The Notch signalling system: recent insights into the complexity of a conserved pathway

Guruharsha, K. G.; Kankel, Mark W.; Artavanis‐Tsakonas, Spyros

doi:10.1038/nrg3272

Cited by 620 publications

(589 citation statements)

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“…NOTCH proteins are a highly conserved family of transmembrane receptors (10) that play a major role in cell fate determination (11,12), biliary tract development (13,14), and in liver cancer (15,16). Although much information has been obtained about the NOTCH signaling pathway, we do not fully understand the pathobiology of human ALGS liver disease.…”

Section: Introductionmentioning

confidence: 99%

Human hepatic organoids for the analysis of human genetic diseases

Guan¹,

Xu²,

Garfin³

et al. 2017

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Section: Introductionmentioning

confidence: 99%

Human hepatic organoids for the analysis of human genetic diseases

Guan¹,

Xu²,

Garfin³

et al. 2017

JCI Insight

176

196

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“…The evolutionarily conserved NOTCH signalling pathway is a key regulator of cell specification during embryonic development and adult tissue homeostasis (reviewed by Andersson et al, 2011;Artavanis-Tsakonas and Muskavitch, 2010;Guruharsha et al, 2012;Koch et al, 2013). In mammalian cells, there are four NOTCH receptors (NOTCH1-4) and several transmembrane ligands such as Delta-like (DLL1, DLL3, DLL4) and Jagged (JAG1 and JAG2).…”

Section: Introductionmentioning

confidence: 99%

NOTCH activation interferes with cell fate specification in the gastrulating mouse embryo

et al. 2015

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NOTCH signalling is an evolutionarily conserved pathway involved in intercellular communication essential for cell fate choices during development. Although dispensable for early aspects of mouse development, canonical RBPJ-dependent NOTCH signalling has been shown to influence lineage commitment during embryonic stem cell (ESC) differentiation. NOTCH activation in ESCs promotes the acquisition of a neural fate, whereas its suppression favours their differentiation into cardiomyocytes. This suggests that NOTCH signalling is implicated in the acquisition of distinct embryonic fates at early stages of mammalian development. In order to investigate in vivo such a role for NOTCH signalling in shaping cell fate specification, we use genetic approaches to constitutively activate the NOTCH pathway in the mouse embryo. Early embryonic development, including the establishment of anterior-posterior polarity, is not perturbed by forced NOTCH activation. By contrast, widespread NOTCH activity in the epiblast triggers dramatic gastrulation defects. These are fully rescued in a RBPJ-deficient background. Epiblast-specific NOTCH activation induces acquisition of neurectoderm identity and disrupts the formation of specific mesodermal precursors including the derivatives of the anterior primitive streak, the mouse organiser. In addition, we show that forced NOTCH activation results in misregulation of NODAL signalling, a major determinant of early embryonic patterning. Our study reveals a previously unidentified role for canonical NOTCH signalling during mammalian gastrulation. It also exemplifies how in vivo studies can shed light on the mechanisms underlying cell fate specification during in vitro directed differentiation.

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“…11,12 When ligand binds to its receptor, metalloproteinase and gamma secretase will cleave Notch receptor, leading to releasing ICN (intracellular domain of Notch) from the plasma membrane and subsequent translocating into nucleus. 13,14 Thus, ICN forms a complex with CSL (CBF1/Su(H)/Lag-1) and triggers the transcription of its targets such as cyclin D, Hey family and Hes (hairy enhancer of split) family. 15 Deregulated Notch signaling has been observed in a variety of human cancers including prostate cancer.…”

Section: Introductionmentioning

confidence: 99%