Role of Delta-Like-3 in Mammalian Somitogenesis and Vertebral Column Formation

Chapman, Gavin; Dunwoodie, Sally L.

doi:10.1007/978-0-387-09606-3_5

Cited by 3 publications

(3 citation statements)

References 148 publications

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“…1 and 2, although larger portions of mN1 (e.g. EGF [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18] were also analyzed to confirm that utilization of glycosylation sites was not affected by the size of the fragment being analyzed. Modified peptides were identified by neutral loss of the O-glucose saccharides upon low energy CID fragmentation.…”

Section: Mouse Notch1 Is Extensively Modified With O-glucose Inmentioning

confidence: 99%

“…Defects in Notch signaling have been implicated in a number of human diseases, including several forms of cancer, vascular defects such as cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (4 -6), multiple sclerosis (6), and a number of developmental syndromes (4,(7)(8)(9)(10). The canonical Notch signaling pathway is initiated by the interaction of Notch with its ligand on an apposed cell.…”

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confidence: 99%

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O-Glucose Trisaccharide Is Present at High but Variable Stoichiometry at Multiple Sites on Mouse Notch1

Rana¹,

Nita‐Lazar²,

Takeuchi

et al. 2011

Journal of Biological Chemistry

120

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Notch activity is regulated by both O-fucosylation and O-glucosylation, and Notch receptors contain multiple predicted sites for both. Here we examine the occupancy of the predicted O-glucose sites on mouse Notch1 (mN1) using the consensus sequence C 1 XSXPC 2 . We show that all of the predicted sites are modified, although the efficiency of modifying O-glucose sites is site-and cell type-dependent. For instance, although most sites are modified at high stoichiometries, the site at EGF 27 is only partially glucosylated, and the occupancy of the site at EGF 4 varies with cell type. O-Glucose is also found at a novel, nontraditional consensus site at EGF 9. Based on this finding, we propose a revision of the consensus sequence for O-glucosylation to allow alanine N-terminal to cysteine 2: C 1 XSX(A/P)C 2 . We also show through biochemical and mass spectral analyses that serine is the only hydroxyamino acid that is modified with O-glucose on EGF repeats. The O-glucose at all sites is efficiently elongated to the trisaccharide Xyl-Xyl-Glc. To establish the functional importance of individual O-glucose sites in mN1, we used a cell-based signaling assay. Elimination of most individual sites shows little or no effect on mN1 activation, suggesting that the major effects of O-glucose are mediated by modification of multiple sites. Interestingly, elimination of the site in EGF 28, found in the Abruptex region of Notch, does significantly reduce activity. These results demonstrate that, like O-fucose, the O-glucose modifications of EGF repeats occur extensively on mN1, and they play important roles in Notch function.The Notch family of single-pass transmembrane receptors is essential for early metazoan development, activating the expression of many genes involved in cell differentiation and tissue morphogenesis (1-3). Defects in Notch signaling have been implicated in a number of human diseases, including several forms of cancer, vascular defects such as cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (4 -6), multiple sclerosis (6), and a number of developmental syndromes (4, 7-10). The canonical Notch signaling pathway is initiated by the interaction of Notch with its ligand on an apposed cell. Upon ligand binding, Notch undergoes presenilin-1-dependent proteolysis, releasing a soluble Notch intracellular domain, which enters the cell nucleus to interact directly with the transcription factors from the CSL family and regulate Notch target genes (2). There are four members of the Notch family in vertebrates (Notch1 to Notch4) interacting with several classes of Notch ligands: ligands of the DSL family (Delta-like 1, 3, and 4 and Jagged 1 and 2) (1) and newly characterized ligands without the DSL domain, such as DNER and MAGP-1 and -2 (11-13).The Notch proteins consist of a large extracellular domain (ECD), 5 a transmembrane region, and a large intracellular domain (1, 2, 14). The majority of the ECD consists of tandem epidermal growth factor-like (EGF) repeats (36 EGF repeats are ...

