Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders leading to infertility in women affecting reproductive, endocrine and metabolic systems. Recent genome-wide 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 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 upregulation of serum luteinizing hormone, hyperandrogenism, increased production of ovarian and circulating anti-Müllerian hormone. Our data implicate that Erbb4 deletion in granulosa cells leads to defective intercellular junctions between the granulosa cells 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.

中文翻译：

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Erbb4 在卵泡发生过程中调节卵母细胞微环境。

多囊卵巢综合征 (PCOS) 是最常见的内分泌疾病之一，可导致女性不孕，影响生殖、内分泌和代谢系统。最近对 PCOS 队列的全基因组关联研究揭示了ERBB4受体酪氨酸激酶 4 基因中的单核苷酸多态性 (SNP) ，但其在卵巢发育或卵泡发生过程中的作用仍知之甚少。由于没有模拟所有 PCOS 生殖特征的遗传动物模型可用，我们有条件地删除了Amh控制下的鼠颗粒细胞中的Erbb4发起人。虽然我们已经证明 Erbb4 缺失通过影响生殖功能（异步发情周期导致少数排卵和低生育力）和代谢功能（肥胖）显示异常卵巢功能，但它们的卵巢也存在严重的结构和功能异常（卵母细胞发育受损）。激素分析显示血清黄体生成素上调、雄激素过多症、卵巢和循环抗苗勒管激素的产生增加。我们的数据表明颗粒细胞中Erbb4 的缺失导致颗粒细胞和卵母细胞之间的细胞间连接缺陷，导致调节卵泡局部微环境的基因表达发生变化。体外通过 shRNA 降低 Erbb4 水平的培养测定证实 Erbb4 对调节 Amh 水平至关重要。总之，我们的结果表明 Erbb4 在卵巢中的功能作用，特别是在卵泡发生期间，其表达降低在生殖病理生理学（如 PCOS 发展）中起着重要作用。