The transcription factor GATA4 is required for follicular development and normal ovarian function

• Published in: Developmental biology Vol. 381; no. 1; pp. 144 - 158
• Main Authors: Efimenko, Evgeni, Padua, Maria B., Manuylov, Nikolay L., Fox, Shawna C., Morse, Deborah A., Tevosian, Sergei G.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-09-2013
• Subjects: Alleles; Animals; Cell Differentiation; Cell Proliferation; DNA-Binding Proteins - metabolism; Female; FOG2; GATA4; GATA4 Transcription Factor - genetics; Gene Deletion; Gene Expression Regulation, Developmental; Hypothalamus - metabolism; Mice; Mice, Inbred C57BL; Mutation; Ovarian Cysts - metabolism; Ovarian development; Ovarian Follicle - embryology; Ovary - embryology; Ovary - metabolism; Pituitary Gland - metabolism; Transcription Factors - metabolism; Zinc Fingers; FOG2; GATA4; Ovarian development
• ISSN: 0012-1606; 1095-564X
• DOI: 10.1016/j.ydbio.2013.06.004

Sex determination in mammals requires interaction between the transcription factor GATA4 and its cofactor FOG2. We have recently described the function of both proteins in testis development beyond the sex determination stage; their roles in the postnatal ovary, however, remain to be defined. Here, we use gene targeting in mice to determine the requirement of GATA4 and FOG2 in ovarian development and folliculogenesis. The results from this study identify an essential role of the GATA4 protein in the ovarian morphogenetic program. We show that in contrast to the sex determination phase, which relies on the GATA4–FOG2 complex, the subsequent regulation of ovarian differentiation is dependent upon GATA4 but not FOG2. The loss of Gata4 expression within the ovary results in impaired granulosa cell proliferation and theca cell recruitment as well as fewer primordial follicles in the ovarian cortex, causing a failure in follicular development. Preantral follicular atresia is observed within the few follicles that develop despite Gata4 deficiency. The depletion of the follicular pool in GATA4 deficient ovary results in the formation of ovarian cysts and sterility.
•We report a key role for GATA4 protein in the ovarian morphogenetic program in mice.•Subsequent to sex determination, ovarian development requires GATA4, but not FOG2.•The loss of Gata4 leads to a block in a key transition during follicular development.•Depletion of the follicular pool results in the formation of ovarian cysts and sterility.•Gata4 might be considered as a candidate gene for ovarian dysfunction in humans.