Department of Experimental Medicine, University of Rome "Tor Vergata", Rome, Italy.
Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy.
Nat Commun. 2021 Jan 15;12(1):383. doi: 10.1038/s41467-020-20669-0.
The transcription factor p63 mediates distinct cellular responses, primarily regulating epithelial and oocyte biology. In addition to the two amino terminal isoforms, TAp63 and ΔNp63, the 3'-end of p63 mRNA undergoes tissue-specific alternative splicing that leads to several isoforms, including p63α, p63β and p63γ. To investigate in vivo how the different isoforms fulfil distinct functions at the cellular and developmental levels, we developed a mouse model replacing the p63α with p63β by deletion of exon 13 in the Trp63 gene. Here, we report that whereas in two organs physiologically expressing p63α, such as thymus and skin, no abnormalities are detected, total infertility is evident in heterozygous female mice. A sharp reduction in the number of primary oocytes during the first week after birth occurs as a consequence of the enhanced expression of the pro-apoptotic transcriptional targets Puma and Noxa by the tetrameric, constitutively active, TAp63β isoform. Hence, these mice show a condition of ovary dysfunction, resembling human primary ovary insufficiency. Our results show that the p63 C-terminus is essential in TAp63α-expressing primary oocytes to control cell death in vivo, expanding the current understanding of human primary ovarian insufficiency.
转录因子 p63 介导不同的细胞反应，主要调节上皮细胞和卵母细胞的生物学功能。除了两个氨基末端异构体 TAp63 和 ΔNp63 外，p63 mRNA 的 3' 端还经历组织特异性的选择性剪接，导致产生几种异构体，包括 p63α、p63β 和 p63γ。为了研究不同异构体在细胞和发育水平上如何发挥不同的功能，我们通过在 Trp63 基因中缺失外显子 13 ，开发了一种将 p63α 替换为 p63β 的小鼠模型。在这里，我们报告说，虽然在两个生理上表达 p63α 的器官中，如胸腺和皮肤，没有检测到异常，但杂合雌性小鼠表现出明显的不孕。出生后第一周，初级卵母细胞的数量急剧减少，这是由于四聚体、组成性激活的 TAp63β 异构体增强了促凋亡转录靶标 Puma 和 Noxa 的表达。因此，这些小鼠表现出卵巢功能障碍的状态，类似于人类原发性卵巢功能不全。我们的结果表明，p63 C 端对于 TAp63α 表达的初级卵母细胞中体内细胞死亡的控制是必不可少的，这扩展了对人类原发性卵巢功能不全的现有理解。
