NOTCH signaling in Sertoli cells regulates gonocyte fate

Garcia, Thomas; Hofmann, Marie‐Claude

doi:10.4161/cc.25627

Cited by 48 publications

(30 citation statements)

References 91 publications

(98 reference statements)

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“…Our previous studies indicated that constitutive overactivation of NOTCH signaling drove early germ cell differentiation in the fetus leading to a Sertoli cell-only phenotype shortly after birth (33,44). Conversely, knockout of the pathway through ablation of RBPJ, a signaling mediator downstream of all NOTCH receptors, led to a 30% increase of the number of germ cells in the adult testis (34).…”

Section: Cyp26b1 Down-regulation Is Associated With Activated Notch Smentioning

confidence: 99%

Undifferentiated spermatogonia regulateCyp26b1expression through NOTCH signaling and drive germ cell differentiation

et al. 2019

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Cytochrome P450 family 26 subfamily B member 1 (CYP26B1) regulates the concentration of all–trans retinoic acid (RA) and plays a key role in germ cell differentiation by controlling local distribution of RA. The mechanisms regulating Cyp26b1 expression in postnatal Sertoli cells, the main components of the stem cell niche, are so far unknown. During gonad development, expression of Cyp26b1 is maintained by Steroidogenic Factor 1 (SF‐1) and Sex‐Determining Region Y. Box‐9 (SOX9), which ensure that RA is degraded and germ cell differentiation is blocked. Here, we show that the NOTCH target Hairy/Enhancer‐of‐Split Related with YRPW Motif 1 (HEY1), a transcriptional repressor, regulates germ cell differentiation via direct binding to the Cyp26b1 promoter and thus inhibits its expression in Sertoli cells. Further, using in vivo germ cell ablation, we demonstrate that undifferentiated type A spermatogonia are the cells that activate NOTCH signaling in Sertoli cells through their expression of the NOTCH ligand JAGGED‐1 (JAG1) at stage VIII of the seminiferous epithelium cycle, therefore mediating germ cell differentiation by a ligand concentration‐dependent process. These data therefore provide more insights into the mechanisms of germ cell differentiation after birth and potentially explain the spatiotemporal RA pulses driving the transition between undifferentiated to differentiating spermatogonia.—Parekh, P. A., Garcia, T. X., Waheeb, R., Jain, V., Gandhi, P., Meistrich, M. L., Shetty, G., Hofmann, M.‐C. Undifferentiated spermatogonia regulate Cyp26b1 expression through NOTCH signaling and drive germ cell differentiation. FASEB J. 33, 8423–8435 (2019). http://www.fasebj.org

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Section: Cyp26b1 Down-regulation Is Associated With Activated Notch Smentioning

confidence: 99%

Undifferentiated spermatogonia regulateCyp26b1expression through NOTCH signaling and drive germ cell differentiation

et al. 2019

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“…During postnatal development and along the spermatogenic cycle of adult male mouse, three Notch receptors (Notch 1-3) and ligands (Delta-like 1, 4 and Jagged 1, 2) were identified in the testis (Mori et al, 2003;Garcia & Hofmann, 2013;Murta et al, 2013;Okada et al, 2017;Kami nska et al, 2018). Although Notch receptors were identified both in germ and in Sertoli cells, Notch 1 signaling in adult seminiferous tubules is activated predominantly in Sertoli cells (Garcia & Hofmann, 2013;Liu et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Notch signaling regulates nuclear androgen receptor AR and membrane androgen receptor ZIP9 in mouse Sertoli cells

