Structure, function and regulation of versican: the most abundant type of proteoglycan in the extracellular matrix. Sotoodehnejadnematalahi F 2014 et al.
One of the main members of the large aggregating proteoglycans (PGs) family is versican which is able to bind to hyaluronate. Versican is a chondroitin sulfate proteoglycan and is a key ingredient of the extracellular matrix. Due to its widespread expression in the body, versican is involved in cell adhesion, proliferation and migration. Induced expression of versican is often observed in tissues such as breast, brain, ovary, gastrointestinal tract, prostate, and melanoma. In addition, versican has important role in development. For example, versican conducts the embryonic cell migration which is essential in the formation of the heart and outlining the path for neural crest cell migration. Several studies in the past decade up to now have shown that versican produced by mononuclear cells has an important role in wound healing and blood vessel formation and suggested that it promotes tumorigenesis and angiogenesis. In this mini-review, we summarise and discuss the role of versican in healthy and pathological tissues and suggest the possible function of transcription factors and signalling pathway in regulation of versican.
/////////////////////////
chondroitin sulfate proteoglycans were first identified in hyaline cartilage, where they specifically interact with hyaluronan and
form large supramolecular complexes. Together with other matrix glycoproteins, they provide mechanical support and a fixed
negative charge. The core protein of fibroblast chondroitin
sulfate proteoglycan was designated versican in recognition of its versatile modular structure. Decorin (125255) and biglycan
(301870) are 2 other soft tissue proteoglycans.
NCBI Summary:
This gene is a member of the aggrecan/versican proteoglycan family. The protein encoded is a large chondroitin sulfate proteoglycan and is a major component of the extracellular matrix. This protein is involved in cell adhesion, proliferation, proliferation, migration and angiogenesis and plays a central role in tissue morphogenesis and maintenance. Mutations in this gene are the cause of Wagner syndrome type 1. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2009]
General function
Cell adhesion molecule
Comment
Cellular localization
Extracellular Matrix, Secreted
Comment
Role of Versican and ADAMTS-1 in Polycystic Ovary Syndrome. Özler S et al. (2016) Background: ADAMTS-1 is a matrix metalloproteinase which cleaves versican in the cumulus oocyte complex, under the effect of luteinizing hormone surge in the periovulatory period. Altered levels of it may have a role in the disease pathogenesis. We aimed to detect serum versican and a disintegrin and metalloproteinase with thrombospondin motif- 1 (ADAMTS-1) levels in polycystic ovary syndrome (PCOS) patients, and compare the results with the healthy controls. Methods: Thirty eight PCOS patients and forty healthy controls, aged between 15-22 years were included in the study. They were sampled for their basal hormone levels, serum versican and ADAMTS-1. Serum versican, and ADAMTS-1 levels were measured by enzyme-linked immunosorbent assay (ELISA). A multivariate logistic regression model was used to identify the independent risk factors of PCOS. Results: Serum versican levels were significantly decreased in PCOS group when compared with the controls. The best versican cut-off value for PCOS was calculated to be 33.65 with 76.74% sensitivity, 52.94% specifity. Serum versican levels, homeostasis model assessment- insulin resistance index, Ferriman Galloway score higher than 8, and oligomenorrhea were the strongest predictors of PCOS. Serum versican levels were significantly decreased in PCOS patients. Besides, ADAMTS-1 and versican levels in serum were significantly and positively correlated with each other. Conclusion: Serum versican levels were significantly decreased in patients with PCOS. This suggests a possible role of versican in ovulatory dysfunction and in the pathogenesis of PCOS.//////////////////
Ovarian function
Follicle development, Antrum/Follicular fluid formation, Cumulus expansion, Ovulation, Luteinization, Oocyte maturation, Early embryo development
Comment
Activation of Mouse Cumulus-Oocyte Complex Maturation In Vitro Through EGF-Like Activity of Versican. Dunning KR et al. (2015) In vitro maturation of oocytes is suboptimal to in vivo maturation with altered gene expression and compromised oocyte quality. The large proteoglycan versican is abundant in mouse cumulus oocyte complexes (COCs) matured in vivo but absent in cultured COCs. Versican is also positively correlated with human oocyte quality. Versican contains an EGF motif and based on epidermal growth factor (EGF)-like activities in other systems we hypothesized that versican acts as an EGF-like signaling factor during COC maturation. Here we purified recombinant versican and compared its function to EGF during in vitro maturation (IVM). Versican significantly increased cumulus expansion and induced cumulus-specific genes Ptgs2, Tnfaip6 and Has2, which was blocked by EGF receptor antagonist. Microarray analysis revealed that versican has overlapping function with EGF however a subset of genes were uniquely altered following 6 h IVM with either treatment. Following 6 h of IVM both Areg and Ereg were significantly increased by both treatments while Egln3, Nr4a1, Nr4a2, Nr4a3, and Adamts5 were significantly higher following versican treatment compared to EGF. In contrast Sprr1a and Aqp3 were increased after 6h EGF and not versican treatment. To determine whether there were temporal differences, COCs were cultured with EGF or versican for 0-12 h. Versican-induced expression occurred later, but remained elevated for longer compared to EGF for Ptgs2, Ereg and Nr4a3. The unique expression profiles of Aqp3 and Nr4a3 during IVM were similarly regulated in vivo. These data indicate that versican has EGF-like effects on COC gene expression, but with distinct temporal characteristics.//////////////////
