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.
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.
|Chaudhary, J; Hamra, F K (2015) Discovering in vitro spermatogenesis stimulating factors. Cell Death Dis 6:e1937|
|Chapman, Karen M; Medrano, Gerardo A; Chaudhary, Jaideep et al. (2015) NRG1 and KITL Signal Downstream of Retinoic Acid in the Germline to Support Soma-Free Syncytial Growth of Differentiating Spermatogonia. Cell Death Discov 1:|
|Hamra, F Kent (2015) Diagnosing spermatogonial stemness. Biol Reprod 92:119|
|Chapman, Karen M; Medrano, Gerardo A; Jaichander, Priscilla et al. (2015) Targeted Germline Modifications in Rats Using CRISPR/Cas9 and Spermatogonial Stem Cells. Cell Rep 10:1828-35|
|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|
|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|
|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|
|Goertz, Meredith J; Wu, Zhuoru; Gallardo, Teresa D et al. (2011) Foxo1 is required in mouse spermatogonial stem cells for their maintenance and the initiation of spermatogenesis. J Clin Invest 121:3456-66|
|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|
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