Disease relevance of Notch1

• Unexpectedly, ablation of Notch1 results in epidermal and corneal hyperplasia followed by the development of skin tumors and facilitated chemical-induced skin carcinogenesis [1].
• Itch genetically interacts with Notch1 in a mouse autoimmune disease model [2].
• In the coculture on the monolayer of OP-9, which was originally known to support B cell specific development, hemopoietic progenitors developed into Thy-1(+)CD25(+) T lineage cells if the progenitor cells were infected with the retrovirus containing Notch1 intracellular domains [3].
• RESULTS: We observed that N2a neuroblastoma cells expressing an activated form of Notch, Notch1(IC), produced shorter neurites compared with controls, whereas N2a cell lines expressing a dominant-negative Notch1 or a dominant-negative Delta1 construct extended longer neurites with a greater number of primary neurites [4].
• 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 [5].
• These results provide a molecular and cellular framework for understanding the role of Notch signaling in the etiology of congenital heart disease [6].
• Notch1 co-opts Lef1 during the process of transformation to maintain survival of T-cell lymphomas [7].

Psychiatry related information on Notch1

• Recently, Notch receptors have been hypothesized to play a role in neurodegeneration and in particular in Alzheimer's disease (Notch1) and CADASIL (Notch3) [8].
• Learning and memory deficits in Notch mutant mice [9].
• Deficits in the Notch pathway are responsible for Alagille and Cadasil syndromes, which are associated with mental retardation and dementia [9].
• Similarly, Notch homologues in Caenorhabditis elegans are involved in cell decision-making steps [10].
• Transient administration of Notch ligands to the brain of adult rats increases the numbers of newly generated precursor cells and improves motor skills after ischaemic injury [11].

High impact information on Notch1

• HectH9-mediated ubiquitination of Myc is required for transactivation of multiple target genes, recruitment of the coactivator p300, and induction of cell proliferation by Myc [12].
• Expression of the basic helix-loop-helix factor Hes7, an effector of Notch signaling, follows a 2-hour oscillatory cycle controlled by negative feedback; this is proposed to be the molecular basis for the somite segmentation clock [13].
• Th2 differentiation induced by APC is abrogated in T cells lacking the Notch effector RBPJkappa [14].
• Expression of these different Notch ligands on APC is induced by Th1- or Th2-promoting stimuli [14].
• Notch1 deficiency in skin and in primary keratinocytes results in increased and sustained expression of Gli2, causing the development of basal-cell carcinoma-like tumors [1].

Chemical compound and disease context of Notch1

• Additionally, the aberrant expression of adipsin, and its presence in feces may serve as a noninvasive biomarker of gastrointestinal toxicity associated with perturbed Notch signaling [15].
• The efficacy of STI571 in reducing Abeta without affecting Notch-1 cleavage may prove useful as a basis for developing novel therapies for Alzheimer's disease [16].
• Interestingly, the signals generated by pertussis toxin, which increase Notch expression, can dominate the signals by phorbol ester and ionomycin, steering thymocyte development to CD8 lineage [17].

Biological context of Notch1

• Our results indicate that Notch1 functions as a tumor-suppressor gene in mammalian skin [1].
• Embryos homozygous for mutations of both the Notch4 and Notch1 genes often displayed a more severe phenotype than Notch1 homozygous mutant embryos [18].
• Here, we show that suppression of Wnt signaling by Notch1 activation is mediated, at least in part, by down-modulation of Wnts gene expression. p21 is a negative regulator of Wnts transcription downstream of Notch1 activation, independently of effects on the cell cycle [19].
• The Notch1 tumor-suppressor function was associated with down-regulation of Wnt signaling [19].
• Consistent with these results, expression of Cre recombinase in sensory neurons from numb conditional mutants results in reduced endocytosis, a significant increase in nuclear Notch1, and severe reductions in axon branch points and total axon length [20].

Anatomical context of Notch1

• 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 [21].
• Therefore, we used a tissue-specific inducible gene-targeting approach to study the physiological role of the Notch1 receptor in the mouse epidermis and the corneal epithelium of adult mice [1].
• Hence, PS1 is required for the spatiotemporal expression of Notch1 and Dll1, which are essential for somite segmentation and maintenance of somite borders [22].
• Presenilin 1 is required for Notch1 and DII1 expression in the paraxial mesoderm [22].
• Pax5 thereby interfered with T lineage commitment and early thymocyte development by repressing the transcription of the T cell specification gene Notch1 [23].

