title: Notch signaling represses GATA4-induced expression of genes involved in steroid biosynthesis.
abstract: Notch2 and Notch3 and genes of the Notch signaling network are dynamically expressed in developing follicles, where they are essential for granulosa cell proliferation and meiotic maturation. Notch receptors, ligands, and downstream effector genes are also expressed in testicular Leydig cells, predicting a potential role in regulating steroidogenesis. In this study, we sought to determine if Notch signaling in small follicles regulates the proliferation response of granulosa cells to FSH and represses the up-regulation steroidogenic gene expression that occurs in response to FSH as the follicle grows. Inhibition of Notch signaling in small preantral follicles led to the up-regulation of the expression of genes in the steroid biosynthetic pathway. Similarly, progesterone secretion by MA-10 Leydig cells was significantly inhibited by constitutively active Notch. Together, these data indicated that Notch signaling inhibits steroidogenesis. GATA4 has been shown to be a positive regulator of steroidogenic genes, including STAR protein, P450 aromatase, and 3B-hydroxysteroid dehydrogenase. We observed that Notch downstream effectors HEY1, HEY2, and HEYL are able to differentially regulate these GATA4-dependent promoters. These data are supported by the presence of HEY/HES binding sites in these promoters. These studies indicate that Notch signaling has a role in the complex regulation of the steroidogenic pathway.
authors.affiliation: School of Life SciencesArizona State University, PO Box 874501, Tempe, Arizona 85827-45012, USAReproductionMother and Child Health, Centre de Recherche du CHU de Québec and Centre de Recherche en Biologie de la Reproduction (CRBR), Quebec City, Quebec, CanadaDepartment of ObstetricsGynecology, and Reproduction, Laval University, Quebec City, Quebec, Canada G1K 7P4.
authors.forename: Rajani M
authors.initials: RM
authors.lastname: George
authors.affiliation: School of Life SciencesArizona State University, PO Box 874501, Tempe, Arizona 85827-45012, USAReproductionMother and Child Health, Centre de Recherche du CHU de Québec and Centre de Recherche en Biologie de la Reproduction (CRBR), Quebec City, Quebec, CanadaDepartment of ObstetricsGynecology, and Reproduction, Laval University, Quebec City, Quebec, Canada G1K 7P4.
authors.forename: Katherine L
authors.initials: KL
authors.lastname: Hahn
authors.affiliation: School of Life SciencesArizona State University, PO Box 874501, Tempe, Arizona 85827-45012, USAReproductionMother and Child Health, Centre de Recherche du CHU de Québec and Centre de Recherche en Biologie de la Reproduction (CRBR), Quebec City, Quebec, CanadaDepartment of ObstetricsGynecology, and Reproduction, Laval University, Quebec City, Quebec, Canada G1K 7P4.
authors.forename: Alan
authors.initials: A
authors.lastname: Rawls
authors.affiliation: School of Life SciencesArizona State University, PO Box 874501, Tempe, Arizona 85827-45012, USAReproductionMother and Child Health, Centre de Recherche du CHU de Québec and Centre de Recherche en Biologie de la Reproduction (CRBR), Quebec City, Quebec, CanadaDepartment of ObstetricsGynecology, and Reproduction, Laval University, Quebec City, Quebec, Canada G1K 7P4 School of Life SciencesArizona State University, PO Box 874501, Tempe, Arizona 85827-45012, USAReproductionMother and Child Health, Centre de Recherche du CHU de Québec and Centre de Recherche en Biologie de la Reproduction (CRBR), Quebec City, Quebec, CanadaDepartment of ObstetricsGynecology, and Reproduction, Laval University, Quebec City, Quebec, Canada G1K 7P4.
authors.forename: Robert S
authors.initials: RS
authors.lastname: Viger
authors.affiliation: School of Life SciencesArizona State University, PO Box 874501, Tempe, Arizona 85827-45012, USAReproductionMother and Child Health, Centre de Recherche du CHU de Québec and Centre de Recherche en Biologie de la Reproduction (CRBR), Quebec City, Quebec, CanadaDepartment of ObstetricsGynecology, and Reproduction, Laval University, Quebec City, Quebec, Canada G1K 7P4 Jeanne.Wilson-Rawls@asu.edu.
authors.forename: Jeanne
authors.initials: J
authors.lastname: Wilson-Rawls
mesh_terms: D000818:Animals; D001483:Base Sequence; D049109:Cell Proliferation / Q000187:drug effects; D019295:Computational Biology; D005260:Female; D005640:Follicle Stimulating Hormone / Q000494:pharmacology; D050991:GATA4 Transcription Factor / Q000235:genetics*; D006107:Granulosa Cells / Q000187:drug effects; D007985:Leydig Cells / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D011374:Progesterone / Q000378:metabolism; D051883:Receptor, Notch2 / Q000378:metabolism; D000071656:Receptor, Notch3; D051880:Receptors, Notch / Q000235:genetics* / Q000378:metabolism; D013256:Steroids / Q000096:biosynthesis*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D050991:GATA4 Transcription Factor; C484171:Gata4 protein, mouse; C497765:Notch2 protein, mouse; C499373:Notch3 protein, mouse; D051883:Receptor, Notch2; D000071656:Receptor, Notch3; D051880:Receptors, Notch; D013256:Steroids; D011374:Progesterone; D005640:Follicle Stimulating Hormone