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Foxo1 is required in mouse spermatogonial stem cells for their maintenance and the initiation of spermatogenesis
Meredith J. Goertz, … , F. Kent Hamra, Diego H. Castrillon
Meredith J. Goertz, … , F. Kent Hamra, Diego H. Castrillon
Published August 25, 2011
Citation Information: J Clin Invest. 2011;121(9):3456-3466. https://doi.org/10.1172/JCI57984.
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Research Article Reproductive biology

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

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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

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

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Figure 3

Foxo1 is specifically expressed in gonocytes and undifferentiated spermatogonia and regulates Kit.

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Foxo1 is specifically expressed in gonocytes and undifferentiated sperma...
(A) Kit and Foxo1 immunostains at time points and genotypes as shown. P7 Foxo1 testis serves as negative control for Foxo1 immunostaining. Larger boxes contain high-magnification views of the smaller boxes. The Kit inset shows Kit expression in Leydig cells as internal positive control. Other insets illustrate subcellular distributions of Foxo1 and Kit. Scale bar: 20 μm. (B) Subcellular distribution of Foxo1 in spermatogonia. C, cytoplasmic; N, nuclear. (C) Developmental profile of Kit mRNA levels in mouse testis by microarray (arbitrary units on y axis).

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