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Abstract
Fertilization of the mammalian oocyte requires interactions between spermatozoa and expanded cumulus extracellular matrix (ECM) that surrounds the oocyte. This review focuses on key molecules that play an important role in the formation of the cumulus ECM, generated by the oocyte-cumulus complex. In particular, the specific inhibitors (AG1478, lapatinib, indomethacin and MG132) and progesterone receptor antagonist (RU486) exerting their effects through the remodeling of the ECM of the cumulus cells surrounding the oocyte have been described. After gonadotropin stimulus, cumulus cells expand and form hyaluronan (HA)-rich cumulus ECM. In pigs, the proper structure of the cumulus ECM depends on the interaction between HA and serum-derived proteins of the inter-alpha-trypsin inhibitor (IαI) protein family. We have demonstrated the synthesis of HA by cumulus cells, and the presence of the IαI, tumor necrosis factor-alpha-induced protein 6 and pentraxin 3 in expanding oocyte-cumulus complexes (OCC). We have evaluated the covalent linkage of heavy chains of IαI proteins to HA, as the principal component of the expanded HA-rich cumulus ECM, in porcine OCC cultured in medium with specific inhibitors: AG1478 and lapatinib (both inhibitors of epidermal growth factor receptor tyrosine kinase activity); MG132 (a specific proteasomal inhibitor), indomethacin (cyclooxygenase inhibitor); and progesterone receptor antagonist (RU486). We have found that both RU486 and indomethacin does not disrupt the formation of the covalent linkage between the heavy chains of IαI to HA in the expanded OCC. In contrast, the inhibitors AG1478 and lapatinib prevent gonadotropin-induced cumulus expansion. Finally, the formation of oocyte-cumulus ECM relying on the covalent transfer of heavy chains of IαI molecules to HA has been inhibited in the presence of MG132.
Highlights
Fertilization of the mammalian oocyte requires interactions between spermatozoa and expanded cumulus extracellular matrix (ECM) that surrounds the oocyte
Whether heavy chains (HCs) of serum-derived IαI-related molecules are covalently linked to HA in porcine expanded oocyte-cumulus complexes (OCC) in vivo, the experiments with OCC isolated from the antral follicles of pigs treated with PMSG or PMSG followed by hCG for 24 h were performed [12]
FSH rapidly induces porcine OCC to express epidermal growth factor (EGF)-like growth factors [47] and TACE/ADAM17, a protease that cleaves and activates the EGF transmembrane precursors [48]. It has been shown [45] that AG1478, the inhibitor of epidermal growth factor receptor (EGFR) tyrosine kinase activity, reduces 50% of the synthesis and 90% of the HA retained in the cumulus ECM, and prevents the expansion of porcine OCC stimulated with FSH for 24 h in vitro culture
Summary
The extracellular matrix (ECM) is an important structure that is present in all tissues. Naba et al [2] defined ECM proteins of the mammalian matrisome by analysis of the human and mouse genome. It comprises 1–1.5% of the mammalian proteome. Proteoglycans are important structural macromolecules in tissues. They consist of a core protein with attached glycosaminoglycan side chains. Hyaluronan is the only glycosaminoglycan synthesized at the cell membrane and it is present in a protein-free form [4]. The size of HA depends on the relative activity of HA-synthesizing and degrading enzymes. The importance of the function of the ECM is demonstrated by the embryonic lethality caused by mutations in genes that encode components of the ECM [8,9]
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