Notch signaling represses GATA4-induced expression of genes involved in steroid biosynthesis

Significance Statement

The Notch signaling pathway regulates cell fate decisions in many tissues. We, and others, have demonstrated that Notch signaling pathway genes are expressed in a dynamic fashion in granulosa cells of developing follicles, and in Leydig and Sertoli cells of the adult testis. However, the downstream target genes of Notch-signaling had remained elusive. In this study, we provide the first evidence that Notch signaling inhibits the expression of genes in the steroid biosynthetic pathway. The promoters of specific enzymes involved in steroid biosynthesis, Star, HSD3B2, and Cyp19aI, were repressed by activated Notch, in the presence of their activator, GATA4. We postulate that Notch signaling may mediate the biphasic response of granulosa cells to paracrine cues such as FSH. In growing preantral follicles active Notch signaling represses expression of steroid synthetic genes, thus inducing a proliferative response, but in larger follicles, Notch signaling is attenuated and FSH induces differentiation. The Notch signaling pathway genes are expressed in the pituitary and adrenal glands as well. These data indicate that Notch signaling could have a global effect on steroid synthesis within the hypothalamic-pituitary-gonadal axis; this will be an important future consideration.

About the author

Dr. Jeanne Wilson-Rawls is the corresponding author on this study. She received a PhD in Cellular and Molecular Biology from St. Louis School of Medicine and completed a post-doctoral fellowship with Dr. Eric N. Olson at UT Southwestern Medical Center at Dallas. Currently, she is an associate professor of Genomics, Evolution & Bioinformatics in the School of Life Sciences at Arizona State University. Her research group has been studying Notch signaling and cell lineage decisions in the development and regeneration of muscle and development and maturation of germ cells.

Journal Reference

Reproduction. 2015;150(4):383-94.

George RM¹, Hahn KL¹, Rawls A¹, Viger RS^2,3, Wilson-Rawls J¹.

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School of Life Sciences,Arizona State University, PO Box 874501, Tempe, Arizona 85827-45012, USA
Reproduction,Mother and Child Health, Centre de Recherche du CHU de Québec and Centre de Recherche en Biologie de la Reproduction (CRBR), Quebec City, Quebec, Canada
Department of Obstetrics,Gynecology, and Reproduction, Laval University, Quebec City, Quebec, Canada G1K 7P4

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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.

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