Modulation of TGFbeta1-dependent myofibroblast differentiation by hyaluronan. , 2009, The American journal of pathology.

[19]  P. Kongtawelert,et al.  Versican/PG-M Assembles Hyaluronan into Extracellular Matrix and Inhibits CD44-mediated Signaling toward Premature Senescence in Embryonic Fibroblasts* , 2009, Journal of Biological Chemistry.

[20]  David Silverstein,et al.  Growth factor binding to the pericellular matrix and its importance in tissue engineering. , 2007, Advanced drug delivery reviews.

[21]  B. Toole,et al.  Cartilage link protein 1 (Crtl1), an extracellular matrix component playing an important role in heart development. , 2007, Developmental biology.

[22]  Paul G Scott,et al.  Crystal structure of the dimeric protein core of decorin, the archetypal small leucine-rich repeat proteoglycan. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[23]  M. Shionyu,et al.  Distinct Interaction of Versican/PG-M with Hyaluronan and Link Protein* , 2003, Journal of Biological Chemistry.

[24]  Takeo Matsumoto,et al.  Targeted disruption of dermatopontin causes abnormal collagen fibrillogenesis. , 2002, The Journal of investigative dermatology.

[25]  Martin Vingron,et al.  Variance stabilization applied to microarray data calibration and to the quantification of differential expression , 2002, ISMB.

[26]  Zenzo Isogai,et al.  Versican Interacts with Fibrillin-1 and Links Extracellular Microfibrils to Other Connective Tissue Networks* , 2002, The Journal of Biological Chemistry.

[27]  D Heinegård,et al.  The Proteoglycans Aggrecan and Versican Form Networks with Fibulin-2 through Their Lectin Domain Binding* , 2001, The Journal of Biological Chemistry.

[28]  B. Toole,et al.  Hyaluronan and hyaluronan-binding proteins. Probes for specific detection. , 2001, Methods in molecular biology.

[29]  A. Caplan,et al.  Age-related changes in the proteoglycans of human skin. , 2000, Archives of biochemistry and biophysics.

[30]  R. Timpl,et al.  Fibulin-1 Is a Ligand for the C-type Lectin Domains of Aggrecan and Versican* , 1999, The Journal of Biological Chemistry.

[31]  T. Wight,et al.  Formation of hyaluronan- and versican-rich pericellular matrix is required for proliferation and migration of vascular smooth muscle cells. , 1999, Arteriosclerosis, thrombosis, and vascular biology.

[32]  R. Markwald,et al.  The Cspg2 gene, disrupted in the hdf mutant, is required for right cardiac chamber and endocardial cushion formation. , 1998, Developmental biology.

[33]  Renato V. Iozzo,et al.  Targeted Disruption of Decorin Leads to Abnormal Collagen Fibril Morphology and Skin Fragility , 1997, Journal of Cell Biology.

[34]  J. Couchman,et al.  Association of versican with dermal matrices and its potential role in hair follicle development and cycling. , 1995, The Journal of investigative dermatology.

[35]  J. Uitto,et al.  Differential expression of the versican and decorin genes in photoaged and sun-protected skin. Comparison by immunohistochemical and northern analyses. , 1995, Laboratory investigation; a journal of technical methods and pathology.

[36]  K. Ito,et al.  Multiple Forms of Mouse PG-M, a Large Chondroitin Sulfate Proteoglycan Generated by Alternative Splicing (*) , 1995, The Journal of Biological Chemistry.

[37]  L. Bruckner-Tuderman,et al.  Versican is expressed in the proliferating zone in the epidermis and in association with the elastic network of the dermis , 1994, The Journal of cell biology.

[38]  K. Ito,et al.  cDNA cloning of PG-M, a large chondroitin sulfate proteoglycan expressed during chondrogenesis in chick limb buds. Alternative spliced multiforms of PG-M and their relationships to versican. , 1993, The Journal of biological chemistry.

[39]  H. Larjava,et al.  Differential regulation of extracellular matrix proteoglycan (PG) gene expression. Transforming growth factor-beta 1 up-regulates biglycan (PGI), and versican (large fibroblast PG) but down-regulates decorin (PGII) mRNA levels in human fibroblasts in culture. , 1991, The Journal of biological chemistry.

[40]  E. Ruoslahti,et al.  Multiple domains of the large fibroblast proteoglycan, versican. , 1989, The EMBO journal.

[41]  M. Yamagata,et al.  Hyaluronic acid modulates proliferation of mouse dermal fibroblasts in culture. , 1988, Journal of cell science.

[42]  Y. Ninomiya,et al.  Activation of collagen synthesis in primary culture of rat liver parenchymal cells (hepatocytes) , 1985, Journal of cellular physiology.