Disease relevance of Notch3

• Recently, Notch receptors have been hypothesized to play a role in neurodegeneration and in particular in Alzheimer's disease (Notch1) and CADASIL (Notch3) [1].
• Constitutive activation of NF-kappaB and T-cell leukemia/lymphoma in Notch3 transgenic mice [2].
• Expression of activated Notch3 in transgenic mice enhances generation of T regulatory cells and protects against experimental autoimmune diabetes [3].
• Although the mice did not live long enough to assess tumor development, these findings demonstrate that ectopic expression of Notch3 in airway epithelium potentially contributes to the multistep evolution of lung cancer through the inhibition of terminal differentiation [4].
• We have previously demonstrated the expression of Notch3 in a subset of lung adenocarcinomas [4].

Psychiatry related information on Notch3

• Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an increasingly recognized adult-onset autosomal dominant vascular dementia, caused by highly stereotyped mutations in the Notch3 receptor [5].

High impact information on Notch3

• Notch3 is required for arterial identity and maturation of vascular smooth muscle cells [6].
• We further show that Notch3 is required for arterial specification of vSMC but not of endothelial cells [6].
• Delta1-Notch3 interactions bias the functional differentiation of activated CD4+ T cells [7].
• We provide genetic and biochemical evidence that Notch3 triggers multiple NF-kappaB activation pathways [8].
• The phenotypes of pre-malignant thymocytes and of lymphomas indicate a novel and particular role for Notch3 in co-ordinating growth and differentiation of thymocytes, across the pre-T/T cell transition, consistent with the normal expression pattern of Notch3 [2].

Chemical compound and disease context of Notch3

• Furthermore, streptozotocin-induced autoimmune diabetes fails to develop in transgenic mice carrying the constitutively active intracellular domain of Notch3 in thymocytes and T cells [3].

Biological context of Notch3

• These results support the idea that other Notch genes functionally compensate for Notch3 during embryonic development [9].
• It is notable that Notch2 and Notch3 showed an effect on T lymphopoiesis similar to that of Notch1 [10].
• These expression patterns imply that the different Notch genes may have very distinct functions during hematopoiesis, and that Notch3 could be a specific regulator of mast cell development [11].
• Here, we provide direct evidence that the Delta1 interaction with Notch3 on CD4+ T cells transduces signals, promoting development toward the Th1 phenotype [7].
• Our data suggest that a finely tuned interplay between Notch3 and pre-TCR pathways converges on regulation of NF-kappaB activity, leading to differential NF-kappaB subunit dimerization that regulates distinct gene clusters involved in either cell differentiation or proliferation/leukemogenesis [8].

Anatomical context of Notch3

• Notch2, Notch3, and Dll1 are initially expressed by most cells within the pituitary primordium and become restricted to a subset of the progenitor cell pool as differentiated pituitary cells begin to appear [12].
• Therefore, the thymus might be a target tissue affected by Notch3 deficiency [9].
• 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 [13].
• Notch3, Dll-1 and Dtx1exhibit a stage dependent expression as their mRNAs are detected in 2-cell embryos and in hatched blastocysts, but are absent or weakly detected at the morula stage [14].
• In addition we could detect Notch3 mRNA and protein in cell lines representing mast cell progenitors [11].

Associations of Notch3 with chemical compounds

• Notch3 and 4 were not detected in the presence or absence of cortisol [15].
• During regeneration of spermatogonia in busulfan-treated mice, the nuclei of all proliferating cells showed staining for the intracellular domain of Notch3 [16].
• Here we describe the generation of a mouse knockin model for one of the most prevalent CADASIL mutations, an arginine to cysteine transition at position 141, R141C, which corresponds to mutation R142C in mouse NOTCH 3 [17].

Regulatory relationships of Notch3

• These observations support a model in which the upregulation of pre-TCR signalling seems to be the prerequi-site for Notch3-induced inhibition of E2A, thus leading to the development of lymphoma in Notch3 transgenic mice [18].
• As somitogenesis begins, Notch 2 expression is activated in newly forming somites while Notch 3 is activated in mature somites [19].
• It has been shown that Notch3-induced T-cell leukaemia is abrogated by the inactivation of pTalpha/pre-T-cell antigen receptor (pre-TCR) [18].

Other interactions of Notch3

• Notch1, Notch2 and Notch3 were immunohistochemically detected in non-neuroendocrine cells [20].
• Moreover, a differential distribution of Notch3, with respect to Notch1, was observed in distinct age-related thymocyte subsets [21].
• These results suggest distinct roles of Notch1 and Notch3 in the neurogenesis of the peripheral olfactory system [22].
• Notch 3 and Jagged 1 were absent from developing articular cartilage but were present in deeper layers at later time points (> 1 month) and both receptor and ligand were expressed in hypertrophic chondrocytes at all ages examined [23].
• There is also evidence that the mouse Notch4 gene is the result of a rapid divergence from a Notch3-like gene [24].

Analytical, diagnostic and therapeutic context of Notch3

• To analyze the in vivo role of the Notch3 gene in mice, we created a deletion allele by gene targeting [25].
• In situ hybridization data showed that Notch2, Notch3, and Jagged2 were expressed in an overlapping pattern in the granulosa cells of developing follicles [26].

References