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，主要调节上皮和卵母细胞生物学。除两个氨基末端同工型TAp63和ΔNp63外，p63 mRNA的3'端还经历了组织特异性的可变剪接，产生了多种同工型，包括p63α，p63β和p63γ。为了在体内研究不同的亚型如何在细胞和发育水平上实现不同的功能，我们开发了一种小鼠模型，该模型通过删除Trp63中的外显子13来用p63β取代p63α基因。在这里，我们报告说，虽然在生理上表达p63α的两个器官（如胸腺和皮肤）中未发现异常，但在杂合雌性小鼠中总的不育是明显的。出生后第一周原代卵母细胞数量的急剧减少是由于四聚体组成型活性TAp63β亚型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况，类似于人原发性卵巢功能不全。我们的结果表明，p63 C末端对于表达TAp63α的原代卵母细胞在体内控制细胞死亡至关重要，从而扩大了对人类原发性卵巢功能不全的当前了解。