TY - JOUR
T1 - Foxo1 is required in mouse spermatogonial stem cells for their maintenance and the initiation of spermatogenesis
AU - Goertz, Meredith J.
AU - Wu, Zhuoru
AU - Gallardo, Teresa D.
AU - Hamra, F. Kent
AU - Castrillon, Diego H.
PY - 2011/9/1
Y1 - 2011/9/1
N2 - 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 selfrenewal and differentiation, with implications for common diseases, including male infertility and testicular cancer, due to abnormalities in SSC function.
AB - 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 selfrenewal and differentiation, with implications for common diseases, including male infertility and testicular cancer, due to abnormalities in SSC function.
UR - http://www.scopus.com/inward/record.url?scp=80052356550&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=80052356550&partnerID=8YFLogxK
U2 - 10.1172/JCI57984
DO - 10.1172/JCI57984
M3 - Article
C2 - 21865646
AN - SCOPUS:80052356550
SN - 0021-9738
VL - 121
SP - 3456
EP - 3466
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 9
ER -