title: The NOTCH Ligand JAG1 Regulates GDNF Expression in Sertoli Cells.
abstract: In the seminiferous epithelium of the testis, Sertoli cells are key niche cells directing proliferation and differentiation of spermatogonial stem cells (SSCs) into spermatozoa. Sertoli cells produce glial cell line-derived neurotrophic factor (GDNF), which is essential for SSC self-renewal and progenitor expansion. While the role of GDNF in the testis stem cell niche is established, little is known about how this factor is regulated. Our previous studies on NOTCH activity in Sertoli cells demonstrated a role of this pathway in limiting stem/progenitor cell numbers, thus ultimately downregulating sperm cell output. In this study we demonstrate through a double-mutant mouse model that NOTCH signaling in Sertoli cells functions solely through the canonical pathway. Further, we demonstrate through Dual luciferase assay and chromatin immunoprecipitation quantitative polymerase chain reaction (ChIP-qPCR) analysis that the NOTCH targets HES1 and HEY1, which are transcriptional repressors, directly downregulate GDNF expression by binding to the Gdnf promoter, thus antagonizing the effects of FSH/cAMP. Finally, we demonstrate that testicular stem/progenitors cells are activating NOTCH signaling in Sertoli cells in vivo and in vitro through the NOTCH ligand JAG1 at their surface, indicating that these cells may ensure their own homeostasis through negative feedback regulation.
authors.affiliation: 1 Department of Endocrine Neoplasia and Hormonal Disorders, University of Texas, MD Anderson Cancer Center , Houston, Texas.|2 Department of Biology, University of Houston-Clear Lake , Houston, Texas.
authors.forename: Thomas X
authors.initials: TX
authors.lastname: Garcia
authors.affiliation: 1 Department of Endocrine Neoplasia and Hormonal Disorders, University of Texas, MD Anderson Cancer Center , Houston, Texas.
authors.forename: Parag
authors.initials: P
authors.lastname: Parekh
authors.affiliation: 1 Department of Endocrine Neoplasia and Hormonal Disorders, University of Texas, MD Anderson Cancer Center , Houston, Texas.
authors.forename: Pooja
authors.initials: P
authors.lastname: Gandhi
authors.affiliation: 1 Department of Endocrine Neoplasia and Hormonal Disorders, University of Texas, MD Anderson Cancer Center , Houston, Texas.|3 Department of Orthopedic Surgery, University of Texas Health Science Center , Houston, Texas.
authors.forename: Krishna
authors.initials: K
authors.lastname: Sinha
authors.affiliation: 1 Department of Endocrine Neoplasia and Hormonal Disorders, University of Texas, MD Anderson Cancer Center , Houston, Texas.
authors.forename: Marie-Claude
authors.initials: MC
authors.lastname: Hofmann
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D025461:Feedback, Physiological; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism*; D000072100:Jagged-1 Protein / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D011401:Promoter Regions, Genetic; D051880:Receptors, Notch / Q000378:metabolism; D012708:Sertoli Cells / Q000166:cytology / Q000378:metabolism*; D015398:Signal Transduction; D013091:Spermatogenesis; D013093:Spermatogonia / Q000166:cytology / Q000378:metabolism; D055153:Stem Cell Niche; D000072056:Transcription Factor HES-1 / Q000235:genetics / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; D051100:Glial Cell Line-Derived Neurotrophic Factor; C489734:Hes1 protein, mouse; C120420:Hey1 protein, mouse; C000606274:Jag1 protein, mouse; D000072100:Jagged-1 Protein; D051880:Receptors, Notch; D000072056:Transcription Factor HES-1; D000242:Cyclic AMP
keywords: GDNF; JAG1; NOTCH; Sertoli cell; spermatogenesis; spermatogonia