In Drosophila, the 'Notch' gene controls differentiation to various cell fates in many tissues. Three mammalian 'Notch'
homologs have been identified. All 3 are very highly conserved relative to the Drosophila gene, which suggests that
they are important for cell differentiation in mammals. 'Delta' and 'Jagged' are Notch ligands .
NCBI Summary:
The jagged 1 protein encoded by JAG1 is the human homolog of the Drosophilia jagged protein. Human jagged 1 is the ligand for the receptor notch 1, the latter is involved in signaling processes. Mutations that alter the jagged 1 protein cause Alagille syndrome. Jagged 1 signalling through notch 1 has also been shown to play a role in hematopoiesis. [provided by RefSeq, Nov 2019]
Contact-dependent cleavage of Jagged1 in oocytes reveals potential bidirectional notch signaling during follicular growth in the mouse. Kandasamy H et al. (2021)//////////////////Activation of Notch Signaling by Oocytes and Jag1 in Mouse Ovarian Granulosa Cells. Hubbard N et al. (2019) The Notch pathway plays diverse and complex roles in cell signaling during development. In the mammalian ovary, Notch is important for the initial formation and growth of follicles, and for regulating the proliferation and differentiation of follicular granulosa cells during the peri-ovulatory period. This study seeks to determine the contribution of female germ cells toward the initial activation and subsequent maintenance of Notch signaling within somatic granulosa cells of the ovary. To address this issue, Transgenic Notch Reporter (TNR) mice were crossed with Sohlh1-mCherry (S1CF) transgenic mice to visualize Notch active cells (EGFP) and germ cells (mCherry) simultaneously in the neonatal ovary. To test the involvement of oocytes in activation of Notch signaling in ovarian somatic cells, we ablated germ cells using Busulfan, a chemotherapeutic alkylating agent, or investigated KitWv/Wv (viable dominant white-spotting) mice that lack most germ cells. The data reveal that Notch pathway activation in granulosa cells is significantly suppressed when germ cells are reduced. We further demonstrate that disruption of the gene for the Notch ligand Jag1 in oocytes similarly impacts Notch activation and that recombinant JAG1 enhances Notch target gene expression in granulosa cells. These data are consistent with the hypothesis that germ cells provide a ligand, such as Jag1, that is necessary for activation of Notch signaling in the developing ovary.//////////////////
Notch signaling regulates differentiation and steroidogenesis in female mouse ovarian granulosa cells. Prasasya RD et al. (2017) The Notch pathway is a highly conserved juxtacrine signaling mechanism that is important for many cellular processes during development, including differentiation and proliferation. While Notch is important during ovarian follicle formation and early development, its functions during the gonadotropin-dependent stages of follicle development are largely unexplored. We observed positive regulation of Notch activity and expression of Notch ligands and receptors following activation of the LH-receptor in prepubertal mouse ovary. JAG1, the most abundantly expressed Notch ligand in mouse ovary, revealed a striking shift in localization from oocytes to somatic cells following hormone stimulation. Using primary cultures of granulosa cells, we investigated the functions of Jag1 using siRNA knockdown. The loss of JAG1 led to suppression of granulosa cell differentiation as marked by reduced expression of enzymes and factors involved in steroid biosynthesis, and in steroid secretion. Jag1 knockdown also resulted in enhanced cell proliferation. These phenotypes were replicated, although less robustly, following knockdown of the obligate canonical Notch transcription factor RBPJ. Intracellular signaling analysis revealed increased activation of the mitogenic PI3K/AKT and MAPK/ERK pathways following Notch knockdown, with a MEK inhibitor blocking the enhanced proliferation observed in Jag1 knockdown granulosa cells. Activation of YB-1, a known regulator of granulosa cell differentiation genes was suppressed by Jag1 knockdown. Overall, this study reveals a role of Notch signaling in promoting the differentiation of preovulatory granulosa cells, adding to the diverse functions of Notch in the mammalian ovary.//////////////////
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?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.
