title: Foxo1 is required in mouse spermatogonial stem cells for their maintenance and the initiation of spermatogenesis.
abstract: Spermatogonial stem cells (SSCs) capable of self-renewal and differentiation are the foundation for spermatogenesis. Although several factors important for these processes have been identified, the fundamental mechanisms regulating SSC self-renewal and differentiation remain unknown. Here, we investigated a role for the Foxo transcription factors in mouse spermatogenesis and found that Foxo1 specifically marks mouse gonocytes and a subset of spermatogonia with stem cell potential. Genetic analyses showed that Foxo1 was required for both SSC homeostasis and the initiation of spermatogenesis. Combined deficiency of Foxo1, Foxo3, and Foxo4 resulted in a severe impairment of SSC self-renewal and a complete block of differentiation, indicating that Foxo3 and Foxo4, although dispensable for male fertility, contribute to SSC function. By conditional inactivation of 3-phosphoinositide-dependent protein kinase 1 (Pdk1) and phosphatase and tensin homolog (Pten) in the male germ line, we found that PI3K signaling regulates Foxo1 stability and subcellular localization, revealing that the Foxos are pivotal effectors of PI3K-Akt signaling in SSCs. We also identified a network of Foxo gene targets--most notably Ret--that rationalized the maintenance of SSCs by the Foxos. These studies demonstrate that Foxo1 expression in the spermatogenic lineage is intimately associated with the stem cell state and revealed what we believe to be novel Foxo-dependent mechanisms underlying SSC self-renewal and differentiation, with implications for common diseases, including male infertility and testicular cancer, due to abnormalities in SSC function.
authors.affiliation: Department of Pathology, University of Texas Southwestern Medical Center, 6000 Harry Hines Boulevard, Dallas, Texas 75390-9072, USA.
authors.forename: Meredith J
authors.initials: MJ
authors.lastname: Goertz
authors.forename: Zhuoru
authors.initials: Z
authors.lastname: Wu
authors.forename: Teresa D
authors.initials: TD
authors.lastname: Gallardo
authors.forename: F Kent
authors.initials: FK
authors.lastname: Hamra
authors.forename: Diego H
authors.initials: DH
authors.lastname: Castrillon
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins; D002454:Cell Differentiation / Q000502:physiology; D005260:Female; D000071161:Forkhead Box Protein O1; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D007248:Infertility, Male / Q000503:physiopathology; D008297:Male; D051379:Mice; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics / Q000378:metabolism; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D015398:Signal Transduction / Q000502:physiology; D013091:Spermatogenesis / Q000502:physiology*; D013093:Spermatogonia / Q000166:cytology* / Q000502:physiology; D013234:Stem Cells / Q000166:cytology / Q000502:physiology*; D013737:Testis / Q000166:cytology
chemical_list: D018797:Cell Cycle Proteins; D000071161:Forkhead Box Protein O1; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D051096:Proto-Oncogene Proteins c-ret; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; C474033:FoxO3 protein, mouse; C525394:FoxO4 protein, mouse; C467200:Foxo1 protein, mouse; C000631433:Pdk1 protein, mouse; C494999:Ret protein, mouse; C487757:Pten protein, mouse