Mouse Germ Line Stem Cells Undergo Rapid and Stochastic Turnover

Klein, Allon M.; Nakagawa, Takako; Ichikawa, Rie; Yoshida, Shosei; Simons, Benjamin D.

doi:10.1016/j.stem.2010.05.017

Cited by 215 publications

(225 citation statements)

References 21 publications

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“…4C). These data are consistent with previous studies that showing that SSCs follow a neutral competition model (6,31,33,34), although additional, detailed analyses are needed to validate this model further.…”

Section: Discussionsupporting

confidence: 91%

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Paracrine Wnt/β-catenin signaling mediates proliferation of undifferentiated spermatogonia in the adult mouse testis

Takase

Nusse

2016

Proc. Natl. Acad. Sci. U.S.A.

120

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Spermatogonial stem cells (SSCs) fuel the production of male germ cells but the mechanisms behind SSC self-renewal, proliferation, and differentiation are still poorly understood. Using the Wnt target gene Axin2 and genetic lineage-tracing experiments, we found that undifferentiated spermatogonia, comprising SSCs and transit amplifying progenitor cells, respond to Wnt/β-catenin signals. Genetic elimination of β-catenin indicates that Wnt/β-catenin signaling promotes the proliferation of these cells. Signaling is likely initiated by Wnt6, which is uniquely expressed by neighboring Sertoli cells, the only somatic cells in the seminiferous tubule that support germ cells and act as a niche for SSCs. Therefore, unlike other stem cell systems where Wnt/β-catenin signaling is implicated in self-renewal, the Wnt pathway in the testis specifically contributes to the proliferation of SSCs and progenitor cells.

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Section: Discussionsupporting

confidence: 91%

“…4C). These results are consistent with a neutral competition model in which tissue stem cells are routinely lost and replaced in a stochastic manner, as previously demonstrated by the use of specific Cre lines of GFRα1, Ngn3, and Bmi1 in the testis (6,31,33,34).…”

Section: Multiple Gfrα1supporting

confidence: 90%

Paracrine Wnt/β-catenin signaling mediates proliferation of undifferentiated spermatogonia in the adult mouse testis

Takase

Nusse

2016

Proc. Natl. Acad. Sci. U.S.A.

120

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“…4 and Table S5), consistent with their relative in vitro transforming potential (23,24). Of note, s may encompass a number of biological processes other than the balance between symmetric and asymmetric division, including differential survival of cells undergoing stochastic divisions (42) and cell competition (43). In this context, survival simply implies the production of mature sperm, so this could be impaired by several pathologies such as spermatogenic arrest, senescence, or apoptosis (44).…”

Section: Discussionmentioning

confidence: 81%

Contributions of intrinsic mutation rate and selfish selection to levels of de novo HRAS mutations in the paternal germline

Giannoulatou

McVean

Taylor

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

114

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The RAS proto-oncogene Harvey rat sarcoma viral oncogene homolog (HRAS) encodes a small GTPase that transduces signals from cell surface receptors to intracellular effectors to control cellular behavior. Although somatic HRAS mutations have been described in many cancers, germline mutations cause Costello syndrome (CS), a congenital disorder associated with predisposition to malignancy. Based on the epidemiology of CS and the occurrence of HRAS mutations in spermatocytic seminoma, we proposed that activating HRAS mutations become enriched in sperm through a process akin to tumorigenesis, termed selfish spermatogonial selection. To test this hypothesis, we quantified the levels, in blood and sperm samples, of HRAS mutations at the p.G12 codon and compared the results to changes at the p.A11 codon, at which activating mutations do not occur. The data strongly support the role of selection in determining HRAS mutation levels in sperm, and hence the occurrence of CS, but we also found differences from the mutation pattern in tumorigenesis. First, the relative prevalence of mutations in sperm correlates weakly with their in vitro activating properties and occurrence in cancers. Second, specific tandem base substitutions (predominantly GC>TT/AA) occur in sperm but not in cancers; genomewide analysis showed that this same mutation is also overrepresented in constitutional pathogenic and polymorphic variants, suggesting a heightened vulnerability to these mutations in the germline. We developed a statistical model to show how both intrinsic mutation rate and selfish selection contribute to the mutational burden borne by the paternal germline.paternal age effect | male mutation bias | RASopathy | testis

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“…This stochastic evolution model eventually results in a clonally identical stem cell pool within one niche. A similar stochastic model applies to germ-line stem cell maintenance in the mouse male germ line (Klein et al 2010). …”

Section: Discussionmentioning

confidence: 99%

Novel Tools for Genetic Manipulation of Follicle Stem Cells in the Drosophila Ovary Reveal an Integrin-Dependent Transition from Quiescence to Proliferation

et al. 2015

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In many tissues, the presence of stem cells is inferred by the capacity of the tissue to maintain homeostasis and undergo repair after injury. Isolation of self-renewing cells with the ability to generate the full array of cells within a given tissue strongly supports this idea, but the identification and genetic manipulation of individual stem cells within their niche remain a challenge. Here we present novel methods for marking and genetically altering epithelial follicle stem cells (FSCs) within the Drosophila ovary. Using these new tools, we define a sequential multistep process that comprises transitioning of FSCs from quiescence to proliferation. We further demonstrate that integrins are cell-autonomously required within FSCs to provide directional signals that are necessary at each step of this process. These methods may be used to define precise roles for specific genes in the sequential events that occur during FSC division after a period of quiescence.

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Mouse Germ Line Stem Cells Undergo Rapid and Stochastic Turnover

Cited by 215 publications

References 21 publications

Paracrine Wnt/β-catenin signaling mediates proliferation of undifferentiated spermatogonia in the adult mouse testis

Paracrine Wnt/β-catenin signaling mediates proliferation of undifferentiated spermatogonia in the adult mouse testis

Contributions of intrinsic mutation rate and selfish selection to levels of de novo HRAS mutations in the paternal germline

Novel Tools for Genetic Manipulation of Follicle Stem Cells in the Drosophila Ovary Reveal an Integrin-Dependent Transition from Quiescence to Proliferation

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