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The p63 C-terminus is essential for murine oocyte integrity

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2021

Nat Commun. 2021 Jan 15;12(1):383. doi: 10.1038/s41467-020-20669-0.

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 De Felici, Francesca Gioia Klinger, Margherita Annicchiarico-Petruzzelli, Herbert Valensise, Gerry Melino, Eleonora Candi

Department of Experimental Medicine, University of Rome "Tor Vergata", Rome, Italy. Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy. Institute of Biophysical Chemistry, Center for Biomolecular Magnetic Resonance and Cluster of Excellence Macromolecular Complexes (CEF), Goethe University, Frankfurt, Germany. Ludwig Institute for Cancer Research, University of Oxford, Oxford, OX3 7DQ, UK. The Francis Crick Institute, London, NW11ST, UK. School of Life Sciences, University of Nottingham, Nottingham, UK. IDI-IRCCS, Via dei Monti di Creta, Rome, Italy. Department of Surgery, University of Rome "Tor Vergata", Rome, Italy. Policlinico "Casilino", Rome, Italy. Department of Experimental Medicine, University of Rome "Tor Vergata", Rome, Italy. melino@uniroma2.it. Department of Experimental Medicine, University of Rome "Tor Vergata", Rome, Italy. candi@uniroma2.it. IDI-IRCCS, Via dei Monti di Creta, Rome, Italy.

Service type: Knockout mice

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.

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