Foxo1 is a Marker of Spermatogonial Stem Cells Required for their Maintenance and the Initiation of Spermatogenesis in Mice
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE31282 | GEO | 2011/08/10
SECONDARY ACCESSION(S): PRJNA145857
REPOSITORIES: GEO
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Project description:Foxo factors in spermatogonial stem cells Total RNA obtained from postnatal day 4 (pd4) Foxo1 null and wild-type testes.
2011-08-09 | E-GEOD-31282 | biostudies-arrayexpress
Project description: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.
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Project description:Maintenance and self-renewal of the spermatogonial stem cell (SSC) population is the cornerstone of male fertility. In this manuscript we have identified a key role for the nucleosome remodelling protein Chromodomain Helicase DNA binding protein 4 (CHD4) in regulating SSC function. Gene expression analyses revealed that CHD4 expression is largely restricted to spermatogonia in the mouse testis, and is particularly enriched in SSCs. Using spermatogonial transplantation techniques and RNAi mediated knockdown it was established that loss of Chd4 expression significantly impairs SSC regenerative capacity, resulting in a ~50% reduction in colonisation of recipient testes. A single cell RNA-seq comparison depicted reduced expression of ‘self-renewal’ genes such as Gfra1 and Pten following Chd4 knockdown, along with increased expression of signature progenitor genes, Neurog3 and Dazl. Co-immunoprecipitation analyses demonstrated that CHD4 regulates gene expression in spermatogonia not only though its traditional association with the remodelling complex NuRD, but also via interaction with the GDNF-responsive transcription factor SALL4. Cumulatively, the results of this study depict a previously unappreciated fundamental role for CHD4 in controlling fate decisions in the spermatogonial pool.
2021-06-17 | PXD022066 | Pride
Project description:Male mammals produce sperm for most of postnatal life and therefore require a robust germ line stem cell system, with precise balance between self-renewal and differentiation. Prior work established doublesex- and mab-3-related transcription factor 1 (Dmrt1) as a conserved transcriptional regulator of male sexual differentiation. Here we investigate the role of Dmrt1 in mouse spermatogonial stem cell (SSC) homeostasis. We find that Dmrt1 maintains SSCs during steady state spermatogenesis, where it regulates expression of Plzf, another transcription factor required for SSC maintenance. We also find that Dmrt1 is required for recovery of spermatogenesis after germ cell depletion. Committed progenitor cells expressing Ngn3 normally do not contribute to SSCs marked by the Id4-Gfp transgene, but do so when spermatogonia are chemically depleted using busulfan. Removal of Dmrt1 from Ngn3-positive germ cells blocks the replenishment of Id4-GFP-positive SSCs and recovery of spermatogenesis after busulfan treatment. Our data therefore reveal that Dmrt1 supports SSC maintenance in two ways: allowing SSCs to remain in the stem cell pool under normal conditions; and enabling progenitor cells to help restore the stem cell pool after germ cell depletion.
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Project description:In vitro and in vivo aging of mouse spermatogonial stem cells alters stem cell function based on quantitative spermatogonial stem cell transplantation analyses. We used microarrays to identify differential gene expression in vitro and in vivo aged spermatogonial stem cells to identify potential causes of observed phenotypic differences in aged spermatogonial stem cell function. Spermatogonial stem cells were isolated from young and serial-transplanted aged mouse donors and cultured for short and long periods. Spermatogonial stem cells were isolated from cultures and subjected to microarray analysis to identify differential gene expression.
2011-02-04 | E-GEOD-27043 | biostudies-arrayexpress
Project description:To understand the role of the nucleosome remodelling protein CHD4 in regulating spermatogonial stem cell function, we performed single cell RNA-sequencing on undifferentiated spermatogonia from primary culture that had been transfected with either control (non-targeting) siRNA or Chd4 siRNA. Transcriptome profiling revealed reduced expression of ‘self-renewal’ genes following Chd4 knockdown, along with increased expression of signature progenitor genes. Overall, CHD4 was demonstrated to primarily act as an activator of gene expression in SSCs. In pairing these data with additional analyses, including use of an Id4-eGfp transgenic mouse line, spermatogonial transplantation, and co-immunoprecipitation experiments: the findings of our study demonstrated a previously unappreciated and fundamental role for CHD4 in controlling fate decisions in the spermatogonial pool.
