The p63 C-terminus is essential for murine oocyte integrity

Area of Science:

• Molecular Biology
• Developmental Biology
• Genetics

Background:

• The transcription factor p63 is crucial for epithelial and oocyte biology.
• p63 exists in N-terminal isoforms (TAp63, ΔNp63) and C-terminal isoforms (p63α, p63β, p63γ) generated by alternative splicing.
• Understanding the in vivo functions of different p63 isoforms is essential for developmental and cellular regulation.

Purpose of the Study:

• To investigate the in vivo functions of distinct p63 isoforms at cellular and developmental levels.
• To develop a mouse model to study the impact of p63 isoform switching on biological processes.
• To elucidate the role of the p63 C-terminus in oocyte biology and its implications for ovarian function.

Main Methods:

• Development of a Trp63 gene mouse model with exon 13 deletion, replacing p63α with p63β.
• Analysis of physiological and developmental abnormalities in the generated mouse model.
• Assessment of oocyte number, apoptosis markers (Puma, Noxa), and ovarian function in heterozygous female mice.

Main Results:

• The mouse model exhibited no abnormalities in thymus and skin, organs normally expressing p63α.
• Heterozygous female mice displayed total infertility due to a sharp reduction in primary oocytes.
• Enhanced expression of pro-apoptotic targets Puma and Noxa by the TAp63β isoform led to oocyte loss and ovarian dysfunction.

Conclusions:

• The C-terminus of p63 is critical for controlling cell death in TAp63α-expressing primary oocytes.
• The TAp63β isoform, when replacing TAp63α, promotes apoptosis in oocytes, leading to ovarian insufficiency.
• This study provides insights into the molecular mechanisms underlying primary ovarian insufficiency and the distinct roles of p63 isoforms.