Regulation of sex-specific development by transcription factors

Johns Hopkins University, Baltimore MD

Investigators

Abstract

Project Summary Homologs of Drosophila Doublesex (Dsx), the Dsx, MAB-3 Related Transcription Factors (DMRTs), are known to control gonad sexual dimorphism across the animal kingdom, from planaria and water fleas, to worms, flies, mice and man. Patients with mutations in DMRT1 exhibit XY gonad dysgenesis and infertility, indicating that DMRT1 is essential for male gonad development in humans. Given the universal nature of DMRT involvement in gonad sexual dimorphism, a key question becomes how do these transcription factors regulate this process and what are their target genes? Here we propose to study these questions using both genomic and developmental approaches. In particular, a developmental process of high interest is the formation of the gonad stem cell systems and the somatic cells that support the germline. In mammals, this process is highly dimorphic as the testis has a stem cell system but the ovary does not. However, in many animals, both the ovary and the testis have stem cell systems, since both sexes need to produce large numbers of gametes for an extended period of life. These stem cell systems are also highly dimorphic between the sexes. Further, gonads of many organisms have a somatic stem cell (SSC) population, in addition to the germline stem cells (GSCs), and the SSCs produce differentiating daughter cells that nurture the developing gametes. For example, the Cyst Stem Cells (CySCs) in the Drosophila testis interact with GSCs and produce Cyst Cells that associate with differentiating germ cells, and so these cell types together perform a function similar to mammalian Sertoli cells. Here, we propose to study how Dsx acts to control two key aspects of the male and female stem cell systems, the stem cell niches and the male and female SSCs, using both developmental and genomic approaches.