2021-05-06 | GSE163027 | GEO
Project description:Recycling and de-novo deposition of histones during DNA replication is a critical challenge faced by eukaryotic cells and is coordinated by histone chaperones. Spermatogenesis is highly regulated sophisticated process necessitating not only histone modification but loading of testis specific histone variants. Here, we show that Germ Cell Nuclear Acidic protein (GCNA), a germ cell specific protein in adult mice, can bind histones and purified GCNA exhibits histone chaperone activity. GCNA associates with the DNA replication machinery and supports progression through S-phase in murine undifferentiated spermatogonia (USGs). Whilst GCNA is dispensable for embryonic germ cell development, it is required for the maintenance of the USG pool and for long-term production of sperm. Our work describes the role of a germ cell specific histone chaperone in USGs maintenance in mice. These findings provide a mechanistic basis for the male infertility observed in patients carrying GCNA mutations.
| S-EPMC10250205 | biostudies-literature
Project description:A bioenergetic balance between glycolysis and mitochondrial respiration is particularly important for stem cell fate specification. It however remains to be determined whether undifferentiated spermatogonia switch their preference of bioenergy production during differentiation. In this study, we found that ATP generation in spermatogonia was gradually increased upon retinoic acid-induced differentiation. To accommodate this elevated energy demand, retinoic acid signaling concomitantly switched ATP production in spermatogonia from glycolysis to mitochondrial respiration, accompanied by increased levels of reactive oxygen species. In addition, inhibition of glucose conversion to glucose-6-phosphate or pentose phosphate pathway blocked the formation of c-Kit+ differentiating germ cells, suggesting that metabolites produced from glycolysis are required for spermatogonial differentiation. We further demonstrated that the expression levels of several metabolic regulators and enzymes were significantly altered upon retinoic acid-induced differentiation by both RNA-seq analyses and quantitative proteomics. Taken together, our data unveil a critically regulated bioenergetic balance between glycolysis and mitochondrial respiration which is required for spermatogonial proliferation and differentiation.
2021-09-09 | PXD019136 | Pride
Project description:Continual spermatogenesis relies on the activities of a tissue-specific stem cell population referred to as spermatogonial stem cells (SSCs). Fate decisions of stem cells are influenced by their niche environments, a major component of which is soluble factors secreted by support cells. At present, the factors that constitute the SSC niche are undefined. We explored the role of chemokine (C-X-C motif) ligand 12 (CXCL12) signaling via its receptor C-X-C chemokine receptor type 4 (CXCR4) in regulation of mouse SSC fate decisions. Immunofluorescent staining for CXCL12 protein in cross sections of testes from both pup and adult mice revealed its localization at the basement membrane of seminiferous tubules. Within the undifferentiated spermatogonial population of mouse testes, a fraction of cells were found to express CXCR4 and possess stem cell capacity. Inhibition of CXCR4 signaling in primary cultures of mouse undifferentiated spermatogonia resulted in SSC loss, in part by reducing proliferation and increasing the transition to a progenitor state primed for differentiation upon stimulation by retinoic acid. In addition, CXCL12-CXCR4 signaling in mouse SSCs was found to be important for colonization of recipient testes following transplantation, possibly by influencing homing to establish stem-cell niches. Furthermore, inhibition of CXCR4 signaling in testes of adult mice impaired SSC maintenance, leading to loss of the germline. Collectively, these findings indicate that CXCL12 is an important component of the growth factor milieu of stem cells in mammalian testes and that it signals via the CXCR4 to regulate maintenance of the SSC pool.
| S-EPMC4074255 | biostudies-literature
Project description:In vitro and in vivo aging of mouse spermatogonial stem cells alters stem cell function based on quantitative spermatogonial stem cell transplantation analyses. We used microarrays to identify differential gene expression in vitro and in vivo aged spermatogonial stem cells to identify potential causes of observed phenotypic differences in aged spermatogonial stem cell function.
2011-02-04 | GSE27043 | GEO