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Research Article |
Divisions of Urology,4
Endocrinology and Oncology,5 Department of Surgery
Department of Pathology and Immunology,6 Washington University School of Medicine, St. Louis, Missouri 63110
ABSTRACT
Normal spermatogenesis is essential for reproduction and depends on proper spermatogonial stem cell (SSC) function. Genes and signaling pathways that regulate SSC function have not been well defined. We report that glial cell-line-derived neurotrophic factor (GDNF) signaling through the RET tyrosine kinase/GFRA1 receptor complex is required for spermatogonial self-renewal in mice. GFRA1 and RET expression was identified in a subset of gonocytes at birth, was restricted to SSCs during normal spermatogenesis, and RET expressing cells were abundant in a cryptorchid model of SSC self-renewal. We used the whole-testis transplantation technique to overcome the limitation of neonatal lethality of Gdnf-, Gfra1-, and Ret-deficient mice and found that each of these genes is required for postnatal spermatogenesis and not for embryological testesdevelopment. Each mutant testis shows severe SSC depletion by Postnatal Day 7 during the first wave of spermatogenesis. These defects were due to lack of SSC proliferation and an inability of SSCs to maintain an undifferentiated state. Our results demonstrate that GDNF-mediated RET signaling is critical for the fate of undifferentiated spermatogonia and that abnormalities in this pathway may contribute to male infertility and testicular germ cell tumors.
developmental biology, sperm, spermatogenesis, sperm maturation, testis
1 Supported by NIH grants HD44766–02 (C.K.N.), HD047396–01 (S.J.), AG13730 and NS39358 (J.M.), and by a Faculty Scholarship of American College of Surgeons (C.K.N.).
2 Correspondence: Cathy K. Naughton, 660 South Euclid Avenue, Box 8118, St. Louis, MO 63110. FAX: 314 576 8880; naughtonc{at}msnotes.wustl.edu
3 These authors contributed equally to this work.
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