Anna Maria Lena, Valerio Rossi, Susanne Osterburg, Artem Smirnov, Christian Osterburg, Marcel Tuppi, Angela Cappello, Ivano Amelio, Volker Dötsch, Massimo De Felici, Francesca Gioia Klinger, Margherita Annicchiarico-Petruzzelli, Herbert Valensise, Gerry Melino

Abstract

The transcription factor p63 mediates distinct cellular responses, primarily regulating epi- thelial 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.