Nawaito Sherin A, Esmael Mostafa, Souchkova Ouliana, Cardinal Tatiana, Bernas Guillaume, Bergeron Karl-F, Gayda Fanny, Bergeron Francis, Bouchard Marie-France, Zhou Xiang, Ongaro Luisina, Bernard Daniel J, Short Jacob, Wray Susan, Viger Robert S, Mounier Catherine, Pilon Nicolas
Molecular Genetics of Development Laboratory, Department of Biological Sciences, Université du Québec à Montréal, Montreal, Canada.
Centre d'Excellence en Recherche sur les Maladies Orphelines - Fondation Courtois, Université du Québec à Montréal, Montreal, Canada.
FASEB J. 2025 Jun 30;39(12):e70717. doi: 10.1096/fj.202401718RR.
Polycystic ovary syndrome (PCOS) is a heterogenous disorder characterized by reproductive and metabolic abnormalities. PCOS etiology remains poorly understood, although the hypothalamus is suspected to play a central role in many cases. Human genetic studies have also shown an association with the transcription factor-coding gene GATA4, but without providing a functional link. Here, we show that adult Greywick female mice may bridge this gap. These mice phenocopy PCOS with partial penetrance, due to the serendipitous insertion of a Gata4 promoter-driven transgene in a strong enhancer region. Resulting robust transgene expression in subsets of hypothalamic neurons and glia impairs endogenous Gata4 expression, resulting in misexpression of genes linked to the control of fertility and food intake. We also show that this previously overlooked role of GATA4 in the hypothalamus can be replicated by conditional knockout approaches. Overall, this study sheds light not only on PCOS etiology but also on the role played by GATA4 in the central control of reproduction.
多囊卵巢综合征（PCOS）是一种以生殖和代谢异常为特征的异质性疾病。尽管怀疑下丘脑在许多病例中起核心作用，但PCOS的病因仍知之甚少。人类遗传学研究也表明与转录因子编码基因GATA4有关联，但未提供功能联系。在此，我们表明成年Greywick雌性小鼠可能填补这一空白。由于Gata4启动子驱动的转基因偶然插入到一个强增强子区域，这些小鼠部分模拟了PCOS。下丘脑神经元和神经胶质细胞亚群中由此产生的强大转基因表达损害了内源性Gata4表达，导致与生育控制和食物摄入相关的基因表达错误。我们还表明，GATA4在下丘脑中这一先前被忽视的作用可以通过条件性敲除方法重现。总体而言，这项研究不仅揭示了PCOS的病因，还揭示了GATA4在生殖中枢控制中所起的作用。
