Notch signalling in vertebrate neural development

Louvi, Angeliki; Artavanis‐Tsakonas, Spyros

doi:10.1038/nrn1847

Cited by 810 publications

(745 citation statements)

References 152 publications

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“…Two ADAMs were postulated to cleave Notch ligands in mammalian cells, ADAM10 and -17. ADAM10 was implicated in the processing of mouse (13) and rat Delta-like 1 (Dll1) 3 (14), whereas ADAM17 was suggested to cleave rat Jagged 1 (14). Proteolytic cleavage of Dll1 in ADAM10 Ϫ/Ϫ mouse embryonic fibroblasts (MEFs) still amounts to 50% of the processing observed in ADAM10 ϩ/ϩ MEFs (13), suggesting that ADAM10 is only partially responsible for Dll1 cleavage and other ADAMs may account for the remaining processing in ADAM10 Ϫ/Ϫ cells.…”

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confidence: 99%

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Proteolytic Processing of Delta-like 1 by ADAM Proteases

Dyczynska

Sun

et al. 2007

Journal of Biological Chemistry

118

114

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Delta-like 1 (Dll1) is a mammalian ligand for Notch receptors.Interactions between Dll1 and Notch in trans activate the Notch pathway, whereas Dll1 binding to Notch in cis inhibits Notch signaling. Dll1 undergoes proteolytic processing in its extracellular domain by ADAM10. In this work we demonstrate that Dll1 represents a substrate for several other members of the ADAM family. In co-transfected cells, Dll1 is constitutively cleaved by ADAM12, and the N-terminal fragment of Dll1 is released to medium. ADAM12-mediated cleavage of Dll1 is cell density-dependent, takes place in cis orientation, and does not require the presence of the cytoplasmic domain of ADAM12. Full-length Dll1, but not its N-or C-terminal proteolytic fragment, co-immunoprecipitates with ADAM12. By using a Notch reporter construct, we show that Dll1 processing by ADAM12 increases Notch signaling in a cell-autonomous manner. Furthermore, ADAM9 and ADAM17 have the ability to process Dll1. In contrast, ADAM15 does not cleave Dll1, although the two proteins still co-immunoprecipitate with each other. Asn-353 present in the catalytic motif of ADAM12 and other Dll1-processing ADAMs, but absent in ADAM15, is necessary for Dll1 cleavage. Dll1 cleavage is reduced in ADAM9/12/15 ؊/؊ mouse embryonic fibroblasts (MEFs), suggesting that the endogenous ADAM9 and/or ADAM12 present in wild type MEFs contribute to Dll1 processing. Finally, the endogenous Dll1 present in primary mouse myoblasts undergoes cleavage in confluent, differentiating myoblast cultures, and this cleavage is decreased by ADAM12 small interfering RNAs. Our findings expand the role of ADAM proteins in the regulation of Notch signaling.

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confidence: 99%

“…Notch signaling regulates cell fate decisions during development and in the adult (1)(2)(3). The signaling pathway is activated by direct interactions between Notch receptor, a transmembrane protein present at the surface of a signal-receiving cell, and a DSL (Delta/Serrate/Lag2) ligand, a transmembrane protein at the surface of a signal-sending cell.…”

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confidence: 99%

Proteolytic Processing of Delta-like 1 by ADAM Proteases

Dyczynska

Sun

et al. 2007

Journal of Biological Chemistry

118

114

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“…In the nucleus, NICD forms a complex with Rbpj and activates the expression of several transcriptional repressors, such as Hes1 and Hes5, which inhibit neurogenesis (15,27,29). Thus, activation of the Notch pathway is essential to maintain both developing and adult NSCs (36). This property of the Notch pathway enables it to promote glioma growth (30), and its inhibition by drugs could abolish glioma stem-like cells and reduce tumorigenesis (17).…”

