This project will significantly impact biology and medicine by better defining molecular mechanisms that regulate spermatogonial stem cell development.
Each specific aim i s centered on defining the structure, function and testicular endocrinology of a family of survival, proliferation and differentiation factors, termed neuregulins. Neuregulins comprise a large family of ligands for transmembrane receptors in the erythoblastoma virus B (ErbB) family of tyrosine kinases. Preliminary studies show that neuregulins and their receptors are expressed together on undifferentiated spermatogonia, and that neuregulin-like factors are required for formation of aligned spermatogonia in culture. The proposed studies are based on these findings and will represent a new area of investigation in reproductive biology. The goal of Specific Aim 1 is to define the structures of neuregulin and ErbB family members expressed by undifferentiated spermatogonia in culture. Ligand-receptor pairs identified will then be used to determine mechanisms by which neuregulins regulate spermatogonial development in culture.
Specific Aim 2 will focus on defining the spatial and temporal expression of one neuregulin receptor, termed ErbB3, in the rat testes. Preliminary studies show that expression of ErbB3 is highly restricted to type A-single spermatogonia within rat testes. Because type A-single spermatogonia are considered stem spermatogonia, and because specific molecular markers for these cells have yet to be defined, ErbB3-expressing spermatogonia will be tested for their ability to function as spermatogonial stem cells in chimeric rodent testes, as Specific Aim 3. The proposed project should have a positive impact on human health;elucidating molecular mechanisms that regulate spermatogonial development may well lead to treatments and cures for male infertility, provide new targets for contraceptive development, assist in the preservation of endangered species, afford alternative methods to produce transgenic animals valuable in medicine, and potentially allow for selection against harmful genetic defects in the male germline.

Public Health Relevance

The proposed project should have a positive impact on human health;elucidating molecular mechanisms that regulate spermatogonial development may well lead to treatments and cures for male infertility, provide new targets for contraceptive development, assist in the preservation of endangered species, afford alternative methods to produce transgenic animals valuable in medicine, and potentially allow for selection against harmful genetic defects in the male germline.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD053889-04
Application #
8318543
Study Section
Cellular, Molecular and Integrative Reproduction Study Section (CMIR)
Program Officer
Moss, Stuart B
Project Start
2009-09-30
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
4
Fiscal Year
2012
Total Cost
$308,213
Indirect Cost
$111,899
Name
University of Texas Sw Medical Center Dallas
Department
Pharmacology
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
Dandapat, Abhijit; Bosnakovski, Darko; Hartweck, Lynn M et al. (2014) Dominant lethal pathologies in male mice engineered to contain an X-linked DUX4 transgene. Cell Rep 8:1484-96
Abid, Shadaan N; Richardson, Timothy E; Powell, Heather M et al. (2014) A-single spermatogonia heterogeneity and cell cycles synchronize with rat seminiferous epithelium stages VIII-IX. Biol Reprod 90:32
Chapman, Karen M; Powell, Heather M; Chaudhary, Jaideep et al. (2013) Linking spermatid ribonucleic acid (RNA) binding protein and retrogene diversity to reproductive success. Mol Cell Proteomics 12:3221-36
Taurog, Joel D; Rival, Claudia; van Duivenvoorde, Leonie M et al. (2012) Autoimmune epididymoorchitis is essential to the pathogenesis of male-specific spondylarthritis in HLA-B27-transgenic rats. Arthritis Rheum 64:2518-28
Ivics, Zoltan; Izsvak, Zsuzsanna; Chapman, Karen M et al. (2011) Sleeping Beauty transposon mutagenesis of the rat genome in spermatogonial stem cells. Methods 53:356-65
Ivics, Zoltan; Izsvak, Zsuzsanna; Medrano, Gerardo et al. (2011) Sleeping Beauty transposon mutagenesis in rat spermatogonial stem cells. Nat Protoc 6:1521-35