Notch Signaling Regulates Ovarian Follicle Formation and Coordinates Follicular Growth

Abstract

Ovarian follicles form through a process in which somatic pregranulosa cells encapsulate individual germ cells from germ cell syncytia. Complementary expression of the Notch ligand, Jagged1, in germ cells and the Notch receptor, Notch2, in pregranulosa cells suggests a role for Notch signaling in mediating cellular interactions during follicle assembly. Using a Notch reporter mouse, we demonstrate that Notch signaling is active within somatic cells of the embryonic ovary, and these cells undergo dramatic reorganization during follicle histogenesis. This coincides with a significant increase in the expression of the ligands, Jagged1 and Jagged2; the receptor, Notch2; and the target genes, Hes1 and Hey2. Histological examination of ovaries from mice with conditional deletion of Jagged1 within germ cells (J1 knockout [J1KO]) or Notch2 within granulosa cells (N2 knockout [N2KO]) reveals changes in follicle dynamics, including perturbations in the primordial follicle pool and antral follicle development. J1KO and N2KO ovaries also contain multi-oocytic follicles, which represent a failure to resolve germ cell syncytia, and follicles with enlarged oocytes but lacking somatic cell growth, signifying a potential role of Notch signaling in follicle activation and the coordination of follicle development. We also observed decreased cell proliferation and increased apoptosis in the somatic cells of both conditional knockout lines. As a consequence of these defects, J1KO female mice are subfertile; however, N2KO female mice remain fertile. This study demonstrates important functions for Jagged1 and Notch2 in the resolution of germ cell syncytia and the coordination of somatic and germ cell growth within follicles of the mouse ovary.

Crucial Genes and Pathways in Chicken Germ Stem Cell Differentiation

“…TGF-␤ signaling could regulate testis formation and male germ cell development (9). Notch signaling was reported antagonistically to regulate germ line stem cell niche formation in Drosophila male embryonic gonads (19) and deletion of Jagged1, a Notch ligand, could lead to the formation of multicystic follicles in the mouse ovary (20). These reports provide support that our selected candidate key signaling pathways play an important role in the differentiation of the male germ cells.…”

ADAM10–Notch signaling governs the recruitment of ovarian pregranulosa cells and controls folliculogenesis in mice

“…A functional role for Notch signaling in controlling primordial follicle formation has recently been reported (Trombly et al, 2009;Vanorny et al, 2014;Xu and Gridley, 2013). As an upstream regulator of Notch signaling, ADAM10 might play a similar role in regulating the formation of primordial follicles according to our findings.…”

“…To assess whether ADAM10 is required in vivo for folliculogenesis, we conditionally deleted ADAM10 in a somatic lineage of perinatal ovaries using an anti-Müllerian hormone type 2 receptor-Cre (Amhr2-Cre) mouse line (Jamin et al, 2002), which mediates the expression of CRE recombinase in somatic cells of ovaries from 12.5 dpc (Jamin et al, 2002;Jorgez et al, 2004;Vanorny et al, 2014). qRT-PCR analysis of ovaries showed that the levels of Adam10 mRNA in Amhr2-Cre; Adam10 f/d ovaries was 52.8% that of control littermates (Fig.…”

“…Both ADAM10 and Notch signaling regulate the proliferation and differentiation of LGR5 + stem (or progenitor) cells in various mouse organs, such as the intestine, stomach and cochlea (Bramhall et al, 2014;Demitrack et al, 2015;Tsai et al, 2014;VanDussen et al, 2012). More specifically, an increasing body of evidence has shown that Notch signaling is indispensable for the formation of ovarian primordial follicles (Trombly et al, 2009;Vanorny et al, 2014;Xu and Gridley, 2013). However, whether and how ADAM10 plays a role in the establishment of the primordial follicle pool has not been addressed, and the relationship between ADAM10 and Notch signaling in primordial follicle formation remains unknown.…”

Second-generation Notch1 activity-trap mouse line (N1IP::CreHI) provides a more comprehensive map of cells experiencing Notch1 activity

“…Whereas in the Drosophila ovary the Notch receptor is expressed in the niche, the receptor is required in the germ line stem cells in C. elegans. In rodent ovaries, Notch2 is expressed in granulosa cells and the Jag1 ligand is expressed in the germ cells (Johnson et al, 2001;Vanorny et al, 2014;Xu and Gridley, 2013). The ovary of sexually mature virgin N1IP::Cre HI ; Rosa +/R26R females showed ubiquitous labeling in granulosa cells (Fig.…”