The creation of sexual dimorphism in the gonad is critical for proper germ cell development and sexual reproduction. In Drosophila, both the testis and ovary have germline stem cell populations that are regulated by their respective stem cell niches and are essential for continuous production of gametes. Germline stem cell formation requires specific interactions between the germ cells and somatic gonad, and both the germline stem cells and their niches exhibit important differences in males and females. This is also true in other species, such as mammals, where the male and female exhibit clear differences in their ability to form germline stem cells. This proposal focuses on understanding how the niches and germline stem cells are formed during development, and how sexual identity in the germ cells and soma work together to control sexual dimorphism in the niche and germline stem cells. We will first study the role of the cadherins in the formation of the niche and germline stem cells. DE- cadherin and DN-cadherin are expressed in the developing germline stem cell niche in both males and females, and are localized to the interface between the niche and germline stem cells. We will investigate whether these cell-cell adhesion molecules are important for morphogenesis of the niche and for regulating the behavior of the germline stem cells. Second, we will study how the formation of the male vs. female niche is regulated by the critical sex determination factor doublesex (dsx). Our preliminary data indicate that dsx regulates sexual dimorphism in the niche and that the male niche may be able to trans- differentiate to form the female niche. We will study how dsx influences niche formation during gonad development. Third, we will study how sex determination in the germ cells interacts with a sex-specific soma to control germ cell development and germline stem cell formation. In flies, as well as mammals, the sex of the germ cells must match the sex of the soma for proper germ cell development and fertility. We will investigate why germ cells fail to respond appropriately to a soma of a different sex. Finally, we will investigate the role of a new gene, no child left behind (nclb), in male germline stem cell development. nclb is expressed in male germ cells at the time they become germline stem cells, and nclb mutants exhibit a severe loss of male germline stem cells. Our data indicate that the NCLB protein is a chromatin- associated factor and we will test the hypothesis that NCLB is required for proper epigenetic control of male germline stem cell development. The proposed work will further our understanding of how sex-specific development of the soma and germ cells interact to control germline stem cell formation. This work has clear implications for our understanding of human sexual development and fertility, as well as the broader question of how adult stem cells develop and are regulated by their niches.

Public Health Relevance

In this proposal, we will study how proper sexual development of the germ cells and somatic gonad combine to regulate germline stem cell formation and fertility. This is relevant to the many human syndromes that exhibit infertility and/or improper sexual development. Further, an understanding of how stem cell niches form and regulate their stem cell population is relevant for understanding how adult stem cells normally function and how their misregulation can result in disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM084356-04
Application #
8206746
Study Section
Cellular, Molecular and Integrative Reproduction Study Section (CMIR)
Program Officer
Haynes, Susan R
Project Start
2009-03-01
Project End
2012-12-31
Budget Start
2012-01-01
Budget End
2012-12-31
Support Year
4
Fiscal Year
2012
Total Cost
$389,413
Indirect Cost
$144,792
Name
Johns Hopkins University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Casper, Abbie L; Baxter, Kelly; Van Doren, Mark (2011) no child left behind encodes a novel chromatin factor required for germline stem cell maintenance in males but not females. Development 138:3357-66
Murray, Sheryl M; Yang, Shu Yuan; Van Doren, Mark (2010) Germ cell sex determination: a collaboration between soma and germline. Curr Opin Cell Biol 22:722-9
Casper, Abbie L; Van Doren, Mark (2009) The establishment of sexual identity in the Drosophila germline. Development 136:3821-30