et al. 2019

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Background Notch signaling pathway is involved in contact‐dependent communication between the cells of seminiferous epithelium, and its proper activity is important for undisturbed spermatogenesis. Objectives The aim was to assess the effect of Notch pathway inhibition on the expression of nuclear (AR) and membrane (ZIP9) androgen receptors and androgen‐regulated genes, claudin‐5 and claudin‐11, in TM4 mouse Sertoli cell line. Materials and methods DAPT (γ‐secretase inhibitor) treatment and recombination signal binding protein silencing were employed to reduce Notch signaling, whereas immobilized ligands were used to activate Notch pathway in TM4 cells. To reveal specific effect of each androgen receptor, AR or ZIP9 silencing was performed. Results Notch pathway inhibition increased the expression of AR and ZIP9 mRNA and proteins (p < 0.01; p < 0.05) in TM4 cells, whereas incubation with Notch ligands, rDLL1 or rJAG1, reduced AR (p < 0.01; p < 0.001) and ZIP9 (p < 0.05; p < 0.01) expressions, respectively. Testosterone enhanced the expression of both receptors (p < 0.05; p < 0.01). Androgen‐regulated claudin‐5 and claudin‐11 (p < 0.01; p < 0.001) and cAMP (p < 0.001) were elevated in Notch‐inhibited cells, while activation of Notch signaling by DLL1 or JAG1 reduced claudin‐11 or claudin‐5 level (p < 0.01; p < 0.001), respectively. Discussion Our findings indicate opposite effect of Notch and androgen signaling on the expression of androgen receptors in TM4 cells. We demonstrated that AR expression is regulated by DLL1‐mediated Notch signaling, whereas JAG1 is involved in the regulation of ZIP9. The expression of both claudins and cAMP production is under inhibitory influence of Notch pathway. The effects of Notch signaling on claudin‐5 and claudin‐11 expression are mediated by ZIP9 and AR, respectively. Conclusion Notch signaling may be considered as an important pathway controlling Sertoli cell physiology, and its alterations may contribute to disturbed response of Sertoli cells to androgens.

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“…While the function of the Notch pathway in ovarian development has been extensively studied in model organisms such as Drosophila and C. elegans (Andersson et al 2011, Greenwald & Kovall 2013), there is limited information available on the function of Notch signaling in the mammalian gonad, and only recently have reports become available implicating Notch signaling in ovarian (Manosalva et al 2013, Xu & Gridley 2013, Vanorny et al 2014) or testicular (Tang et al 2008, Garcia & Hofmann 2013, Huang et al 2013) development. Within the mammalian ovary, Notch receptors, ligands, modulators, and target/effector genes are expressed and dynamically regulated during follicular development (Table 1).…”

Section: Introductionmentioning

confidence: 99%

The role of Notch signaling in the mammalian ovary

Vanorny

Mayo

2017

Reproduction

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The Notch pathway is a contact-dependent, or juxtacrine, signaling system that is conserved in metazoan organisms and is important in many developmental processes. Recent investigations have demonstrated that the Notch pathway is active in both the embryonic and postnatal ovary and plays important roles in events including follicle assembly and growth, meiotic maturation, ovarian vasculogenesis, and steroid hormone production. Ovarian pathologies resulting from disruption of the Notch pathway in mice affect meiotic spindle assembly, follicle histogenesis, granulosa cell proliferation and survival, corpora luteal function, and ovarian neovascularization. These aberrations result in abnormal folliculogenesis and reduced fertility. Knowledge of the cellular interactions facilitated by the Notch pathway is an important area for continuing research and future studies are expected to enhance our understanding of ovarian function and provide critical insights for improving reproductive health. This review focuses on the expression of Notch pathway components in the ovary, and on the multiple functions of Notch signaling in follicle assembly, maturation, and development. We focus on the mouse, where genetic investigations are possible, and relate this information to the human ovary.

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NOTCH signaling in Sertoli cells regulates gonocyte fate

Cited by 48 publications

References 91 publications

Undifferentiated spermatogonia regulateCyp26b1expression through NOTCH signaling and drive germ cell differentiation

Undifferentiated spermatogonia regulateCyp26b1expression through NOTCH signaling and drive germ cell differentiation

Notch signaling regulates nuclear androgen receptor AR and membrane androgen receptor ZIP9 in mouse Sertoli cells

The role of Notch signaling in the mammalian ovary

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