Disease relevance of Jag2

• We previously reported that mice deficient in Jag2, which encodes a cell surface ligand for the Notch family receptors, have cleft palate associated with palate-tongue fusions [1].
• The AER hyperplasia and its effect on early digital patterning distinguish sm from many other syndactylies that result from later failure of cell death in the interdigital areas [2].

High impact information on Jag2

• In addition, genetic deletion of Jag2 results in a significant increase in sensory hair cells, presumably as a result of a decrease in Notch activation [3].
• Here we show that genes encoding the receptor protein Notch1 and its ligand, Jagged 2, are expressed in alternating cell types in the developing sensory epithelium [3].
• Here we use positional cloning to show that the gene mutated in sm mice encodes the putative Notch ligand Serrate [2].
• In sm homozygotes, the apical ectodermal ridge (AER) is hyperplastic by embryonic day 10.5, leading to abnormal dorsoventral thickening of the limb bud, subsequent merging of the skeletal condensations that give rise to cartilage and bone in the digits, and eventual fusion of digits [2].
• Jagged2 promotes the development of natural killer cells and the establishment of functional natural killer cell lines [4].

Biological context of Jag2

• We report here the cloning of the human and murine JAGGED2 (JAG2), a Serrate-like gene, and the analysis of its expression pattern during embryogenesis [5].
• Jagged2 can inhibit Notch1-32D cell differentiation induced by G-CSF, but Delta4 cannot [6].
• Notch1 and 2 cooperate in limb ectoderm to receive an early Jagged2 signal regulating interdigital apoptosis [7].
• Jagged2 induces cell cycling in confluent fibroblasts susceptible to density-dependent inhibition of cell division [8].
• The Jagged2 gene maps to chromosome 12 and is a candidate for the lgl and sm mutations [9].

Anatomical context of Jag2

• In contrast to the Jag2 gene, which is expressed in hair cells, the Lfng gene is expressed in non-sensory supporting cells in the mouse cochlea [10] [10].
• We have shown previously that in mice homozygous for a targeted null mutation of the Jagged2 (Jag2) gene, which encodes a Notch ligand, supernumerary hair cells differentiate in the cochlea of the inner ear [7] [10].
• In mice homozygous for targeted mutations of both Jag2 and Lfng, the generation of supernumerary hair cells in the inner hair cell row is suppressed, while supernumerary hair cells in the outer hair cell rows are unaffected [10].
• At E12.5, Jag2 expression is upregulated in differentiated neurons of the central and peripheral nervous system and in the inner neuroblastic layer of the developing retina [5].
• Jag2 was found to be expressed as early as E9 in the surface ectoderm of the branchial arches and in the apical ectodermal ridge (AER) of the developing limb [5].

Regulatory relationships of Jag2

• Here we demonstrate that a mutation in the Lfng gene partially suppresses the effects of the Jag2 mutation on hair cell development [10].
• Notably, the expression of Jagged2 is downregulated throughout the palate epithelium in Fgf10 mutants while Tgfbeta3 is misexpressed in the palatal epithelium at the oral side [11].

Other interactions of Jag2

• Expression of Jagged2 and Delta1 seldom was affected by the stimuli [12].
• Notch 2 and 4, Delta and Jagged 2 showed a broadly similar distribution, being present throughout the articular cartilage during development and becoming increasingly restricted to deeper layers with age [13].
• Results in Jag2 mutant cochleae suggest that Math1 transcripts are ultimately maintained in a larger number of cells as compared with wild-type, while transcripts for HES5 are dramatically reduced throughout the epithelium [14].
• At the molecular level, we show that Fgf10 is epistatic to Jagged2 and Tgfbeta3 in the developing palate [11].

Analytical, diagnostic and therapeutic context of Jag2

• When in situ hybridization was performed, expression of the murine Jagged2 homolog was found to be highest in fetal thymus, epidermis, foregut, dorsal root ganglia, and inner ear [15].
• In Northern blot analysis of RNA from tissues of 2-week-old mice, the 5.0-kb Jagged2 transcript was most abundant in heart, lung, thymus, skeletal muscle, brain, and testis [15].
• Using a coculture system we found that exogenous, full-length mJagged2 promoted the survival and proliferation of hematopoietic progenitors, including the high-proliferative potential colony-forming cells [16].
• Western blot analyses showed that endothelial cells also expressed high levels of Jagged2, but stromal fibroblasts did not [16].

References