The orphan nuclear receptor NR5A2 is implicated in a multitude of biological processes including cholesterol homeostasis and development. Its role in cholesterol metabolism and cell proliferation is now well established in vitro and in vivo. Both in vitro and gene expression studies have suggested a role for NR5A2 in ovarian function. In this study, we provide in vivo evidence for its involvement in reproductive function by demonstrating that heterozygosity for a null mutation of NR5A2 leads to a reduction in female fertility. Furthermore, we showed that NR5A2+/- females display a severe reduction in ovarian progesterone production and that progesterone supplementation can rescue the NR5A2+/- subfertility phenotype. We also provide evidence that one of the mechanisms by which NR5A2 regulates ovarian progesterone production is through modulating the expression of SCAR, which controls one of the rate-limiting steps of progesterone synthesis. / A targeted disruption of the NR5A2 gene in the mouse leads to early lethality in utero between embryonic days 6.0 and 7.5, showing that NR5A2 plays a crucial role during early embryogenesis. The molecular mechanisms underlying this early lethality, however, are poorly understood. In this study, we used a morphological and marker gene analysis to characterize the NR5A2-/- embryonic phenotype and showed that although initial axis specification occurs in NR5A2-/- embryos, primitive streak and mesoderm fail to form. Using a chimeric approach, we demonstrated a requirement for NR5A2 function in the visceral endoderm (VE), an extra-embryonic tissue, for proper primitive streak morphogenesis and gastrulation. Our results also indicate a reduction in the expression of VE marker genes involved in the nutritive function of this tissue, suggesting that NR5A2 play a dual role in the VE, being implicated in the mediation of both its patterning and nutritive activity. / Taking advantage of the LacZ knock-in approach used to inactivate the NR5A2 gene, we also demonstrated that NR5A2 is expressed during craniofacial and nervous system development, suggesting a novel role for NR5A2 in head formation and neural development.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:QMM.111861 |
| Date | January 2006 |
| Creators | Labelle-Dumais, Cassandre. |
| Publisher | McGill University |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Format | application/pdf |
| Coverage | Doctor of Philosophy (Division of Experimental Medicine.) |
| Rights | All items in eScholarship@McGill are protected by copyright with all rights reserved unless otherwise indicated. |
| Relation | alephsysno: 002587398, proquestno: AAINR32363, Theses scanned by UMI/ProQuest. |
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