The proto-oncogene Ret is required for male foetal germ cell survival

Miles, Denise C.; Bergen, Jocelyn A. van den; Wakeling, Stephanie; Anderson, Richard B.; Sinclair, Andrew H.; Western, Patrick

doi:10.1016/j.ydbio.2012.02.014

Cited by 20 publications

(15 citation statements)

References 41 publications

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“…These affected and unaffected germ cells are presumably exposed to similar environments, indicating that they have qualitatively different responses to the treatment. Although perplexing, this stochastic response in germ cells is not unusual, as we have made similar observations in fetal germ cells of Ret null mice (in which all germ cells lack Ret) and in an epigenetic model that we are currently analyzing [63]. Such variation in germ cell development may prove informative by providing important clues to the mechanisms underlying failed germ cell development and formation of germ cell tumours.…”

Section: Discussionsupporting

confidence: 58%

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Signaling through the TGF Beta-Activin Receptors ALK4/5/7 Regulates Testis Formation and Male Germ Cell Development

et al. 2013

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The developing testis provides an environment that nurtures germ cell development, ultimately ensuring spermatogenesis and fertility. Impacts on this environment are considered to underlie aberrant germ cell development and formation of germ cell tumour precursors. The signaling events involved in testis formation and male fetal germ cell development remain largely unknown. Analysis of knockout mice lacking single Tgfβ family members has indicated that Tgfβ's are not required for sex determination. However, due to functional redundancy, it is possible that additional functions for these ligands in gonad development remain to be discovered. Using FACS purified gonadal cells, in this study we show that the genes encoding Activin's, TGFβ's, Nodal and their respective receptors, are expressed in sex and cell type specific patterns suggesting particular roles in testis and germ cell development. Inhibition of signaling through the receptors ALK4, ALK5 and ALK7, and ALK5 alone, demonstrated that TGFβ signaling is required for testis cord formation during the critical testis-determining period. We also show that signaling through the Activin/NODAL receptors, ALK4 and ALK7 is required for promoting differentiation of male germ cells and their entry into mitotic arrest. Finally, our data demonstrate that Nodal is specifically expressed in male germ cells and expression of the key pluripotency gene, Nanog was significantly reduced when signaling through ALK4/5/7 was blocked. Our strategy of inhibiting multiple Activin/NODAL/TGFβ receptors reduces the functional redundancy between these signaling pathways, thereby revealing new and essential roles for TGFβ and Activin signaling during testis formation and male germ cell development.

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Section: Discussionsupporting

confidence: 58%

“…Staining with each marker was repeated as a minimum in biological triplicate. TUNEL staining was performed as described in Miles et al 2012 [63].…”

Section: Methodsmentioning

confidence: 99%

Signaling through the TGF Beta-Activin Receptors ALK4/5/7 Regulates Testis Formation and Male Germ Cell Development

et al. 2013

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“…RET and GFRA1 are co-receptors for GDNF, which is required postnatally for spermatogonial stem cell self-renewal (Hofmann, 2008; Jain et al, 2004; Naughton et al, 2006). In addition, loss of Ret , but not Gdnf , compromises germ cell survival in the fetal testis (Miles et al, 2012). At E15.5 expression profiling detected misregulation of both Ret (down 2.3-fold in B6 and 2.6-fold in 129Sv) and Gdnf (down 1.8-fold in B6 and 2.4-fold in 129Sv Dmrt1 mutants).…”

Section: Resultsmentioning

confidence: 99%

Interaction between DMRT1 function and genetic background modulates signaling and pluripotency to control tumor susceptibility in the fetal germ line

