Disease relevance of Notch2

• Using gene targeting procedures, we disrupted the mouse Notch2 gene by replacing all but one of the ankyrin repeat sequences in the cytoplasmic domain with the E. coli (beta)-galactosidase gene [1].
• In the present work we present evidence that gamma-radiation-induced thymic lymphomas in (C57BL/6 J x BALB/c) F1 hybrid mice often exhibit increased levels of Notch1 expression, but, contrary to what was expected, they also exhibit a clearly reduced Notch2 mRNA expression, suggesting a cooperative antagonism of these genes [2].
• Deletion of Notch1 and/or Notch2 in melanoblasts did not induce a congenital defect [3].
• Disruption of pulmonary Notch-2 signaling continued in newborn low-Foxf1(+/-) mice, which died of lung hemorrhage and failed to compensate for Foxf1 haploinsufficiency [4].
• We demonstrate that different lots of a baculovirus-derived recombinant N2 protein, in the absence of other influenza virus proteins, can induce neuraminidase-specific antibodies, reduce the replication of both homologous and heterovariant virus in mice, and suppress disease, as it is manifested by total body weight loss [5].

High impact information on Notch2

• Examination of the RNA expression pattern of the Notch2 gene, another Notch gene family member, indicated that it partially overlapped the Notch1 expression pattern [6].
• Notch2 is preferentially expressed in mature B cells and indispensable for marginal zone B lineage development [7].
• Notch1 but not Notch2 is essential for generating hematopoietic stem cells from endothelial cells [8].
• During ductal plate remodeling, Notch2 and Hes1 were up-regulated exclusively in the biliary epithelial cells that form tubular structures [9].
• 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 [9].

Biological context of Notch2

• We report that expression of Notch signaling genes is spatially and temporally regulated in pituitary embryogenesis and implicate Notch2 in the differentiation of several cell lineages [10].
• We also show a marked downregulation in the expression of Notch2, Jagged1, Hes1, mSfrp1, and mFrz7 in cerebella of developing mice with reduced Hh signaling, suggesting that Hh signaling regulates the expression of these genes [11].
• Cells from Notch2 mutant mice attach and grow normally in culture, demonstrating that Notch2 deficiency does not interfere with cell proliferation and that expression of the Notch2-(beta)-gal fusion protein is not toxic per se [1].
• Notch2 homozygous mutant mice die prior to embryonic day 11.5, whereas heterozygotes show no apparent abnormalities and are fully viable [1].
• Although studies have shown that the Notch2 family member is critical for embryonic development, little is known concerning its role in hematopoiesis [12].

Anatomical context of Notch2

• All of the genes examined (except Notch2) are also expressed in subsets of cells within circumvallate taste buds in adult mice, although Notch1 is restricted to basal cells adjacent to taste buds [13].
• In the newborn mouse liver, Notch2 and Notch3 are expressed in opposing cell populations, suggesting they play different roles in cell fate determination during bile duct development [14].
• Testosterone influenced the expression of Notch1, Notch2 and Jagged1 induced by lipopolysaccharide in macrophages [15].
• Analysis of Notch2 expression patterns, revealed by X-gal staining, demonstrated that the Notch2 gene is expressed in a wide variety of tissues including neuroepithelia, somites, optic vesicles, otic vesicles, and branchial arches, but not heart [1].
• In situ hybridization data showed that Notch2, Notch3, and Jagged2 were expressed in an overlapping pattern in the granulosa cells of developing follicles [16].

Associations of Notch2 with chemical compounds

• The elevated expression of Notch1 and Notch2 induced by lipopolysaccharide was repressed by testosterone at lower levels, but enhanced at higher hormone levels [15].
• In addition, Notch2 expression correlated with the incorporation of bromodeoxyuridine both in vivo and in vitro [17].
• Treatment with kainic acid resulted in marked Notch2 induction in pyramidal neurons of CA1 and in a subpopulation of CA3 neurons surviving the lesion and protein expression was still detectable 6 weeks after drug treatment [18].
• Long-lasting induction of Notch2 in the hippocampus of kainate-treated adult mice [18].

Physical interactions of Notch2

• However, activation of Notch-1 and Notch-2 with cell-bound Notch ligand did not result in differentiation of mature DCs or macrophages [19].

Regulatory relationships of Notch2

• Immunohistochemical analysis showed that Jagged1 was expressed in the cells surrounding the portal veins and Notch2 was expressed in most hepatic cells at mid gestation when ductal plates are formed surrounding the portal veins [20].
• As somitogenesis begins, Notch 2 expression is activated in newly forming somites while Notch 3 is activated in mature somites [21].

Other interactions of Notch2

• All Notch signaling pathway receptors and ligands tested were expressed in the rhombic lip at embryonic date 14, with highest levels of Notch2 and Jag1 [22].
• Notch1, Notch2 and Notch3 were immunohistochemically detected in non-neuroendocrine cells [23].
• Transgenic overexpression of Prop1 is not sufficient for enhancement of endogenous Notch2 expression, indicating that there are multiple inputs into this pathway [10].
• Hypertrophic chondrocytes within the growth plate also expressed Notch 2 and 4, Delta and Jagged 2 (which was also expressed in prehypertrophs) [24].
• In contrast, in newborn high-Foxf1(+/-) lungs, Notch-2 signaling was restored to the level found in wild-type mice, which was associated with normal microvascular formation and survival [4].

Analytical, diagnostic and therapeutic context of Notch2

• In situ hybridization studies show no indication of altered Notch1 expression patterns in Notch2 mutant mice [1].
• Notch2 expression by glial cells was clearly confirmed in dissociated cell cultures [17].

References