Activation of Mouse Cumulus-Oocyte Complex Maturation In Vitro Through EGF-Like Activity of Versican1

Abstract

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 is absent in cultured COCs. Versican is also positively correlated with human oocyte quality. Versican contains an epidermal growth factor (EGF) motif, and based on 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 with that of 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 was uniquely altered following 6 h of IVM with either treatment. Following 6 h of IVM, both Areg and Ereg were significantly increased by both treatments, whereas Egln3, Nr4a1, Nr4a2, Nr4a3, and Adamts5 were significantly higher following versican treatment compared with EGF. In contrast, Sprr1a and Aqp3 were increased after 6 h of EGF but 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 with 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.

Periovulatory insulin signaling is essential for ovulation, granulosa cell differentiation, and female fertility

“…In support of this, VCAN contains an epidermal growth factor-like motif whose activity promotes cumulus expansion and oocyte maturation. 73 An N-terminal VCAN cleavage peptide, versikine, is | 2389 SEKULOVSKI Et aL. thought to modulate cell proliferation and apoptosis, although its mechanism of action is unclear.…”

Effects of Gangliosides on Spermatozoa, Oocytes, and Preimplantation Embryos

“…During capacitation, GM1 localizes to the sterol-poor postacrosomal plasma membrane and then moves to the sterol-rich plasma membrane in rat spermatozoa [78]. The distribution of GM1 on ejaculated boar spermatozoa changes in a sequential manner from overlying the sperm tail to the sperm head during methyl-β-cyclodextrin(MBCD)-mediated capacitation [79]. In live bovine and mouse sperm heads, GM1 also localizes to the sterol-rich plasma membrane overlying the acrosome (APM), and labeling GM1 using the pentameric cholera toxin subunit B (CTB) induces a dramatic redistribution of signal from the APM to the sterol-poor postacrosomal plasma membrane upon sperm death [80].…”

Ovarian Folliculogenesis

“…This gonadotropin also elevates the expression of TNF-α-induced protein 6 (Tnfaip6), which links the HA covalently to the heavy chain of serum-derived inter-α-trypsin inhibitor (IαI) upon its interaction with multimers of pentraxin 3 (PTX3). Another protein that interacts with HA to stabilize the COC matrix is Versican, a complex matricellular proteoglycan, which is also rapidly induced in GC by the LH surge (Dunning et al 2015). Prostaglandin synthase 2 (PTGS2; also known as COX2), the rate-limiting enzyme in the synthesis of prostaglandins, is also essential for cumulus expansion and may function upstream of TNFAIP6 (reviewed by Edson et al 2009).…”