Foxo1 is required in mouse spermatogonial stem cells for their maintenance and the initiation of spermatogenesis

Meredith J. Goertz, Zhuoru Wu, Teresa D. Gallardo, F. Kent Hamra, Diego H. Castrillon

Research output: Contribution to journalArticle

129 Citations (Scopus)

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 selfrenewal and differentiation, with implications for common diseases, including male infertility and testicular cancer, due to abnormalities in SSC function.

Original languageEnglish (US)
Pages (from-to)3456-3466
Number of pages11
JournalJournal of Clinical Investigation
Volume121
Issue number9
DOIs
StatePublished - Sep 1 2011

Fingerprint

Spermatogenesis
Stem Cells
Maintenance
Phosphatidylinositol 3-Kinases
3-Phosphoinositide-Dependent Protein Kinases
Spermatogonia
Gene Regulatory Networks
Phosphoprotein Phosphatases
Male Infertility
Testicular Neoplasms
Germ Cells
Fertility
Cell Differentiation
Homeostasis
Transcription Factors
Cell Self Renewal

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Foxo1 is required in mouse spermatogonial stem cells for their maintenance and the initiation of spermatogenesis. / Goertz, Meredith J.; Wu, Zhuoru; Gallardo, Teresa D.; Hamra, F. Kent; Castrillon, Diego H.

In: Journal of Clinical Investigation, Vol. 121, No. 9, 01.09.2011, p. 3456-3466.

Research output: Contribution to journalArticle

@article{baa55c488d1a4d6486bcbcdc07bb696b,
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 selfrenewal and differentiation, with implications for common diseases, including male infertility and testicular cancer, due to abnormalities in SSC function.",
author = "Goertz, {Meredith J.} and Zhuoru Wu and Gallardo, {Teresa D.} and Hamra, {F. Kent} and Castrillon, {Diego H.}",
year = "2011",
month = "9",
day = "1",
doi = "10.1172/JCI57984",
language = "English (US)",
volume = "121",
pages = "3456--3466",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "9",

}

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

VL - 121

SP - 3456

EP - 3466

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

SN - 0021-9738

IS - 9

ER -