GDNF‐mediated signaling via RET tyrosine 1062 is essential for maintenance of spermatogonial stem cells

Jijiwa, Mayumi; Kawai, Kumi; Fukihara, Jun; Nakamura, Akinori; Hasegawa, Masaki; Suzuki, Chikage; Sato, Tomoko; Enomoto, Atsushi; Asai, Naoya; Murakumo, Yoshiki; Takahashi, Masahide

doi:10.1111/j.1365-2443.2008.01171.x

Cited by 75 publications

(52 citation statements)

References 36 publications

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“…Ret also acts through these pathways to promote SSC survival and proliferation (2,38). Ret inactivation results in severe defects in SSC proliferation and differentiation by P7, eventually leading to SSC depletion (8,41). The similarity of the Ret and Foxo phenotypes and these previous studies together strongly argue that Ret downregulation accounts for the observed Foxo phenotypes in SSC maintenance.…”

Section: Discussionmentioning

confidence: 47%

“…These findings strongly argue that the PI3K pathway regulates Ret expression in SSCs and, furthermore, that this regulation occurs via the Foxos. Given the requirement for Ret in SSC maintenance (Ret loss-of-function mutations result in germ cell depletion in mice), the control of Ret by the PI3K pathway via Foxo1 rationalizes the SSC self-renewal phenotype observed in our Foxo mutants (41).…”

Section: Essential Role Of Foxo1 In Ssc Self-renewal and Differentiatmentioning

confidence: 99%

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

Goertz¹,

Wu²,

Gallardo³

et al. 2011

J. Clin. Invest.

251

245

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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.

show abstract

Section: Discussionmentioning

confidence: 47%

Section: Essential Role Of Foxo1 In Ssc Self-renewal and Differentiatmentioning

confidence: 99%

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

Goertz¹,

Wu²,

Gallardo³

et al. 2011

J. Clin. Invest.

251

245

View full text Add to dashboard Cite

show abstract

“…Our group and others have demonstrated that glial cellderived neurotrophic factor (GDNF) is the most essential factor for SSC self-renewal and maintenance in rodents [12][13][14][15][16][17][18] and that GDNF signals via binding to its membrane receptor complex containing GFRA1 and RET, both expressed by the spermatogonial stem/progenitor cells [19][20][21][22]. Recent studies have suggested that GDNF signals via multiple pathways to promote the proliferation and self-renewal of SSCs [23][24][25][26][27]. Specifically, we have shown that GDNF acts through the RAS/ MAPK1/2 pathway, stimulating the phosphorylation of RET tyrosine kinase and finally inducing the transcription of the immediate early gene Fos as well as cyclin A and CDK2 protein expression.…”

Section: Introductionmentioning

confidence: 99%

The Molecular Signature of Spermatogonial Stem/Progenitor Cells in the 6-Day-Old Mouse Testis1

Kokkinaki

Lee

et al. 2009

Biology of Reproduction

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To characterize the molecular phenotype of spermatogonial stem cells (SSCs), we examined genes that are differentially expressed in the stem/progenitor spermatogonia compared to nonstem spermatogonia. We isolated type A spermatogonia (stem and nonstem type A) from 6-day-old mice using sedimentation velocity at unit gravity and further selected the stem/progenitor cell subpopulation by magnetic activated cell sorting with an antibody to GDNF-receptor-alpha-1 (GFRA1). It has been previously shown that GFRA1 is expressed in SSCs and is required for their stemness. The purity of the isolated cells was approximately 95% to 99% as indicated by immunocytochemistry using anti-GFRA1. Comparison of GFRA1-positive and GFRA1-negative spermatogonia by microarray analysis revealed 99 known genes and 12 uncharacterized transcripts that are overexpressed in the former cell population with a >2-fold change. Interestingly, the highest level of overexpression was observed for Csf1r, encoding the receptor for macrophage colony-stimulating factor (M-CSF, official symbol CSF1), which has a well-established role in the regulation of myeloid progenitor cells. Analysis of our microarray data with a bioinformatics software program (Ingenuity Systems) revealed the potential role of various signaling pathways in stem/progenitor spermatogonia and suggested a common pathway for GFRA1 and CSF1R that may lead to their proliferation. Further investigation to test this hypothesis has shown that CSF1 promotes cell proliferation in primary cultures of the isolated type A spermatogonia and in the spermatogonial-derived stem cell line C18-4. Semiquantitative RT-PCR and immunohistochemistry confirmed the previously mentioned microarray data. Collectively, this study provides novel molecular signatures for stem/progenitor spermatogonia and demonstrates a role for CSF1/CSF1R signaling in regulating their proliferation.

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“…3). Studies in RET Y1062F knockin mice suggest that GDNF-RET signaling is essential for the self-renewal of SSCs via tyrosine 1062 (Jijiwa et al 2008).…”

Section: Gdnf Signalingmentioning

confidence: 99%

Regulation of spermatogonial stem cell self-renewal and spermatocyte meiosis by Sertoli cell signaling

Chen¹,

Liu²

2015

Reproduction

239

166

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Spermatogenesis is a continuous and productive process supported by the self-renewal and differentiation of spermatogonial stem cells (SSCs), which arise from undifferentiated precursors known as gonocytes and are strictly controlled in a special 'niche' microenvironment in the seminiferous tubules. Sertoli cells, the only somatic cell type in the tubules, directly interact with SSCs to control their proliferation and differentiation through the secretion of specific factors. Spermatocyte meiosis is another key step of spermatogenesis, which is regulated by Sertoli cells on the luminal side of the blood-testis barrier through paracrine signaling. In this review, we mainly focus on the role of Sertoli cells in the regulation of SSC self-renewal and spermatocyte meiosis, with particular emphasis on paracrine and endocrine-mediated signaling pathways. Sertoli cell growth factors, such as glial cell line-derived neurotrophic factor (GDNF) and fibroblast growth factor 2 (FGF2), as well as Sertoli cell transcription factors, such as ETS variant 5 (ERM; also known as ETV5), nociceptin, neuregulin 1 (NRG1), and androgen receptor (AR), have been identified as the most important upstream factors that regulate SSC self-renewal and spermatocyte meiosis. Other transcription factors and signaling pathways (GDNF-RET-GFRA1 signaling, FGF2-MAP2K1 signaling, CXCL12-CXCR4 signaling, CCL9-CCR1 signaling, FSH-nociceptin/OPRL1, retinoic acid/FSH-NRG/ERBB4, and AR/RB-ARID4A/ARID4B) are also addressed.Reproduction (2015) 149 R159-R167

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GDNF‐mediated signaling via RET tyrosine 1062 is essential for maintenance of spermatogonial stem cells

Cited by 75 publications

References 36 publications

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

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

The Molecular Signature of Spermatogonial Stem/Progenitor Cells in the 6-Day-Old Mouse Testis1

Regulation of spermatogonial stem cell self-renewal and spermatocyte meiosis by Sertoli cell signaling

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