Associations of Notch1 with chemical compounds

• However, T cell induction by intracellular Notch1 failed unless both OP-9 and IL-7 were present [3].
• Cortisol increased the rate of Notch1 and 2 transcription and, in transcriptionally arrested cells, did not modify the decay of the transcripts, indicating a transcriptional level of control [24].
• The elevated expression of Notch1 and Notch2 induced by lipopolysaccharide was repressed by testosterone at lower levels, but enhanced at higher hormone levels [25].
• Unique patterns of Notch1, Notch4 and Jagged1 expression in ovarian vessels during folliculogenesis and corpus luteum formation [26].
• Finally we found that OPC-targeted Notch1 ablation in cuprizone-treated Plp-creER Notch1(lox/lox) transgenic mice yielded no significant differences in remyelination parameters between knock-out and control mice [27].
• Accordingly, we found that Notch1 signaling is linked to vitamin A metabolism by regulating the expression of cellular retinol binding protein 1 (CRBP1), required to generate a pool of intracellular retinol [28].
• Overall, our data suggest that an important relationship exists between LPS-mediated inflammation and the Notch1 signaling pathway, and that this relationship intimately involves the nitration of Notch1-IC tyrosine residues [29].

Physical interactions of Notch1

• Functional involvement of the Notch pathway in osteoblastic differentiation has been previously investigated using the truncated intracellular domain, which mimics Notch signaling by interacting with the DNA-binding protein CBF-1 [30].
• Mfge8 (milk fat globule-EGF-factor 8) encodes a soluble integrin-binding protein containing two Notch-like EGF domains and two discoidin domains [31].
• We show here that both mouse and human promoter regions of Nrarp share two conserved regions located approximately 2 and approximately 3 kb upstream of the transcription start site each containing a perfect putative binding site for the Notch-dependent transcription factor Su(H) [32].
• For instance, in fetal brain, it has been shown that the neurogenic transcription factor Neurogenin1 inhibits formation of a STAT3/p300/ Smad1 complex and that the oligodendrocytic transcription factor OLIG2 does the same [33].
• Here we demonstrate that, in differentiating skeletal muscle cells, p300 physically interacts with the myogenic basic helix-loop-helix (bHLH) regulatory protein MyoD at its DNA binding sites [34].

Enzymatic interactions of Notch1

• We show that full-length Notch1 [N1(FL)] transfected into wild type (WT) primary neurons is cleaved in the presence of its biological ligand Delta (Dl) and translocated to the nucleus within 1--3 min of ligand addition [35].
• Presenilin-1 D257A and D385A mutants fail to cleave Notch in their endoproteolyzed forms, but only presenilin-1 D385A mutant can restore its gamma-secretase activity with the compensatory overexpression of normal C-terminal fragment [36].

Regulatory relationships of Notch1

• Pax5 promotes B lymphopoiesis and blocks T cell development by repressing Notch1 [23].
• Here we report that Notch1 can directly regulate Tbx21 through complexes formed on the Tbx21 promoter [37].
• These results provide direct evidence that PS1 controls neuronal differentiation in association with the downregulation of Notch signalling during neurogenesis [38].
• Consistent with a role for Notch1 in regulating Gata2, we observe increased expression of this gene in 32D cells expressing activated Notch1 [39].
• Nrarp overexpression is able to block Notch-induced activation of CBF-1 [40].
• These phenotypes were substantially rescued either by enhancing Notch signaling or by suppressing endogenous ADAM10 activity [41].
• The Down-syndrome-associated kinase DYRK1A is coexpressed with Notch in various tissues during embryonic development [42].

Other interactions of Notch1

• Examination of the RNA expression pattern of the Notch2 gene, another Notch gene family member, indicated that it partially overlapped the Notch1 expression pattern [43].
• Mouse Numb homologs antagonize Notch1 signaling pathways through largely unknown mechanisms [20].
• However, the Notch4 mutation displayed genetic interactions with a targeted mutation of the related Notch1 gene [18].
• Thus, p21 acts as a selective negative regulator of transcription and links the Notch and Wnt signaling pathways in keratinocyte growth control [19].
• The Notch target genes Hey1 and Hey2 are required for embryonic vascular development [44].
• Inhibition of Notch signaling at this stage appears to be mediated by the transient expression of Numb in the hemangioblast-derived blast cell colonies [45].

Analytical, diagnostic and therapeutic context of Notch1

• TUNEL staining showed reduced apoptosis in the thymus of itch animals that carry the Notch1 transgene [2].
• In situ hybridization studies show no indication of altered Notch1 expression patterns in Notch2 mutant mice [46].
• Northern blot experiments showed the expression of Notch1 in MC3T3-E1 osteoblastic cells at early differentiation stages [47].
• ActN1 was detected by immunohistochemistry using an antibody that specifically recognizes the processed form of the intracellular domain of Notch1 cleaved by presenilin/gamma-secretase activity [48].
• Immunofluorescence staining revealed the progressive acquisition of Notch1 and Jagged1 proteins by the emerging endothelium [49].

References