The long-term goal of this project is to use C. elegans to understand the molecular basis of sexual dimorphism and sex-specific organogenesis. Sexual differentiation is central to normal development but the molecular mechanisms controlling it are poorly understood. The focus of this application is on two sexually dimorphic features, male sensory rays (V rays) and the somatic gonad, which serve as paradigms for sex-specific nervous system development and sex-specific organogenesis. The central hypothesis is that specific regulatory pathways act downstream of the master regulator TRA-1 to control sexual differentiation of specific tissues and organs. This laboratory previously discovered two key downstream factors: the DM domain protein MAB-3, and the forkhead protein FKH-6. Guided by strong preliminary data, our specific aims are to elucidate how sex-specific nervous system development is regulated in the male tail by TRA-1 and MAB-3, and how sex-specific gonadogenesis is controlled by TRA-1 and FKH-6.
The first aim i nvestigates the mechanism by which MAB-3 represses the antineural bHLH gene ref-1 in males, evaluates candidate MAB-3 corepressors, finds a protein that activates ref-1, and investigates the role of TRA-1.
The second aim i dentifies targets of FKH-6 regulation and suppressors of fkh-6 mutants, evaluates candidate FKH-6 coregulators, and investigates how TRA-1 both antagonizes and potentiates FKH-6 functions. The proposed research will uncover the molecular basis of a critical but poorly understood aspect of development, using innovative approaches including informatics-based identification of target genes, in vivo DNA binding assays, mining of """"""""phenome"""""""" databases, and development of inducible tissue- specific RNAi methods. This work has clear relevance to human health: DM domain proteins and forkhead proteins control sexual differentiation in mammals, and we recently discovered that mutations in a DM domain gene cause testicular cancer. Failure of sexual differentiation causes sex reversal, sexual ambiguity, urogenital malformation, infertility, and gonadal cancer. This proposal investigates DM domain protein interactions with conserved chromatin regulators, potentially opening the way to development of therapeutic agents. ? ? ?
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