Human cumulus cell gene expression as a biomarker of pregnancy outcome after single embryo transfer. Gebhardt KM et al. OBJECTIVE: To identify the cumulus cell gene expression associated with oocyte developmental competence, specifically live birth, after single ET (SET) assisted reproductive technology. DESIGN: Retrospective gene expression analysis in human cumulus cells from oocytes that established a pregnancy resulting in live birth versus no pregnancy after SET. SETTING: Independent IVF clinic and research institute. PATIENT(S): Women undergoing IVF/intracytoplasmic sperm injection with SET. INTERVENTION(S): Quantitative reverse-transcriptase-polymerase chain reaction analysis was performed on cumulus masses collected before insemination. Oocytes and embryos were cultured and transferred independently in 38 patients undergoing elective SET. Paired cumulus samples from oocytes that developed into high- versus low-grade embryos also were compared. MAIN OUTCOME MEASURE(S): Gene expression profiles of metabolic (ALDOA, LDHA, PFKP, PKM2), signaling (AHR, GREM1, PTGS2, STS), extracellular matrix (HAS2, PTX3, TNFAIP6, VCAN), and loading control GAPDH in individual cumulus masses. RESULT(S): VCAN and PTGS2 mRNA expression was significantly higher in cumulus cells from oocytes yielding a pregnancy resulting in a live birth, while PTX3 mRNA expression trended toward higher expression in pregnant samples. Cumulus cell levels of VCAN, GREM1, and PFKP correlated with birth weight in patients at 38 weeks of gestation. No genes correlated with clinical embryo morphology scores. CONCLUSION(S): Cumulus cell VCAN, PTGS2, GREM1, and PFKP expression may identify oocytes with high developmental potential, leading to enhanced implantation rates and greater developmental capacity throughout gestation.
Formation of the Ovarian Follicular Antrum and Follicular Fluid. Rodgers RJ et al. The formation of the follicular antrum and fluid has received scant attention from researchers and yet both are important processes in follicular development. The central hypothesis on follicular fluid formation suggests that production by granulosa cells of hyaluronan and the chondroitin sulfate proteoglycan versican generates an osmotic gradient. This gradient draws in fluid derived from the thecal vasculature. Inter-alpha-trypsin inhibitor is also present in follicular fluid of species with large follicles, and inter-alpha-trypsin inhibitor and versican could additionally bind or cross-link with hyaluronan, resulting in the retention of these molecules within the follicular antrum. In mice inter-alpha-trypsin inhibitor, derived from serum, is not present in the follicular antrum until after the LH surge showing that there are clearly species differences. Barriers to the movement of fluid across the membrana granulosa are apparently minimal as even relatively large serum proteins are present in follicular fluid. Despite the relative permeability of the follicular wall aquaporins are present in granulosa cells and could be actively involved in the transport of water into the follicle. The formation of an antrum also requires movement of granulosa cells relative to each other to allow the fluid to accumulate. This presumably involves remodeling of cell-cell junctions and in species with small follicles may involve death of centrally located granulosa cells. Remodeling of the stroma and thecal layers also accompanies growth and expansion of the antrum, and presumably involves similar processes that accompany growth of other glands.
Expression regulated by
LH
Comment
Ovarian localization
Cumulus, Granulosa, Theca, Luteal cells
Comment
Processing and localization of ADAMTS-1 and proteolytic cleavage of versican during cumulus matrix expansion and ovulation. Russell DL et al. ADAMTS-1 (a disintegrin and metalloprotease with thrombospondin motifs-1) is a member of the ADAMTS family of metalloproteases which, together with ADAMTS-4 and ADAMTS-5, has been shown to degrade members of the lectican family of proteoglycans. ADAMTS-1 mRNA is induced in granulosa cells of periovulatory follicles by the luteinizing hormone surge through a progesterone receptor-dependent mechanism. Female progesterone receptor knockout (PRKO) mice are infertile primarily due to ovulatory failure and lack the normal periovulatory induction of ADAMTS-1 mRNA. We therefore investigated the protein localization and function of ADAMTS-1 in ovulating ovaries. Antibodies against two specific peptide regions, the pro-domain and the metalloprotease domain of ADAMTS-1, were generated. Pro-ADAMTS-1 of 110 kDa was identified in mural granulosa cells and appears localized to cytoplasmic secretory vesicles. The mature (85-kDa pro-domain truncated) form accumulated in the extracellular matrix of the cumulus oocyte complex (COC) during the process of matrix expansion. Each form of ADAMTS-1 protein increased >10-fold after the ovulatory luteinizing hormone surge in wild-type but not PRKO mice. Versican is also localized selectively to the ovulating COC matrix and was found to be cleaved yielding a 70-kDa N-terminal fragment immunopositive for the neoepitope DPEAAE generated by ADAMTS-1 and ADAMTS-4 protease activity. This extracellular processing of versican was reduced in ADAMTS-1-deficient PRKO mouse ovaries. These observations suggest that one function of ADAMTS-1 in ovulation is to cleave versican in the expanded COC matrix and that the anovulatory phenotype of PRKO mice is at least partially due to loss of this function.
