The creation of distinct male and female forms (sexual dimorphism) is a critical step in the development of sexually reproducing animals. Although the mechanisms that initiate sex determination vary considerably between different species, recent work demonstrates that the pathways that sex determination controls to create sexual dimorphism are more well-conserved. An excellent example is the Doublesex Mab3 Related Transcription Factor (DMRT) family, which have been shown to regulate sexual dimorphism in organisms as diverse as flies, worms, fish, birds, mice and man. However, the molecular pathways by which these key transcription factors control sexual dimorphism remain largely unexplored. The founding member of the DMRT family is the Drosophila protein Doublesex (DSX), which is the main factor controlling male vs. female morphology in flies. The dsx RNA is spliced into distinct forms in males vs. females, which encode the male and female proteins, DSXM and DSXF. How these two, highly-related transcription factors regulate the opposing male vs. female developmental programs is a key question in the field, but few targets for DSX have been identified. We propose to address this question by taking a whole-genome molecular approach to uncover the regulatory network(s) controlled by DSXM and DSXF. We will use chromatin immunoprecipitation followed by high throughput sequencing (ChIP-seq) to identify DSX binding sites in the genome. We will then compare these data to RNA expression profiles on males vs. females to identify DSX target genes. These studies will allow us to identify the regulatory network through which DSX controls gonad sexual dimorphism and address fundamental questions about how the male and female forms of DSX differentially regulate this network. This will also create a strong foundation for future work that focuses on the mechanisms that DSXM and DSXF use to regulate their targets, and what role these targets play in controlling sexually dimorphic development. This work will help us to understand human disorders of sexual development, such as those affecting DMRTs, and will provide a framework for understanding how the alternative splicing of transcription factors in general can lead to a diverse repertoire of downstream responses.

Public Health Relevance

This work studies how the differences between the sexes are regulated during development. This is relevant to our understanding of human Disorders of Sex Development (DSDs), which cause defects in sexual differentiation and infertility.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21HD066244-02
Application #
8204850
Study Section
Cellular, Molecular and Integrative Reproduction Study Section (CMIR)
Program Officer
Taymans, Susan
Project Start
2010-12-01
Project End
2012-11-30
Budget Start
2011-12-01
Budget End
2012-11-30
Support Year
2
Fiscal Year
2012
Total Cost
$164,000
Indirect Cost
$64,000
Name
Johns Hopkins University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218