The Homeobox Transcription Factor RHOX10 Drives Mouse Spermatogonial Stem Cell Establishment

Song, H. C.; Bettegowda, Anilkumar; Lake, Blue B.; Zhao, Adrienne H.; Skarbrevik, David; Babajanian, Eric; Sukhwani, Meena; Shum, Eleen Y.; Phan, Mimi H.; Plank, Terra-Dawn M.; Richardson, Marcy E.; Ramaiah, Madhuvanthi; Sridhar, V.; Rooij, Dirk G. de; Orwig, Kyle E.; Zhang, Kun; Wilkinson, Miles

doi:10.1016/j.celrep.2016.08.090

Cited by 53 publications

(62 citation statements)

References 56 publications

(107 reference statements)

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“…Thus the arrested mutant cells are similar to embryonic proSGs (McCarrey, 2013). This phenotype is similar in some respects to that of Rhox10 mutants, which also have defects in early postnatal germ cell migration and establishment of SSCs (Song et al, 2016). However the perinatal arrest phenotype is more severe in Dmrt1 mutants, suggesting either that Rhox10 acts downstream of Dmrt1 or that the two genes act at least partially in parallel.…”

Section: Dmrt1 and Male Germ Cell Developmentsupporting

confidence: 55%

DMRT proteins and coordination of mammalian spermatogenesis

Zhang

Zarkower

2017

Stem Cell Research

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DMRT genes encode a deeply conserved family of transcription factors that share a unique DNA binding motif, the DM domain. DMRTs regulate development in a broad variety of metazoans and they appear to have controlled sexual differentiation for hundreds of millions of years. In mice, starting during embryonic development, three Dmrt genes act sequentially to help establish and maintain spermatogenesis. Dmrt1 has notably diverse functions that include repressing pluripotency genes and promoting mitotic arrest in embryonic germ cells, reactivating prospermatogonia perinatally, establishing and maintaining spermatogonial stem cells (SSCs), promoting spermatogonial differentiation, and controlling the mitosis/meiosis switch. Dmrt6 acts in differentiating spermatogonia to coordinate an orderly exit from the mitotic/spermatogonial program and allow proper timing of entry to the meiotic/spermatocyte program. Finally, Dmrt7 takes over during the first meiotic prophase to help choreograph a transition in histone modifications that maintains transcriptional silencing of the sex chromosomes. The combined action of these three Dmrt genes helps ensure robust and sustainable spermatogenesis.

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Section: Dmrt1 and Male Germ Cell Developmentsupporting

confidence: 55%

DMRT proteins and coordination of mammalian spermatogenesis

Zhang

Zarkower

2017

Stem Cell Research

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“…Surprisingly, the abundance of these mRNAs was not altered by either overexpression or down‐regulation of miR‐100 (Figure S1, Supporting Information). Conversely, expression of genes that were previously suggested to regulate SSC proliferation—such as Plzf (Promyelocytic leukemia zinc finger protein, or Zinc finger and BTB domain‐containing 16) (Costoya et al, ), Stat3 (Oatley, Kaucher, Avarbock, & Brinster, ), Gfra1 (GDNF receptor alpha 1) (Grasso et al, ), Setdb1 (SET domain bifurcated 1) (An et al, ), Fbxw7 (F‐box and WD repeat domain‐containing 7) (Kanatsu‐Shinohara, Onoyama, Nakayama, & Shinohara, ), Kdm1a (Lysine demethylase 1a) (Lambrot, Lafleur, & Kimmins, ), and Rhox10 (Rhox homeobox 10) (Song et al, )—was different among miR‐100 inhibitor‐, miR‐100 mimic‐, and untreated control SSCs. In particular, Stat3 abundance was negatively regulated by miR‐100 (Figure ).…”

Section: Resultsmentioning

confidence: 99%

“…Rhox homeobox 10)(Song et al, 2016)-was different among miR-100 inhibitor-, miR-100 mimic-, and untreated control SSCs. In particular,Stat3 abundance was negatively regulated by miR-100 (Figure 5).Indeed, STAT3 protein was significantly decreased in mouse SSCs transfected with miR-100 mimic compared to cells receiving the negative-control mimic, whereas STAT3 protein was significantly increased in SSCs with miR-100 inhibitor compared to the negative-control cells.…”

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confidence: 89%

miR‐100 promotes the proliferation of spermatogonial stem cells via regulating Stat3