Krentz

Murphy

Zhang

et al. 2013

Developmental Biology

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Dmrt1(doublesex and mab-3 related transcription factor 1) is a regulator of testis development in vertebrates that has been implicated in testicular germ cell tumors of mouse and human. In the fetal mouse testis Dmrt1 regulates germ cell pluripotency in a strain-dependent manner. Loss of Dmrt1 in 129Sv strain mice results in a >90% incidence of testicular teratomas, tumors consisting cells of multiple germ layers; by contrast, these tumors have never been observed in Dmrt1 mutants of C57BL/6J (B6) or mixed genetic backgrounds. To further investigate the interaction between Dmrt1 and genetic background we compared mRNA expression in wild type and Dmrt1 mutant fetal testes of 129Sv and B6 mice at embryonic day 15.5 (E15.5), prior to overt tumorigenesis. Loss of Dmrt1 caused misexpression of overlapping but distinct sets of mRNAs in the two strains. The mRNAs that were selectively affected included some that changed expression only in one strain or the other and some that changed in both strains but to a greater degree in one versus the other. In particular, loss of Dmrt1 in 129Sv testes caused a more severe failure to silence regulators of pluripotency than in B6 testes. A number of genes misregulated in 129Sv mutant testes also are misregulated in human testicular germ cell tumors (TGCTs), suggesting similar etiology between germ cell tumors in mouse and man. Expression profiling showed that DMRT1 also regulates pluripotency genes in the fetal ovary, although Dmrt1 mutant females do not develop teratomas. Pathway analysis indicated disruption of several signaling pathways in Dmrt1 mutant fetal testes, including Nodal, Notch, and GDNF. We used a Nanos3-cre knock-in allele to perform conditional gene targeting, testing the GDNF coreceptors Gfra1 and Ret for effects on teratoma susceptibility. Conditional deletion of Gfra1 but not Ret in fetal germ cells of animals outcrossed to 129Sv caused a modest but significant elevation in tumor incidence. Despite some variability in genetic background in these crosses, this result is consistent with previous genetic mapping of teratoma susceptibility loci to the region containing Gfra1. Using Nanos3-cre we also uncovered a strong genetic interaction between Dmrt1 and Nanos3, suggesting parallel functions for these two genes in fetal germ cells. Finally, we used chromatin immunoprecipitation (ChIP-seq) analysis to identify a number of potentially direct DMRT1 targets. This analysis suggested that DMRT1 controls pluripotency via transcriptional repression of Esrrb, Nr5a2/Lrh1, and Sox2. Given the strong evidence for involvement of DMRT1 in human TGCT, the downstream genes and pathways identified in this study provide potentially useful candidates for roles in the human disease.

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“…Our molecular analyses demonstrated that these effects correlated with a downregulation of Sertoli cell-specific factors that are essential to maintaining the undifferentiated state of germ cells. These factors include glial cell-derived neurotrophic factor (GDNF), which is required for fetal germ cell proliferation and survival 59,60 and for spermatogonial stem cell self-renewal, 61,62 and CYP26B1, an enzyme that inhibits germ cell progression toward meiosis. 63 Conversely, complete inhibition of NOTCH signaling in Sertoli cells in vitro by the NOTCH inhibitor DAPT resulted in the opposite phenotype, with dose-dependent increases in Gdnf and Cyp26b1 expression.…”

Section: Amh-nicd1 Mouse Modelmentioning

confidence: 99%

“…One such growth factor is GDNF, which is already expressed at high levels by precursors of Sertoli cells at E11.5, 59 and which binds to a receptor complex formed by the receptors RET and GFRA1 in fetal and adult germ cells. 60,73,74 Miles et al recently investigated the putative function of GDNF signaling in the fetal gonad and demonstrated that Gndf is exclusively expressed in the male gonad between E12.5 and E15.5, 60 when gonocytes have entered the gonads but still proliferate until E15.5. These authors demonstrated that RET signaling is required for gonocyte proliferation and maintenance, and that Ret −/− germ cells underwent apoptosis.…”

Section: Phenotype Of Sertoli Cells In Wild-type and Amh-nicd1 Testesmentioning

confidence: 99%

NOTCH signaling in Sertoli cells regulates gonocyte fate

Garcia

Hofmann

2013

Cell Cycle

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The proto-oncogene Ret is required for male foetal germ cell survival

Cited by 20 publications

References 41 publications

Signaling through the TGF Beta-Activin Receptors ALK4/5/7 Regulates Testis Formation and Male Germ Cell Development

Signaling through the TGF Beta-Activin Receptors ALK4/5/7 Regulates Testis Formation and Male Germ Cell Development

Interaction between DMRT1 function and genetic background modulates signaling and pluripotency to control tumor susceptibility in the fetal germ line

NOTCH signaling in Sertoli cells regulates gonocyte fate

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