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Section: Mouse Notch1 Is Extensively Modified With O-glucose Inmentioning

confidence: 99%

mentioning

confidence: 99%

O-Glucose Trisaccharide Is Present at High but Variable Stoichiometry at Multiple Sites on Mouse Notch1

Rana¹,

Nita‐Lazar²,

Takeuchi

et al. 2011

Journal of Biological Chemistry

120

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“…[12–16] The delta-like 3 (DLL3) gene is a member of the Notch signaling pathway and plays important roles in somitogenesis through binding to Notch (a transmembrane receptor). [17,18] DLL3 is a divergent member of Delta/Serrate/lag-2 (DSL) family of Notch ligands. Targeted deletion of DLL3 causes a developmental defect in somite segmentation, and consequently vertebral malformation, closely resembling human spondylocostal dysostosis (SCD).…”

Section: Introductionmentioning

confidence: 99%

Five known tagging DLL3 SNPs are not associated with congenital scoliosis

Yang

Wang²,

Wu³

et al. 2016

Medicine

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Genetic etiology hypothesis is widely accepted in the development of congenital scoliosis (CS). The delta-like 3 (DLL3) gene, a member of the Notch signaling pathway, was implicated to contribute to human CS. In this study, a case–control association study was conducted to determine the association of single nucleotide polymorphism (SNP) in the DLL3 gene with CS in a Chinese Han Population. Five known tagging SNPs of the DLL3 gene were genotyped among 270 Chinese Han subjects (128 nonsyndromic CS patients and 142 matched controls). CS patients were divided into 3 types: type I—failure of formation (29 cases), type II—failure of segmentation (50 cases), and type III—mixed defects (49 cases). The 5 SNPs were analyzed by the allelic and genotypic association analysis, genotype–phenotype association analysis, and haplotype analysis. Allele frequencies of 5 tagging SNPs (SNP1: rs1110627, SNP2: rs3212276, SNP3: rs2304223, SNP4: rs2304222, and SNP5: rs2304214) in CS cases and controls were comparable and there were no available inheritance models. The SNPs were not associated with clinical phenotypes. Moreover, the 5 makers in the DLL3 gene were found to be in strong linkage disequilibrium (LD). Both global haplotype and individual haplotype analyses showed that the haplotypes of SNP1/SNP2/SNP3/SNP4/SNP5 did not correlate with the disease (P >0.05). Together, these data suggest that genetic variants of the DLL3 gene are not associated with CS in the Chinese Han population.

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Role of CSL-dependent and independent Notch signaling pathways in cell apoptosis

et al. 2015

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Apoptosis is a normally biological phenomenon in various organisms, involving complexly molecular mechanisms with a series of signaling processes. Notch signaling is found evolutionarily conserved in many species, playing a critical role in embryonic development, normal tissue homeostasis, angiogenesis and immunoregulation. The focus of this review is on currently novel advances about roles of CSL-dependent and independent Notch signaling pathways in cell apoptosis. The CSL can bind Notch intracellular domain (NIC) to act as a switch in mediating transcriptional activation or inactivation of the Notch signaling pathway downstream genes in the nucleus. It shows that CSL-dependent signaling regulates the cell apoptosis through Hes-1-PTEN-AKT-mTOR signaling, but rather the CSL-independent signaling mediates the cell apoptosis possibly via NIC-mTORC2-AKT-mTOR signaling, providing a new insight into apoptotic mechanisms.

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Role of Delta-Like-3 in Mammalian Somitogenesis and Vertebral Column Formation

Cited by 3 publications

References 148 publications

O-Glucose Trisaccharide Is Present at High but Variable Stoichiometry at Multiple Sites on Mouse Notch1

O-Glucose Trisaccharide Is Present at High but Variable Stoichiometry at Multiple Sites on Mouse Notch1

Five known tagging DLL3 SNPs are not associated with congenital scoliosis

Role of CSL-dependent and independent Notch signaling pathways in cell apoptosis

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