The p63 C-terminus is essential for murine oocyte integrity

Anna Maria Lena, Valerio Rossi, Susanne Osterburg, Artem Smirnov, Christian Osterburg, Marcel Tuppi, Angela Cappello, Ivano Amelio, Volker Dötsch, Massimo Felici, Francesca Gioia Klinger, Margherita Annicchiarico-Petruzzelli, Herbert Valensise, Gerry Melino () and Eleonora Candi ()
Additional contact information
Anna Maria Lena: University of Rome “Tor Vergata”
Valerio Rossi: University of Rome Tor Vergata
Susanne Osterburg: Goethe University
Artem Smirnov: University of Rome “Tor Vergata”
Christian Osterburg: Goethe University
Marcel Tuppi: Goethe University
Angela Cappello: University of Rome “Tor Vergata”
Ivano Amelio: University of Rome “Tor Vergata”
Volker Dötsch: Goethe University
Massimo Felici: University of Rome Tor Vergata
Francesca Gioia Klinger: University of Rome Tor Vergata
Margherita Annicchiarico-Petruzzelli: IDI-IRCCS, Via dei Monti di Creta
Herbert Valensise: University of Rome “Tor Vergata”
Gerry Melino: University of Rome “Tor Vergata”
Eleonora Candi: University of Rome “Tor Vergata”

Nature Communications, 2021, vol. 12, issue 1, 1-14

Abstract: Abstract 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.

Date: 2021
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DOI: 10.1038/s41467-020-20669-0

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