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Comment |
Primordial follicle assembly was regulated by notch signaling pathway in the mice. Chen CL 2014 et al.
Notch signaling pathway, a highly conserved cell signaling system, exists in most multicellular organisms. The objective of this study was to examine Notch signaling pathway in germ cell cyst breakdown and primordial follicle formation. The receptor and ligand genes of Notch pathway (Notch1, Notch2, Jagged1, Jagged2 and Hes1) were extremely down-regulated after newborn mouse ovaries were cultured then exposed to DAPT or L-685,458 in vitro (P<0.01). Since DAPT or L-685,548 inhibits Notch signaling pathway, the expression of protein LHX8 and NOBOX was significantly reduced during the formation of the primordial follicles. Down-regulated mRNA expression of specific genes including Lhx8, Figla, Sohlh2 and Nobox, were also observed. The percentages of female germ cells in germ cell cysts and primordial follicles were counted after culture of newborn ovaries for 3days in vitro. The result showed female germ cells in cysts was remarkably up-regulated while as the oocytes in primordial follicles was significantly down-regulated (P<0.05). In conclusion, Notch signaling pathway may regulate the formation of primordial follicle in mice.
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Suppression of Notch Signaling in the Neonatal Mouse Ovary Decreases Primordial Follicle Formation. Trombly DJ et al. Notch signaling directs cell fate during embryogenesis by influencing cell proliferation, differentiation, and apoptosis. Notch genes are expressed in the adult mouse ovary, and roles for Notch in regulating folliculogenesis are beginning to emerge from mouse genetic models. We investigated how Notch signaling might influence the formation of primordial follicles. Follicle assembly takes place when germ cell syncytia within the ovary break down and germ cells are encapsulated by pre-granulosa cells. In the mouse, this occurs during the first 4-5 days of postnatal life. The expression of Notch family genes in the neonatal mouse ovary was determined through RT-PCR measurements. Jagged1, Notch2, and Hes1 transcripts were the most abundantly expressed ligand, receptor, and target gene, respectively. Jagged1 and Hey2 mRNAs were upregulated over the period of follicle formation. Localization studies demonstrated that JAGGED1 is expressed in germ cells prior to follicle assembly and in the oocytes of primordial follicles. Pre-granulosa cells that surround germ cell nests express HES1. In addition, pre-granulosa cells of primordial follicles expressed NOTCH2 and Hey2 mRNA. We used an ex vivo ovary culture system to assess the requirement for Notch signaling during early follicle development. Newborn ovaries cultured in the presence of DAPT or L-658,458, gamma secretase inhibitors that attenuate Notch signaling, had a marked reduction in primordial follicles compared to vehicle-treated ovaries, and there was a corresponding increase in germ cells that remained within nests. These data support a functional role for Notch signaling in regulating primordial follicle formation.\
Neurotrophins Acting Via TRKB Receptors Activate the JAGGED1-NOTCH2 Cell-Cell Communication Pathway to Facilitate Early Ovarian Development. Dorfman MD et al. Tropomyosin-related kinase (TRK) receptor B (TRKB) mediates the supportive actions of neurotrophin 4/5 and brain-derived neurotrophic factor on early ovarian follicle development. Absence of TRKB receptors reduces granulosa cell (GC) proliferation and delays follicle growth. In the present study, we offer mechanistic insights into this phenomenon. DNA array and quantitative PCR analysis of ovaries from TrkB-null mice revealed that by the end of the first week of postnatal life, Jagged1, Hes1, and Hey2 mRNA abundance is reduced in the absence of TRKB receptors. Although Jagged1 encodes a NOTCH receptor ligand, Hes1 and Hey2 are downstream targets of the JAGGED1-NOTCH2 signaling system. Jagged1 is predominantly expressed in oocytes, and the abundance of JAGGED1 is decreased in TrkB(-/-) oocytes. Lack of TRKB receptors also resulted in reduced expression of c-Myc, a NOTCH target gene that promotes entry into the cell cycle, but did not alter the expression of genes encoding core regulators of cell-cycle progression. Selective restoration of JAGGED1 synthesis in oocytes of TrkB(-/-) ovaries via lentiviral-mediated transfer of the Jagged1 gene under the control of the growth differentiation factor 9 (Gdf9) promoter rescued c-Myc expression, GC proliferation, and follicle growth. These results suggest that neurotrophins acting via TRKB receptors facilitate early follicle growth by supporting a JAGGED1-NOTCH2 oocyte-to-GC communication pathway, which promotes GC proliferation via a c-MYC-dependent mechanism.
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Mutations |
2 mutations
Species: mouse
Mutation name: None
type: null mutation
fertility: subfertile
Comment: Hes1 in the somatic cells of the murine ovary is necessary for oocyte survival and maturation. Manosalva I et al. The Notch pathway plays an important role in ovary development in invertebrates like Drosophila. However its role for the mammalian ovary is unclear. Mammalian Hes genes encode transcriptional factors that mediate many of the activities of the Notch pathway. Here, we have studied the function of Hes1 during embryonic development of the mouse ovary. We find that Hes1 protein is present in somatic cells and oocyte cytoplasm and decreases between E15.5 and P0. Conventional Hes1 knock-out (KO), Hes1 conditional KO in the ovarian somatic, and chemical inhibition of Notch signaling decrease the total number, size and maturation of oocytes and increase the number of pregranulosa cells at P0. These defects correlate with abnormal proliferation and enhanced apoptosis. Expression of the pro-apoptotic gene Inhbb is increased, while the levels of the antiapoptotic and oocyte maturation marker Kit are decreased in the Hes1 KO ovaries. Conversely, overactivation of the Notch pathway in ovarian somatic cells increases the number of mature oocytes and decreases the number of pregranulosa cells. Fertility is also reduced by either Hes1 deletion or Notch pathway overactivation. In conclusion, our data suggest that the Notch-Hes1 pathway regulates ovarian somatic cell development, which is necessary for oocyte survival and maturation.
Species: mouse
Mutation name: None
type: null mutation
fertility: subfertile
Comment: Hes1 in the somatic cells of the murine ovary is necessary for oocyte survival and maturation. Manosalva I et al. The Notch pathway plays an important role in ovary development in invertebrates like Drosophila. However its role for the mammalian ovary is unclear. Mammalian Hes genes encode transcriptional factors that mediate many of the activities of the Notch pathway. Here, we have studied the function of Hes1 during embryonic development of the mouse ovary. We find that Hes1 protein is present in somatic cells and oocyte cytoplasm and decreases between E15.5 and P0. Conventional Hes1 knock-out (KO), Hes1 conditional KO in the ovarian somatic, and chemical inhibition of Notch signaling decrease the total number, size and maturation of oocytes and increase the number of pregranulosa cells at P0. These defects correlate with abnormal proliferation and enhanced apoptosis. Expression of the proapoptotic gene Inhbb is increased, while the levels of the antiapoptotic and oocyte maturation marker Kit are decreased in the Hes1 KO ovaries. Conversely, overactivation of the Notch pathway in ovarian somatic cells increases the number of mature oocytes and decreases the number of pregranulosa cells. Fertility is also reduced by either Hes1 deletion or Notch pathway overactivation. In conclusion, our data suggest that the Notch-Hes1 pathway regulates ovarian somatic cell development, which is necessary for oocyte survival and maturation.
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