Microarray analyses of newborn mouse ovaries lacking Nobox. Choi Y et al. Nobox is a homeobox gene expressed in oocytes and critical in oogenesis. Nobox deficiency leads to rapid loss of postnatal oocytes. Early oocyte differentiation is poorly understood. We hypothesized that lack of Nobox perturbs global expression of genes preferentially expressed in oocytes as well as microRNAs. We compared Nobox knockout and wild-type ovaries using Affymetrix 430 2.0 microarray platform. We discovered that 28 (74%) of 38 of the genes downregulated more than 5-fold in the absence of Nobox were preferentially expressed in oocytes, whereas only 5 (15%) of 33 genes upregulated more than 5-fold in the absence of Nobox were preferentially expressed in oocytes. Protein-binding microarray helped identify nucleotide motifs that NOBOX binds and that several downregulated genes contain within putative promoter regions. MicroRNA population in newborn ovaries deficient of Nobox was largely unaffected. Genes whose proteins are predicted to be secreted but were previously unknown to be significantly expressed in early oogenesis were downregulated in Nobox knockouts and included astacin-like metalloendopeptidase (Astl), Jagged 1 (Jag1), oocyte-secreted protein 1 (Oosp1), fetuin beta (Fetub), and R-spondin 2 (Rspo2). In addition, pluripotency-associated genes Pou5f1 and Sall4 are drastically downregulated in Nobox-deficient ovaries, whereas testes-determining gene Dmrt1 is overexpressed. Our findings indicate that Nobox is likely an activator of oocyte-specific gene expression and suggest that the oocyte plays an important role in suppressing expression of male-determining genes, such as Dmrt1.
Expression regulated by
Growth Factors/ cytokines
Comment
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.
Ovarian localization
Oocyte
Comment
Johnson J,et al reported that Notch pathway genes are expressed in mammalian ovarian
follicles.
Genes that regulate the proliferation and differentiation of
granulosa cells are beginning to be elucidated. In this study, the expression
patterns of Notch receptor genes and their ligands, which have been shown to
regulate cell-fate decisions in many systems during development, were examined
in the mammalian ovary. In situ hybridization data showed that Notch2, Notch3,
and Jagged2 were expressed in an overlapping pattern in the granulosa cells of
developing follicles. Jagged1 was expressed in oocytes exclusively. Downstream
target genes of Notch also were expressed in granulosa cells. These data
implicate the Notch signaling pathway in the regulation of mammalian
folliculogenesis.
Follicle stages
Comment
Unique patterns of Notch1, Notch4 and Jagged1 expression in ovarian vessels during folliculogenesis and corpus luteum formation Vorontchikhina MA, et al .
Notch signaling functions to regulate cell-fate decisions by modulating differentiation, proliferation, and survival of cells. Notch receptors and ligands are expressed in embryonic vasculature and are required for the remodeling of the primary embryonic vasculature of mice. Here, we characterize the expression patterns of Notch1, Notch4, and Jagged1 proteins during the process of folliculogenesis and corpus luteum formation in the mouse ovary, an organ with dynamic physiological angiogenic growth. These Notch proteins and ligand are expressed in a subset of ovarian vessels, including both mature ovarian vasculature as well as angiogenic neovessels. Their expression in the ovary was found in both endothelial and vascular associated mural cells. Our data suggest a complex regulatory role for the Notch signaling pathway during mouse oogenesis and ovarian neovascularization.
Phenotypes
Mutations
3 mutations
Species: mouse
Mutation name: None
type: naturally occurring fertility: fertile Comment:Kiernan et al. (2001) provided experimental evidence that Notch signaling may be involved in specifying sensory
regions by showing that a dominant mouse mutant headturner (Htu) contains a missense mutation in the Jag1 gene
and displays missing posterior and sometimes anterior ampullae, structures that house the sensory cristae.
Heterozygotes also demonstrate a significant reduction in the number of outer hair cells in the organ of Corti.
Species: mouse
Mutation name: None
type: null mutation fertility: subfertile Comment: Notch signaling regulates ovarian follicle formation and coordinates follicular growth. Vanorny DA 2014 et al.
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 (J1KO) or Notch2 within granulosa cells (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 (MOFs), 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.
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Species: other
Mutation name: type: targeted overexpression fertility: fertile Comment: Jagged 1 Rescues the Duchenne Muscular Dystrophy Phenotype. Vieira NM et al. (2015) Duchenne muscular dystrophy (DMD), caused by mutations at the dystrophin gene, is the most common form of muscular dystrophy. There is no cure for DMD and current therapeutic approaches to restore dystrophin expression are only partially effective. The absence of dystrophin in muscle results in dysregulation of signaling pathways, which could be targets for disease therapy and drug discovery. Previously, we identified two exceptional Golden Retriever muscular dystrophy (GRMD) dogs that are mildly affected, have functional muscle, and normal lifespan despite the complete absence of dystrophin. Now, our data on linkage, whole-genome sequencing, and transcriptome analyses of these dogs compared to severely affected GRMD and control animals reveals that increased expression of Jagged1 gene, a known regulator of the Notch signaling pathway, is a hallmark of the mild phenotype. Functional analyses demonstrate that Jagged1 overexpression ameliorates the dystrophic phenotype, suggesting that Jagged1 may represent a target for DMD therapy in a dystrophin-independent manner. PAPERCLIP.//////////////////