p73 Is Required for Ovarian Follicle Development and Regulates a Gene Network Involved in Cell-to-Cell Adhesion

摘要

class="head no_bottom_margin" id="sec1title">IntroductionThe p53 family of proteins, p53, p63, and p73, are sequence-specific transcription factors that are required for cell cycle control, DNA repair, apoptosis, adhesion, organ development, and cell differentiation (, , , , , ). All three p53 family members share a high degree of structural and amino acid sequence similarities within their transactivation domains, DNA binding domains, and oligomerization domains (, ), which accounts for similar genomic binding sites and regulation of overlapping target genes. Unlike p53, p63 and p73 are transcribed from two separate promoters that encode functionally divergent variants. The transcriptionally active (TA) isoform encodes the full-length protein, whereas the alternative transcript (ΔN) encodes an isoform lacking the amino-terminal transactivation domain (, ). Thus, ΔNp63 and ΔNp73 isoforms act as dominant-negative regulators of TAp63 and TAp73 (, , ).p63 and p73 play important roles in cell differentiation and tissue development. p63 is a key regulator of ectodermal differentiation and stratification of the epidermis. Mice lacking p63 fail to develop stratified epithelia, exhibit defective limb and glandular epithelial development, and die shortly after birth due to dehydration (, ). Mice deficient for all isoforms of p73 exhibit runting, sterility, hippocampal dysgenesis and hydrocephalus, as well as chronic infection and inflammation in the lungs, sinus, and ears (href="#bib65" rid="bib65" class=" bibr popnode">Yang et al., 2000). The development of p73-isoform-specific knockout mouse models provided significant insight into the roles of select p73 isoforms. TAp73-deficient mice exhibit sterility, hippocampal dysgenesis, hydrocephalus, premature aging, genomic instability, and increased frequency of tumors (href="#bib58" rid="bib58" class=" bibr popnode">Tomasini et al., 2008). In contrast, mice that lack ΔNp73 are fertile and display signs of neurodegeneration, including hippocampal dysgenesis and hydrocephalus (href="#bib61" rid="bib61" class=" bibr popnode">Wilhelm et al., 2010). Thus the sterility defects observed in the global p73-deficient animals are due to a deficiency in the TAp73 isoform. Recently, our laboratory (href="#bib37" rid="bib37" class=" bibr popnode">Marshall et al., 2016) and others (href="#bib41" rid="bib41" class=" bibr popnode">Nemajerova et al., 2016) discovered that TAp73 is required for multiciliated cell differentiation and acts as a transcriptional regulator of a gene network required for ciliogenesis. The discovery provided mechanistic insight into the diverse phenotypes observed in p73-deficient mouse models. Impaired cilia formation in p73-deficient mice leads to insufficient clearance of pathogens from the lungs and sinuses causing chronic inflammation. Furthermore, loss of cilia in reproductive tissues decreases transport of the sperm and ova through epididymis and fallopian tubes, respectively, leading to infertility.Other phenotypes of p73-deficient mice have been reported that are likely to originate from processes unrelated to ciliogenesis. Male mice that lack TAp73 exhibit increased DNA damage and apoptosis in spermatogonial cells within the testes, which results in defective germ cell maturation and differentiation, required for proper spermatogenesis (href="#bib24" rid="bib24" class=" bibr popnode">Inoue et al., 2014, href="#bib21" rid="bib21" class=" bibr popnode">Holembowski et al., 2014). TAp73-deficient female mice exhibit meiotic spindle formation abnormalities during oocyte maturation and impaired ovulation (href="#bib58" rid="bib58" class=" bibr popnode">Tomasini et al., 2008). We report herein that p73 expression in the ovarian follicle, the structure in which the oocyte develops, is critical for oocyte development, ovulation, and fertility. Specifically, p73 is required in granulosa cells for the expression of a p73-dependent gene set that regulates cell adhesion and migration, including genes that encode key components of granulosa-cell-associated focimatrix.