title: RBPJ in mouse Sertoli cells is required for proper regulation of the testis stem cell niche.
abstract: Stem cells are influenced by their surrounding microenvironment, or niche. In the testis, Sertoli cells are the key niche cells directing the population size and differentiation fate of spermatogonial stem cells (SSCs). Failure to properly regulate SSCs leads to infertility or germ cell hyperplasia. Several Sertoli cell-expressed genes, such as Gdnf and Cyp26b1, have been identified as being indispensable for the proper maintenance of SSCs in their niche, but the pathways that modulate their expression have not been identified. Although we have recently found that constitutively activating NOTCH signaling in Sertoli cells leads to premature differentiation of all prospermatogonia and sterility, suggesting that there is a crucial role for this pathway in the testis stem cell niche, a true physiological function of NOTCH signaling in Sertoli cells has not been demonstrated. To this end, we conditionally ablated recombination signal binding protein for immunoglobulin kappa J region (Rbpj), a crucial mediator of NOTCH signaling, in Sertoli cells using Amh-cre. Rbpj knockout mice had: significantly increased testis sizes; increased expression of niche factors, such as Gdnf and Cyp26b1; significant increases in the number of pre- and post-meiotic germ cells, including SSCs; and, in a significant proportion of mice, testicular failure and atrophy with tubule lithiasis, possibly due to these unsustainable increases in the number of germ cells. We also identified germ cells as the NOTCH ligand-expressing cells. We conclude that NOTCH signaling in Sertoli cells is required for proper regulation of the testis stem cell niche and is a potential feedback mechanism, based on germ cell input, that governs the expression of factors that control SSC proliferation and differentiation.
authors.affiliation: Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Unit 1105, PO Box 301402, Houston, TX 77230-1402, USA Department of Comparative Biosciences, University of Illinois at Urbana-Champaign, Urbana, IL 61802, USA.
authors.forename: Thomas Xavier
authors.initials: TX
authors.lastname: Garcia
authors.affiliation: Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Unit 1105, PO Box 301402, Houston, TX 77230-1402, USA Department of Comparative Biosciences, University of Illinois at Urbana-Champaign, Urbana, IL 61802, USA.
authors.forename: Jaspreet Kaur
authors.initials: JK
authors.lastname: Farmaha
authors.affiliation: Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Unit 1105, PO Box 301402, Houston, TX 77230-1402, USA Department of Biochemistry & Cell Biology, Rice University, PO Box 1892, MS-140, Houston, TX 77251-1892, USA.
authors.forename: Sean
authors.initials: S
authors.lastname: Kow
authors.affiliation: Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Unit 1105, PO Box 301402, Houston, TX 77230-1402, USA Department of Comparative Biosciences, University of Illinois at Urbana-Champaign, Urbana, IL 61802, USA mhofmann@mdanderson.org.
authors.forename: Marie-Claude
authors.initials: MC
authors.lastname: Hofmann
mesh_terms: D000818:Animals; D060833:Cellular Microenvironment / Q000502:physiology*; D018507:Gene Expression Regulation, Developmental / Q000502:physiology; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein / Q000235:genetics / Q000378:metabolism*; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D060888:Real-Time Polymerase Chain Reaction; D051880:Receptors, Notch / Q000378:metabolism; D012708:Sertoli Cells / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D013093:Spermatogonia / Q000502:physiology*; D013234:Stem Cells / Q000502:physiology*; D013737:Testis / Q000166:cytology* / Q000196:embryology* / Q000378:metabolism
chemical_list: D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; C497571:Rbpj protein, mouse; D051880:Receptors, Notch
keywords: Fertility; Mouse; NOTCH signaling; RBPJ; Spermatogenesis; Spermatogonial stem cell; Testicular microlithiasis