Changes in mouse granulosa cell gene expression during early luteinization. McRae RS et al. Changes in gene expression during granulosa cell luteinization have been measured using serial analysis of gene expression (SAGE). Immature normal mice were treated with pregnant mare serum gonadotropin (PMSG) or PMSG followed, 48 h later, by human chorionic gonadotropin (hCG). Granulosa cells were collected from preovulatory follicles after PMSG injection or PMSG/hCG injection and SAGE libraries generated from the isolated mRNA. The combined libraries contained 105,224 tags representing 40,248 unique transcripts. Overall, 715 transcripts showed a significant difference in abundance between the two libraries of which 216 were significantly down-regulated by hCG and 499 were significantly up-regulated. Among transcripts differentially regulated, there were clear and expected changes in genes involved in steroidogenesis as well as clusters of genes involved in modeling of the extracellular matrix, regulation of the cytoskeleton and intra and intercellular signaling. The SAGE libraries described here provide a base for functional investigation of the regulation of granulosa cell luteinization.
McArthur ME, et al 2000 reported the identification and immunolocalization of decorin, versican,
perlecan, nidogen, and chondroitin sulfate proteoglycans in bovine
small-antral ovarian follicles.
Proteoglycans (PGs) consist of a core protein and attached glycosaminoglycans (GAGs)
and have diverse roles in cell and tissue biology. In follicles PGs have been detected only
in follicular fluid and in cultured granulosa cells, and the composition of their GAGs has
been determined. To identify PGs in whole ovarian follicles, not just in follicular fluid and
granulosa cells, small (1-3-mm) bovine follicles were harvested. A proportion of these was
incubated with (35)SO(4) for 24 h to incorporate radiolabel into the GAGs. The freshly
harvested and cultured follicles were sequentially extracted with 6 M urea buffer, the same
buffer with 0.1% Triton X-100 and then with 0.1 M NaOH. Proteoglycans were subjected
to ion-exchange and size-exclusion chromatography. The GAGs were analyzed by
chemical and enzymic digestion, and on the basis of their composition, a list of
known PGs was measured by ELISA analyses. Versican, perlecan, decorin, but not aggrecan
or biglycan, were identified. These, excluding decorin for technical reasons, as well as a
basal lamina glycoprotein, nidogen/entactin, were immunolocalized. Versican was localized
to the thecal layers, including externa and the interna particularly in an area adjacent to the
follicular basal lamina. Perlecan and nidogen were localized to the follicular basal lamina of
antral follicles, both healthy and atretic, but not to that of preantral follicles. Both were
localized to subendothelial basal laminas, but the former was not readily detected in
arteriole smooth muscle layers. This study has confirmed the presence of versican and
perlecan, but not the latter as a component of follicular fluid, and identified decorin and
nidogen in ovarian antral follicles.
Follicle stages
Secondary, Antral, Preovulatory, Corpus luteum
Comment
Russell DL, et al 203 reported hormone-regulated expression and localization of versican in the rodent ovary.
During ovulation, production of a specialized hyaluronan (HA)-rich matrix cross-linked by associated HA binding factors causes expansion of the cumulus oocyte complex. Versican is a member of the hyalectan family that binds HA, provides structure and elasticity to tissues, and impacts cell motility and adhesion. Analysis of mRNA and protein identified isoforms V0, V1, and V3 versican in mouse and rat ovaries throughout follicular development. In situ hybridization localized versican mRNA most specifically to the granulosa cells. Expression was not significantly altered by estradiol or FSH treatment but was increased up to 10-fold during the periovulatory period after human chorionic gonadotropin treatment. In cultured granulosa cells, forskolin and phorbol 12 myristate 13-acetate or FSH + testosterone increased expression of versican. Immunohistochemical analyses verified versican protein in ovulating follicles localized to the expanded cumulus matrix as well as adjacent to the basement membrane. After ovulation, versican was localized around newly formed corpora lutea and vasculature. Unexpectedly, immunohistochemical analyses also demonstrated versican protein on granulosa cells in early primary and small antral follicles. Versican expression and localization were not altered in progesterone receptor or cyclooxygenase-2 null mice, suggesting that transcription of the versican gene is not a target of these two ovulatory mediators. These observations suggest that versican (V0, V1, and V3) is a matrix component of the granulosa layer throughout folliculogenesis and is enriched in remodeling matrices during ovulation and neovascularization of the corpora lutea.