Santos Guasch Gabriela L, Beeler J Scott, Marshall Clayton B, Shaver Timothy M, Sheng Quanhu, Johnson Kimberly N, Boyd Kelli L, Venters Bryan J, Cook Rebecca S, Pietenpol Jennifer A
Department of Biochemistry, Vanderbilt University, Nashville, TN 37232, USA.
Department of Biochemistry, Vanderbilt University, Nashville, TN 37232, USA; Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
iScience. 2018 Oct 26;8:236-249. doi: 10.1016/j.isci.2018.09.018. Epub 2018 Sep 25.
We report that p73 is expressed in ovarian granulosa cells and that 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. Performing RNA sequencing (RNA-seq) on transcripts from murine wild-type and p73-deficient antral follicles, we discovered differentially expressed genes that regulate biological adhesion programs. Through modulation of p73 expression in murine granulosa cells and transformed cell lines, followed by RNA-seq and chromatin immunoprecipitation sequencing, we discovered p73-dependent regulation of a gene set necessary for 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.
我们报告称，p73在卵巢颗粒细胞中表达，p73缺失会导致卵泡发育、排卵和黄体形成减弱，从而导致循环孕酮水平降低以及乳腺分支缺陷。p73缺陷小鼠中的异位孕酮完全挽救了乳腺分支，并部分挽救了卵巢卵泡发育缺陷。对小鼠野生型和p73缺陷型窦状卵泡的转录本进行RNA测序（RNA-seq），我们发现了调节生物粘附程序的差异表达基因。通过调节小鼠颗粒细胞和转化细胞系中的p73表达，随后进行RNA-seq和染色质免疫沉淀测序，我们发现了p73对细胞粘附和迁移所必需的一组基因以及聚焦基质（局灶性上皮内基质）成分的依赖性调节，聚焦基质是颗粒细胞之间促进卵泡成熟的基底层。总之，p73对卵巢卵泡发生至关重要，并作为参与细胞间粘附和迁移的基因网络的关键调节因子发挥作用。
