Disease relevance of Jag1

• Jag1 encodes a ligand in the Notch pathway and has been identified as the disease-causing gene for the developmental disorder Alagille syndrome [1].
• Our results show that Notch1 and Jagged1 are first expressed in the otic vesicle, likely involved in differentiation of the VIIIth nerve ganglion neurons, and subsequently within the inner ear sensory epithelia, temporally coincident with initial hair cell differentiation [2].
• Jagged signalling via Notch receptors on oligodendrocyte precursor cells (OPCs) inhibits their differentiation during development and the finding that both notch and jagged are expressed in multiple sclerosis lesions has fostered the view that this signalling pathway may explain remyelination failure [3].
• Mutations in the DSL (Delta, Serrate, Lag2) Notch (N) ligand Delta-like (Dll) 3 cause skeletal abnormalities in spondylocostal dysostosis, which is consistent with a critical role for N signaling during somitogenesis [4].

High impact information on Jag1

• We demonstrate that Jagged constitutes an instructive signal for Th2 differentiation, which is independent of IL4/STAT6 [5].
• Here we use positional cloning to show that the gene mutated in sm mice encodes the putative Notch ligand Serrate [6].
• Phosphorylation of histone H4 Ser1 regulates sporulation in yeast and is conserved in fly and mouse spermatogenesis [7].
• In this study we show that histone H4 Ser1 is phosphorylated (H4 S1ph) during sporulation, starting from mid-sporulation and persisting to germination, and is temporally distinct from earlier meiosis-linked H3 S10ph involved in chromosome condensation [7].
• Similar vascular defects are observed in Jagged1 and Notch1 knockout mice [8].

Biological context of Jag1

• CONCLUSIONS: Distinct expression patterns of Jagged1 and Manic Fringe suggest that their corresponding proteins could regulate cell fate choices during hematopoiesis and may be responsible for regulating communication between lineage compartments during hematopoietic development [9].
• In a series of screenings of cDNAs constructed by a cDNA library subtraction technique, we identified Jagged1, one of the Notch ligands, as a gene up-regulated by macrophage colony-stimulating factor (M-CSF) in bone marrow macrophages [10].
• Key words: Cell fate, delta, jagged, presenilin, spermatogenesis [11].
• Bile duct proliferation in liver-specific Jag1 conditional knockout mice: effects of gene dosage [1].
• We crossed Jag1(loxP) mice with a transgenic line carrying Cre recombinase under the control of the albumin promoter and alpha-fetoprotein enhancer to ablate Jag1 in hepatoblasts [1].

Anatomical context of Jag1

• In the absence of Jag1, by contrast, the total number of these cells is strongly reduced, with complete loss of cochlear outer hair cells and some groups of vestibular hair cells, indicating that Jag1 is required for the prosensory inductive function of Notch [12].
• Here, using conditional gene targeting, we show that the Jag1 gene is required for the normal development of all six sensory organs within the inner ear [13].
• Our findings suggest that in addition to its role in microfibrils, MAGP-2 may also affect cellular differentiation through modulating the Notch signaling pathway either by binding to cell surface DSL ligands or by facilitating release and/or stabilization of a soluble extracellular form of Jagged1 [14].
• Expression of Jagged1 gene in macrophages and its regulation by hematopoietic growth factors [10].
• The primary bone marrow fibroblastic stromal cells, and murine stromal cell lines, such as PA6 and ST2, also expressed Jagged1 transcript, at levels comparable to the steady-state level in macrophages [10].

Associations of Jag1 with chemical compounds

• We examined the expression and regulation of Notch1, 2, 3, and 4 and their ligands Jagged 1 and 2 and Delta 1 and 3 by cortisol in cultures of osteoblastic MC3T3-E1 cells [15].
• In addition, the expression of Jagged1 was enhanced by various amounts of testosterone [16].
• Unique patterns of Notch1, Notch4 and Jagged1 expression in ovarian vessels during folliculogenesis and corpus luteum formation [17].
• Testosterone influenced the expression of Notch1, Notch2 and Jagged1 induced by lipopolysaccharide in macrophages [16].
• Replacement by alanine of Ser2 of gamma12 (Ser1 of a mature gamma12 protein), a phosphorylation site for protein kinase C, eliminated these effects of gamma12, whereas a mutant in which Ser2 was replaced with glutamic acid showed effects equivalent to wild-type gamma12 [18].

Regulatory relationships of Jag1

• Our findings indicate that the Jagged/Notch signaling pathway might actively participate in the regulation of myelination during central nervous system development and suggest that certain neuronal populations might regulate whether their axons are myelinated by the expression of inhibitory signals such as Jagged1 [19].
• The Notch ligand encoded by the Jag1 gene was expressed in developing glomeruli in cells adjacent to Notch2-expressing cells [20].
• Coculture with Balb3T3 cells stably overexpressing Jagged1 induced transactivation of the Hes1 promoter and increased expression of biliary lineage markers, such as cytokeratin-19 and gamma-glutamyl transpeptidase, in WB-F344 cells [21].
• We show that Jagged1 is required by mitotic cells in the subventricular zone (SVZ) and stimulates self-renewal of multipotent epidermal growth factor-dependent NSCs [22].

Other interactions of Jag1

• Notch ligands with contrasting functions: Jagged1 and Delta1 in the mouse inner ear [12].
• Among the Notch ligands, Delta 1 and Jagged 1 were localized exclusively in spermatogonia and Sertoli cells, respectively [11].
• The related microfibrillar protein MAGP-1 was also found to interact with DSL ligands but, unlike MAGP-2, was unable to facilitate the shedding of Jagged1 [14].
• Expression of the Jagged1 gene was markedly up-regulated by growth factors for the cells, i.e., M-CSF, granulocyte-macrophage colony-stimulating factor, and interleukin-3 [10].
• In S-shaped bodies, Hes1 expression was detected in the middle part which gives rise to the proximal tubule, but also extended into the lower and upper parts which give rise to the glomerulus and distal tubule, respectively, and was similar to the proximal-distal expression patterns for Notch1 and Jagged1 in these nephrogenic structures [23].

Analytical, diagnostic and therapeutic context of Jag1

• RESULTS: The bone marrow macrophages expressed Jagged1 but not Jagged2 and Delta1 at a level that was detectable by Northern blot analysis [10].
• The effect of Jagged1 on biliary differentiation was assessed by using an in vitro 2-cell coculture system with WB-F344 cells, a cell line derived from normal adult rat liver [21].
• METHODS: The expression patterns of Jagged1, Notch2, and Hes1 during mouse liver development were analyzed by semiquantitative reverse-transcription polymerase chain reaction (RT-PCR), immunoblot, and immunohistochemistry [21].
• Using reverse transcription-polymerase chain reaction, in situ hybridization, immunohistochemistry, and Western blotting, we demonstrate expression of Jagged 1 in primary stromal cultures [24].
• Immunofluorescence staining revealed the progressive acquisition of Notch1 and Jagged1 proteins by the emerging endothelium [25].

References