We aim to define in molecular terms how mammalian gonads arise, develop and carry out their role in reproduction. Our preliminary data provide solid evidence that mammalian sex determination requires both GATA4 and FOG2 transcription regulators and relies on their direct interaction to assemble the functioning testes and, possibly, the ovaries as well.
Our Specific Aims are designed to characterize mechanistically how FOG2 and GATA4 control sex determination and development of the gonads and reproductive system. We will identify gonadal lineages and monitor genetic pathways that require FOG2/GATA4 for their function.
In Specific Aim 1 we will use genetically modified mice to re-express FOG2 itself or its potential downstream targets - Sry and Sox9 - in the supporting cell lineage (pre-Sertoli cells) of the FOG2 null embryonic gonad. We will also use Cre/lox conditional targeting technology to knockout FOG2 exclusively in the reproductive system and then further restrict FOG2 loss to the supporting cell lineage only. These approaches are complementary and in the long term should provide a novel genetic description of sex determination and sexual differentiation in both sexes that incorporates the GATA/FOG paradigm. We will clarify the connections between FOG2/GATA4 and other gonadal-restricted transcription factors.
In Specific Aim 2 we will examine biochemically the pair-wise interactions between FOG2 and other key transcription factors in gonadogenesis. We will study the higher-order DNA-protein complexes containing GATA4/FOG2 that are formed on gonad-specific promoters. We will exploit the potential of in vitro assays to further our understanding of the processes in the gonad where FOG2 and GATA4 are required.
In Specific Aim 3 marker analysis and organ cultures will be used to determine if FOG2/GATA4 control cellular migration from mesonephros and/or vascularization in the developing gonad. Sex determination, development of the reproductive system and commonality of morphological transformations between cardiac, gonadal and cancerous cells will remain our long term primary focus.
|Padua, Maria B; Jiang, Tianyu; Morse, Deborah A et al. (2015) Combined loss of the GATA4 and GATA6 transcription factors in male mice disrupts testicular development and confers adrenal-like function in the testes. Endocrinology 156:1873-86|
|Tevosian, Sergei G; Jiménez, Elizabeth; Hatch, Heather M et al. (2015) Adrenal Development in Mice Requires GATA4 and GATA6 Transcription Factors. Endocrinology 156:2503-17|
|Tevosian, Sergei G (2014) Transgenic mouse models in the study of reproduction: insights into GATA protein function. Reproduction 148:R1-R14|
|Padua, Maria B; Fox, Shawna C; Jiang, Tianyu et al. (2014) Simultaneous gene deletion of gata4 and gata6 leads to early disruption of follicular development and germ cell loss in the murine ovary. Biol Reprod 91:24|
|Efimenko, Evgeni; Padua, Maria B; Manuylov, Nikolay L et al. (2013) The transcription factor GATA4 is required for follicular development and normal ovarian function. Dev Biol 381:144-58|
|Tevosian, Sergei (2013) DMRT1 owner's manual: synchronized installation required to operate. Biol Reprod 88:50|
|Tevosian, S G (2013) Genetic control of ovarian development. Sex Dev 7:33-45|
|Tevosian, Sergei G (2012) Gone without the WNT: a requirement for WNT5A in germ cell migration and testis development. Biol Reprod 86:1-2|
|Brody, Matthew J; Hacker, Timothy A; Patel, Jitandrakumar R et al. (2012) Ablation of the cardiac-specific gene leucine-rich repeat containing 10 (Lrrc10) results in dilated cardiomyopathy. PLoS One 7:e51621|
|Zaytouni, Tamara; Efimenko, Evgeni E; Tevosian, Sergei G (2011) GATA transcription factors in the developing reproductive system. Adv Genet 76:93-134|
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