Huang

et al. 2017

Molecular Reproduction Devel

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Micro RNAs play important roles during mammalian spermatogenesis, but the function(s) of specific miRNAs remain largely unknown. Here, we report that miR-100 is predominantly expressed in undifferentiated murine spermatogonia, including spermatogonial stem cells (SSCs). We utilized a miRNA mimic and inhibitor to knock down and overexpress miR-100 in cultured SSCs, respectively, finding that the miR-100 promotes the proliferation of SSCs in vitro. Furthermore, signals promoting SSC maintenance induced, whereas retinoic acid repressed, expression of miR-100. Stat3 expression was modulated by miR-100, with increased transcript and protein abundance in the presence of the miR-100 inhibitor versus reduced protein levels following miR-100 overexpression. Stat3 silencing also mimicked the reduced SSC proliferation phenotype associated with elevated miR-100 levels. Importantly, Stat3 silencing rescued the anti-proliferation capacity of miR-100 inhibitor on cultured SSCs. Given that the Stat3 3' untranslated region was not repressed by pre-miR-100 in a standard luciferase reporter assay, we suggest that miR-100 promotes SSC proliferation by indirect regulation of Stat3.

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“…For the first step, we tried to collect scRNA-seq data sets for mSSCs and mMSCs, which were generated by different research groups, from the GEO database. In this study, scRNA-seq data sets with accession number GSE82174, which was contained transcriptome data for twelve SSCs (WTpA1-WTpA12) from 7 days postnatal C57BL/6J mouse (Song et al, 2016), and GSE70930, which was contained transcriptome data from 16 mice (C57BL/6J) BM-derived MSCs (mMSC1-mMSC16) (Freeman, Jung, & Ogle, 2015) were used. To investigate the gene expression program in mSSCs in comparing with mMSCs, the transcriptome data for all cells were integrated as a count table and submitted to automated single-cell analysis pipeline (ASAP) as a webbased tool (Gardeux, David, Shajkofci, Schwalie, & Deplancke, 2017).…”

Section: Scrna-seq Data Set Preparation For Analysismentioning

confidence: 99%

Comparative analysis of single‐cell RNA sequencing data from mouse spermatogonial and mesenchymal stem cells to identify differentially expressed genes and transcriptional regulators of germline cells

Sisakhtnezhad

Heshmati

2018

Journal Cellular Physiology

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Identifying effective internal factors for regulating germline commitment during development and for maintaining spermatogonial stem cells (SSCs) self-renewal is important to understand the molecular basis of spermatogenesis process, and to develop new protocols for the production of the germline cells from other cell sources. Therefore, this study was designed to investigate single-cell RNA-sequencing data for identification of differentially expressed genes (DEGs) in 12 mouse-derived single SSCs (mSSCs) in compare with 16 mouse-derived single mesenchymal stem cells. We also aimed to find transcriptional regulators of DEGs. Collectively, 1,584 up-regulated DEGs were identified that are associated with 32 biological processes. Moreover, investigation of the expression profiles of genes including in spermatogenesis process revealed that Dazl, Ddx4, Sall4, Fkbp6, Tex15, Tex19.1, Rnf17, Piwil2, Taf7l, Zbtb16, and Cadm1 are presented in the first 30 up-regulated DEGs. We also found 12 basal transcription factors (TFs) and three sequence-specific TFs that control the expression of DEGs. Our findings also indicated that MEIS1, SMC3, TAF1, KAT2A, STAT3, GTF3C2, SIN3A, BDP1, PHC1, and EGR1 are the main central regulators of DEGs in mSSCs. In addition, we collectively detected two significant protein complexes in the protein-protein interactions network for DEGs regulators. Finally, this study introduces the major upstream kinases for the main central regulators of DEGs and the components of core protein complexes. In conclusion, this study provides a molecular blueprint to uncover the molecular mechanisms behind the biology of SSCs and offers a list of candidate factors for cell type conversion approaches and production of germ cells.

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The Homeobox Transcription Factor RHOX10 Drives Mouse Spermatogonial Stem Cell Establishment

Cited by 53 publications

References 56 publications

DMRT proteins and coordination of mammalian spermatogenesis

DMRT proteins and coordination of mammalian spermatogenesis

miR‐100 promotes the proliferation of spermatogonial stem cells via regulating Stat3

Comparative analysis of single‐cell RNA sequencing data from mouse spermatogonial and mesenchymal stem cells to identify differentially expressed genes and transcriptional regulators of germline cells

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