Id4 Marks Spermatogonial Stem Cells in the Mouse Testis

Sun, Feng; Xu, Qing; Zhao, Danfeng; Chen, Charlie Degui

doi:10.1038/srep17594

Cited by 78 publications

(66 citation statements)

References 43 publications

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“…Our lineage tracing data indicate that NGN3-positive cells can give rise to Id4-GFP-positive cells after busulfan-induced cytotoxic stress, suggesting that normal SSCs are restored. These data are in good agreement with a recent study that demonstrated the recovery of ID4-positive cells after busulfan treatment but did not address the source of the new SSCs [17]. The possibility that transit-amplifying germ cells could undergo conditional reversion to SSC function was proposed previously and is consistent with our data [37,38].…”

Section: Discussionsupporting

confidence: 91%

DMRT1 Is Required for Mouse Spermatogonial Stem Cell Maintenance and Replenishment

et al. 2016

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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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Section: Discussionsupporting

confidence: 91%

DMRT1 Is Required for Mouse Spermatogonial Stem Cell Maintenance and Replenishment

et al. 2016

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“…These nuances have presented a barrier to progress in developing a deep understanding of the biology of SSCs and the molecular mechanisms underpinning their functions. Outcomes of previous studies (Oatley et al, 2011;Chan et al, 2014;Sun et al, 2015) and those presented here demonstrate that the stem cell pool of the male germline is contained within the ID4 + spermatogonial population. Two major approaches for assigning stem cell function to specific populations are lineage tracing and transplantation.…”

Section: Discussionsupporting

confidence: 62%

“…Two major approaches for assigning stem cell function to specific populations are lineage tracing and transplantation. Although several cell populations, such as those marked by GFRA1 (Ebata et al, 2005;Grisanti et al, 2009;Hara et al, 2014), PAX7 (Aloisio et al, 2014), BMI1 (Komai et al, 2014) or NEUROG3 (Nakagawa et al, 2010) expression, have been identified as containing at least some SSCs using one of the approaches, the ID4 expressing population is the only one reported to date to be enriched for SSCs using both lineage tracing and transplantation (Chan et al, 2014;Sun et al, 2015). Moreover, in the current study we demonstrate through limiting dilution transplantation analysis that the ID4-EGFP Bright population is mostly, if not purely, SSCs.…”

Section: Discussionmentioning

confidence: 99%

“…Outcomes of those experiments suggested that most, if not all, SSC activity resides in the ID4-EGFP + population (Chan et al, 2014). Furthermore, lineage-tracing studies confirmed that at least some ID4-expressing spermatogonia are SSCs in testes during steadystate conditions (Sun et al, 2015). Although the stem cell purity of the population has not been determined, these findings suggested that the levels of ID4 influence the stem cell-to-progenitor transition.…”

Section: Introductionmentioning

confidence: 99%

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ID4 levels dictate the stem cell state in mouse spermatogonia

et al. 2017

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Spermatogenesis is a classic model of cycling cell lineages that depend on a balance between stem cell self-renewal for continuity and the formation of progenitors as the initial step in the production of differentiated cells. The mechanisms that guide the continuum of spermatogonial stem cell (SSC) to progenitor spermatogonial transition and precise identifiers of subtypes in the process are undefined. Here we used an Id4-eGfp reporter mouse to discover that EGFP intensity is predictive of the subsets, with the ID4-EGFP Bright population being mostly, if not purely, SSCs, whereas the ID4-EGFP Dim population is in transition to the progenitor state. These subsets are also distinguishable by transcriptome signatures. Moreover, using a conditional overexpression mouse model, we found that transition from the stem cell to the immediate progenitor state requires downregulation of Id4 coincident with a major change in the transcriptome. Collectively, our results demonstrate that the level of ID4 is predictive of stem cell or progenitor capacity in spermatogonia and dictates the interface of transition between the different functional states.

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“…SSCs are definitively defined by their stem-like qualities (proliferation, self-renewal, expansion) using functional assays, such as in vivo transplantation, in vitro clonal proliferation, and in vitro cobblestone assays; it has proven difficult to determine SSCs precisely in vivo with a single molecular marker, because many of their phenotypic characteristics overlap with their progeny, the A-type undifferentiated spermatogonia (Ploemacher et al 1989, Brinster & Zimmermann 1994, Dobrinski et al 1999, Kubota & Brinster 2006, Kanatsu-Shinohara et al 2012). Classically, SSCs are characterized in many mammalian systems by the expression of a combination of markers, such as cadherin 1 (CDH1), glial cell line derived neurotrophic factor family receptor alpha 1 (GFRA1), inhibitor of differentiation 4 (ID4), integrins alpha 6 and beta 1, strong expression of zinc finger and BTB domain containing 16 (ZBTB16 HI ; also known as promyelocytic leukemia zinc finger (PLZF HI )), ret proto-oncogene (RET), and Thy1, and the lack of kit oncogene (KIT) and stimulated by retinoic acid 8 (STRA8) expression (Meng et al 2000, Giuili et al 2002, Kubota et al 2003, Naughton et al 2006, Kanatsu-Shinohara et al 2008, Tolkunova et al 2009, Sun et al 2015, Takashima et al 2015). …”

Section: Defining a Spermatogonial Stem Cellmentioning

confidence: 99%

Role of the testis interstitial compartment in spermatogonial stem cell function

Potter¹,

DeFalco²

2017

Reproduction

103

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Male fertility is maintained through intricate cellular and molecular interactions that ensure spermatogonial stem cells (SSCs) proceed in a step-wise differentiation process through spermatogenesis and spermiogenesis to produce sperm. SSCs lie within the seminiferous tubule compartment, which provides a nurturing environment for the development of sperm. Cells outside of the tubules, such as interstitial and peritubular cells, also help direct SSC activity. This review focuses on interstitial (interstitial macrophages, Leydig cells, and vasculature) and peritubular (peritubular macrophages, peritubular myoid cells) cells and their role in regulating SSC self-renewal and differentiation in mammals. Leydig cells, the major steroidogenic cells in the testis, influence SSCs through secreted factors, such as insulin growth factor 1 (IGF1) and colony stimulating factor 1 (CSF1). Macrophages interact with SSCs through various potential mechanisms, such as CSF1 and retinoic acid (RA), to induce proliferation or differentiation of SSCs, respectively. Vasculature influences SSC dynamics through CSF1, vascular endothelial growth factor (VEGF), and regulating oxygen levels. Lastly, peritubular myoid cells produce one of the most well-known factors that is required for SSC self-renewal, glial cell line derived neurotrophic factor (GDNF), as well as CSF1. Overall, SSC interactions with interstitial and peritubular cells are critical for SSC function and are an important underlying factor promoting male fertility.

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Id4 Marks Spermatogonial Stem Cells in the Mouse Testis

Cited by 78 publications

References 43 publications

DMRT1 Is Required for Mouse Spermatogonial Stem Cell Maintenance and Replenishment

DMRT1 Is Required for Mouse Spermatogonial Stem Cell Maintenance and Replenishment

ID4 levels dictate the stem cell state in mouse spermatogonia

Role of the testis interstitial compartment in spermatogonial stem cell function

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