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confidence: 99%

MicroRNA-146a Inhibits Glioma Development by Targeting Notch1

Mei

Bachoo²,

Zhang³

2011

Molecular and Cellular Biology

157

131

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Dysregulated epidermal growth factor receptor (EGFR) signaling through either genomic amplification or dominant-active mutation (EGFR vIII ), in combination with the dual inactivation of INK4A/ARF and PTEN, is a leading cause of gliomagenesis. Our global expression analysis for microRNAs revealed that EGFR activation induces miR-146a expression, which is further potentiated by inactivation of PTEN. Unexpectedly, overexpression of miR-146a attenuates the proliferation, migration, and tumorigenic potential of Ink4a/Arf ؊/؊ Pten ؊/؊ Egfr vIII murine astrocytes. Its ectopic expression also inhibits the glioma development of a human glioblastoma cell line in an orthotopic xenograft model. Such an inhibitory function of miR-146a on gliomas is largely through downregulation of Notch1, which plays a key role in neural stem cell maintenance and is a direct target of miR-146a. Accordingly, miR-146a modulates neural stem cell proliferation and differentiation and reduces the formation and migration of glioma stem-like cells. Conversely, knockdown of miR-146a by microRNA sponge upregulates Notch1 and promotes tumorigenesis of malignant astrocytes. These findings indicate that, in response to oncogenic cues, miR-146a is induced as a negative-feedback mechanism to restrict tumor growth by repressing Notch1. Our results provide novel insights into the signaling pathways that link neural stem cells to gliomagenesis and may lead to new strategies for treating brain tumors.Gliomas are the most frequently observed brain tumors, with glioblastoma multiforme (GBM) being the most common and aggressive form in adults (35). Despite major therapeutic improvements made by combining neurosurgery, chemotherapy, and radiotherapy, the prognosis and survival rate for patients with GBM is still extremely poor (7). The deadly nature of GBM originates from explosive growth and invasive behavior, which are fueled by dysregulation of multiple signaling pathways. Epidermal growth factor receptor (EGFR) activation, in cooperation with loss of tumor suppressor functions, such as mutations in Ink4a/Arf and Pten genes, constitutes a lesion signature for GBM (4). Such dysregulated genetic pathways are sufficient to transform neural stem cells (NSCs) or astrocytes into cancer stem-like cells. This gives rise to highgrade malignant gliomas with a pathological phenotype resembling human GBM (5, 59). However, the downstream events underlying these genetic dysregulations in gliomagenic cells have not been fully elucidated.MicroRNAs are 20-to 22-nucleotide noncoding RNA molecules that have emerged as key players in controlling NSC self-renewal and differentiation (11,57). Aberrant expression of miRNAs, such as miR-21, miR-124, and miR-137, is linked to glioma formation (49). miR-199b-5p and miR-34a impair cancer stem-like cells through the negative regulation of several components of the Notch pathway in brain tumors (18,21). The Notch pathway is an evolutionarily conserved signaling pathway that plays an important role in neurogenesis (3, 10, 23). Upon bindi...

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“…Specifically, Notch1 and Notch2 targeted deletion in melanocytes led to inactivation of the RBP-J R gene in a dose-dependent manner, and three intact alleles of Notch1 and Notch2 are required for preventing precocious hair graying [98]. Notch 3 and 4 are not implicated in this phenotype [99,100].…”

Section: Molecular Control Of Hair Follicle Development and Cyclingmentioning

confidence: 99%

Biology of Human Hair: Know Your Hair to Control It

Araújo

Fernandes

Cavaco‐Paulo

et al. 2010

Advances in Biochemical Engineering/Biotechnology

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Hair can be engineered at different levels-its structure and surfacethrough modification of its constituent molecules, in particular proteins, but also the hair follicle (HF) can be genetically altered, in particular with the advent of siRNA-based applications. General aspects of hair biology are reviewed, as well as the most recent contributions to understanding hair pigmentation and the regulation of hair development. Focus will also be placed on the techniques developed specifically for delivering compounds of varying chemical nature to the HF, indicating methods for genetic/biochemical modulation of HF components for the treatment of hair diseases. Finally, hair fiber structure and chemical characteristics will be discussed as targets for keratin surface functionalization.

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Notch signalling in vertebrate neural development

Cited by 810 publications

References 152 publications

Proteolytic Processing of Delta-like 1 by ADAM Proteases

Proteolytic Processing of Delta-like 1 by ADAM Proteases

MicroRNA-146a Inhibits Glioma Development by Targeting Notch1

Biology of Human Hair: Know Your Hair to Control It

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