Lunatic fringe null female mice are infertile due to defects in meiotic maturation

Abstract

We have demonstrated that Notch genes are expressed in developing mammalian ovarian follicles. Lunatic fringe is an important regulator of Notch signaling. In this study, data are presented that demonstrate that radical fringe and lunatic fringe are expressed in the granulosa cells of developing follicles. Lunatic fringe null female mice were found to be infertile. Histological analysis of the lunatic fringe-deficient ovary demonstrated aberrant folliculogenesis. Furthermore, oocytes from these mutants did not complete meiotic maturation. This is a novel observation because this is the first report describing a meiotic defect that results from mutations in genes that are expressed in the somatic granulosa cells and not the oocytes. This represents a new role for the Notch signaling pathway and lunatic fringe in mammalian folliculogenesis. (Goode et al., 1996a; Goode et al., 1996b;Hicks et al., 2000;Bruckner et al., 2000; Munro and Freeman, 2000;Schwientek, 2002). Brainiac activity is needed in the germ line for proper organization of the follicle (Goode, 1996). Fringe, the homolog of Lfng, is necessary for specification of the polar cells (Grammont and Irvine, 2001). Brainiac has been demonstrated to modify glycosphingolipids by adding GlcNac residues to mannose and galactose moieties on ceramide (Schwientek et al., 2002). In mice, a null mutation of the murine homolog of brainiac demonstrated that this protein is important for very early development, as braniac -/-embryos die prior to implantation (Vollrath et al., 2001). No role for this family of proteins in mammalian folliculogenesis has been described.It has been demonstrated that Lfng is an important regulator of Notch signaling. For example, Lfng null mutants have segmentation defects that are similar to those seen in null mutations of Notch1 and Dll1 (Evrard et al., 1997; Zhang and Gridley, 1997). In somites, where Lfng is the only family member expressed, Notch receptors and ligands are expressed normally in Lfng -/-mutants, but the Notch downstream target gene Hes5 was not detected, indicating a lack of Notch activation in the presence of ligand. However, Hes5 was expressed normally in the neural tube and developing brain of Lfng null mutants, probably due to expression of Mfng and Rfng in these tissues (Evrard et al., 1997). Interestingly, Rfngdeficient mice had no phenotype and Rfng/Lfng double null mutants had only defects associated with a lack of Lfng (Zhang et al., 2000). Folliculogenesis is the process by which oocytes develop in response to hormonal cues. This requires the coordination of the proliferation and differentiation of granulosa cells and the growth and maturation of the oocyte. Primordial follicles consist of a small oocyte surrounded by squamous somatic cells. When recruited to develop, the granulosa cells proliferate and become cuboidal. As these cells continue to proliferate, layers develop around the growing oocyte. Once a follicle has several layers of cells a fluid filled space, the antrum, will begin to form. The antrum sp...

In vitro development of mouse fetal germ cells into mature oocytes

“…One is the abnormal gap junction between the follicular granulosa cells and oocytes that might influence the development of oocytes and block the meiosis (Carabatsos et al 2000, Eppig 2001, Klinger & de Felici 2002, Hahn et al 2005. Several studies have demonstrated that the gap junctions during the development of follicles were required for the progression of the follicular development, and the intercellular connections were thought to be important for transporting small molecules facilitating the growth of mouse oocyte (Carabatsos et al 2000, Eppig 2001, Epifano & Dean 2002, Matzuk et al 2002.…”

Follicular assembly: mechanisms of action

“…There is growing evidence that Notch signaling is important for the regulation of primordial follicle formation. The first suggestion that Notch signaling might be involved in follicle formation came from analysis of lunatic fringe (Lfng) mutants (Hahn et al 2005). LFNG is part of the Fringe family of proteins that regulate Notch signaling (Bruckner et al 2000, Hicks et al 2000.…”

Regulation of Notch signaling by glycosylation

“…Mutations of Fringe give Notch signaling defects that manifest at developmental boundaries in the formation of wings, legs and eyes in Drosophila [7]. In mammals, including humans [48], Lfng is required for Notch signaling during somitogenesis, and affects female meiosis [49] and T cell development in mice [47]. In vivo functions of Rfng are not noticeably developmental [10] and Mfng mutant mice have not been described.…”