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.
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