Erbb4 regulates the oocyte microenvironment during folliculogenesis

Abstract Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders leading to infertility in women affecting reproductive, endocrine and metabolic systems. Recent genomewide association studies on PCOS cohorts revealed a single nucleotide polymorphism (SNP) in the ERBB4 receptor tyrosine kinase 4 gene, but its role in ovary development or during folliculogenesis remains poorly understood. Since no genetic animal models mimicking all PCOS reproductive features are available, we conditionally deleted Erbb4 in murine granulosa cells (GCs) under the control of Amh promoter. While we have demonstrated that Erbb4 deletion displayed aberrant ovarian function by affecting the reproductive function (asynchronous oestrous cycle leading to few ovulations and subfertility) and metabolic function (obesity), their ovaries also present severe structural and functional abnormalities (impaired oocyte development). Hormone analysis revealed an up-regulation of serum luteinizing hormone, hyperandrogenism, increased production of ovarian and circulating anti-Müllerian hormone. Our data implicate that Erbb4 deletion in GCs leads to defective intercellular junctions between the GCs and oocytes, causing changes in the expression of genes regulating the local microenvironment of the follicles. In vitro culture assays reducing the level of Erbb4 via shRNAs confirm that Erbb4 is essential for regulating Amh level. In conclusion, our results indicate a functional role for Erbb4 in the ovary, especially during folliculogenesis and its reduced expression plays an important role in reproductive pathophysiology, such as PCOS development. Graphical Abstract Graphical Abstract Proposed model for the mechanism by which Erbb4 may influences folliculogenesis and fertility. In healthy women, Errb4 receptor is expressed in granulosa cells (GCs), following its binding to Hb-Egf. The intracellular domain (ICD) is then translocated to the nucleus. ICD binds to the DNA to enhance or inhibit the expression of numerous genes (Gja1, Fst, Amh and Kit-L). Thus, the gene activation or inhibition results in the strong adhesion between GCs and decreased level of AMH that are required for normal follicles development. Consequently, the microenvironment and the genes expression are favourable for the normal folliculogenesis. In PCOS condition, Errb4 is significantly down-regulated resulting in non-translocated ICD signalling. As well, luteinizing hormone hypersecretion and hyperinsuline