The NOTCH Ligand JAG1 Regulates GDNF Expression in Sertoli Cells

Garcia, Thomas; Parekh, Parag; Gandhi, Poojabahen; Sinha, Krishna M.; Hofmann, Marie‐Claude

doi:10.1089/scd.2016.0318

Cited by 60 publications

(58 citation statements)

References 64 publications

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“…The involvement of JAG1 in Sertoli cell function has been recently reported by Garcia et al . (), who demonstrated that the production of glial‐derived neurotrophic factor (GDNF), crucial for spermatogonial stem cells self‐renewal and maintenance within the testis stem cell niche, is controlled by JAG1 expressed in spermatogonial cells.…”

Section: Discussionmentioning

confidence: 97%

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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Section: Discussionmentioning

confidence: 97%

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

et al. 2019

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“…There was also a significant decrease in Jag1 expression, which is normally expressed in all spermatogonia, albeit at different levels (Fig. 7E) (48).…”

Section: A Aligned Spermatogonia Down-regulate Cyp26b1 Expression Thrmentioning

confidence: 89%

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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“…In situations with increased numbers of Sertoli cells, the number of SSCs was also increased based on the post‐transplantation colony formation (Oatley et al., ), and a deletion of a downstream effector of Notch, RBPjk, in Sertoli cells results in the increase in the level of Gdnf expression and the number of GFRα1 + spermatogonia (Garcia, Farmaha, Kow, & Hofmann, ). Together, these results have led to the prevailing concept that Sertoli cells comprise an essential niche component regulating SSCs via the production of GDNF (Garcia, Parekh, Gandhi, Sinha, & Hofmann, ; Hofmann, ). Whereas, cell type‐specific disruption of Gdnf has suggested that GDNF expression in the peritubular myoid cells is essential for the normal progression of spermatogenesis (Chen, Willis, & Eddy, ).…”

Section: Elements Involved In the Open Niche Regulation Of Sscsmentioning

confidence: 99%

“…Together, these results have led to the prevailing concept that Sertoli cells comprise an essential niche component regulating SSCs via the production of GDNF (Garcia, Parekh, Gandhi, Sinha, & Hofmann, 2017;Hofmann, 2008). Whereas, cell type-specific disruption of Gdnf has suggested that GDNF expression in the peritubular myoid cells is essential for the normal progression of spermatogenesis (Chen, Willis, & Eddy, 2016).…”

Section: Elements Involved In the Open Ni Che Reg Ul Ati On Of Ssc Smentioning

confidence: 99%

Open niche regulation of mouse spermatogenic stem cells

Yoshida

2018

Dev Growth Differ

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In mammalian testes, robust stem cell functions ensure the continual production of sperm. In testicular seminiferous tubules, spermatogenic stem cells (SSCs) are highly motile and are interspersed between their differentiating progeny, while undergoing self‐renewal and differentiation. In such an “open niche” microenvironment, some SSCs proliferate, while others exit the stem cell compartment through differentiation; therefore, self‐renewal and differentiation are perfectly balanced at the population (or tissue) level, a dynamics termed “population asymmetry.” This is in stark contrast to the classical perception of tissue stem cells being cells that are clustered in a specialized “closed niche” region and that invariantly undergo asymmetric divisions. However, despite its importance, how the self‐renewal and differentiation of SSCs are balanced in an open niche environment is poorly understood. Recent studies have thrown light on the key mechanism that enables SSCs to follow heterogeneous fates, although they are equally exposed to signaling molecules controlling self‐renewal and differentiation. In particular, SSCs show heterogeneous susceptibilities to differentiation‐promoting signals such as Wnt and retinoic acid. Heterogeneous susceptibility to the ubiquitously distributed fate‐controlling extracellular signal might be a key generic mechanism for the heterogeneous fate of tissue stem cells in open niche microenvironments.

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The NOTCH Ligand JAG1 Regulates GDNF Expression in Sertoli Cells

Cited by 60 publications

References 64 publications

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

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

Undifferentiated spermatogonia regulateCyp26b1expression through NOTCH signaling and drive germ cell differentiation

Open niche regulation of mouse spermatogenic stem cells

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