The Role of p73 in Murine Ovarian Follicle Development and Function

Abstract

The p53 family of transcription factors, p53, p63 and p73, regulate a wide array of cellular processes from cell cycle control to organ development and cell differentiation. The goal of this dissertation is to understand the role of p73, as it relates to female reproduction, ovarian function and hormone signaling. We discovered that p73 is expressed in ovarian granulosa ¬cells and loss of p73 leads to attenuated follicle development, ovulation, and corpus luteum formation, resulting in decreased levels of circulating progesterone and defects in mammary gland branching. Ectopic progesterone in p73-deficient mice completely rescued the mammary branching and partially rescued the ovarian follicle development defects. Through modulation of p73 expression in murine granulosa cells and transformed cell lines, followed by RNA-seq and ChIP-seq, we discovered p73-dependent regulation of a gene set involved in cell adhesion and migration, and components of the focimatrix (focal intra-epithelial matrix), a basal lamina between granulosa cells that promotes follicle maturation. In summary, p73 is essential for ovarian folliculogenesis and functions as a key regulator of a gene network involved in cell-to-cell adhesion and migration.