Spermatogonial stem cells (SSCs), male germ line stem cells, provide the foundation for spermatogenesis by their ability to both self-renew and generate daughter cells, which differentiate into spermatozoa. These attributes make SSCs the key component for sustained fertility in males and the preservation of genetic lines. Signaling for mouse SSC self-renewal is mediated by the growth factor glial cell line-derived neurotrophic factor (GDNF) likely through the c-Ret proto-oncogene receptor. Using this growth factor and a defined medium, long-term (more than 6-months) in vitro proliferation of mouse SSCs occurs, which has been confirmed by maintenance of cell surface antigenic markers and ability of cultured SSCs, when transplanted to recipients, to produce donor cell-derived spermatogenesis and progeny. Thus, a unique and powerful system is available to study the molecular mechanisms of mouse SSC self-renewal. We have recently used microarray profiling to identify GDNF-regulated genes in highly enriched populations of SSCs, providing a database of genes that may constitute the core molecular machinery regulating SSC self-renewal and survival. The same growth factor and similar molecular mechanisms are likely used by other mammalian SSCs, because stem cells from many species (e.g. rat, pig, baboon and human) have been shown to proliferate in mouse testes. In addition, important molecules identified for mouse SSC self-renewal may be helpful in understanding mechanisms used by other adult tissue stem cells. The mouse SSC culture system and stem cell transplantation technique will be used to analyze the molecular regulation of mouse SSC self- renewal. The two proposed specific aims are: 1) Investigate GDNF signaling pathways involved in SSC self- renewal, and 2) Determine the biological significance of GDNF-regulated genes in SSC self-renewal. The identification of the signals required for male germ line stem cells to grow and divide will help in understanding male infertility in humans and in establishing a system to culture or grow human SSCs outside the body. Such a culture system could be used to maintain stem cells of a male during chemotherapy, and the stem cells then returned to the male's testes to reestablish fertility after therapy. ? ? ?

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD052728-02
Application #
7485603
Study Section
Cellular, Molecular and Integrative Reproduction Study Section (CMIR)
Program Officer
Tasca, Richard J
Project Start
2007-08-15
Project End
2012-06-30
Budget Start
2008-07-01
Budget End
2009-06-30
Support Year
2
Fiscal Year
2008
Total Cost
$327,994
Indirect Cost
Name
University of Pennsylvania
Department
Veterinary Sciences
Type
Schools of Veterinary Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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Ginsberg, Jill P; Li, Yimei; Carlson, Claire A et al. (2014) Testicular tissue cryopreservation in prepubertal male children: an analysis of parental decision-making. Pediatr Blood Cancer 61:1673-8
Wu, Xin; Goodyear, Shaun M; Abramowitz, Lara K et al. (2012) Fertile offspring derived from mouse spermatogonial stem cells cryopreserved for more than 14 years. Hum Reprod 27:1249-59
Wu, Xin; Goodyear, Shaun M; Tobias, John W et al. (2011) Spermatogonial stem cell self-renewal requires ETV5-mediated downstream activation of Brachyury in mice. Biol Reprod 85:1114-23
Niu, Zhiyv; Goodyear, Shaun M; Rao, Shilpa et al. (2011) MicroRNA-21 regulates the self-renewal of mouse spermatogonial stem cells. Proc Natl Acad Sci U S A 108:12740-5
Schmidt, Jonathan A; Abramowitz, Lara K; Kubota, Hiroshi et al. (2011) In vivo and in vitro aging is detrimental to mouse spermatogonial stem cell function. Biol Reprod 84:698-706
Kubota, Hiroshi; Wu, Xin; Goodyear, Shaun M et al. (2011) Glial cell line-derived neurotrophic factor and endothelial cells promote self-renewal of rabbit germ cells with spermatogonial stem cell properties. FASEB J 25:2604-14
Wu, Xin; Oatley, Jon M; Oatley, Melissa J et al. (2010) The POU domain transcription factor POU3F1 is an important intrinsic regulator of GDNF-induced survival and self-renewal of mouse spermatogonial stem cells. Biol Reprod 82:1103-11
Oatley, Jon M; Kaucher, Amy V; Avarbock, Mary R et al. (2010) Regulation of mouse spermatogonial stem cell differentiation by STAT3 signaling. Biol Reprod 83:427-33
Ginsberg, J P; Carlson, C A; Lin, K et al. (2010) An experimental protocol for fertility preservation in prepubertal boys recently diagnosed with cancer: a report of acceptability and safety. Hum Reprod 25:37-41

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