Embryonic lethality in mice homozygous for a processing-deficient allele of Notch1

Huppert, Stacey S.; Le, Anh H; Schroeter, Eric H.; Mumm, Jeff S.; Saxena, Mohit; Milner, Laurie A.; Kopan, Raphael

doi:10.1038/35016111

Cited by 313 publications

(250 citation statements)

References 28 publications

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“…Limited proteolysis of APP CTF-α, CTF-β, N-cadherin and Notch1 was also hampered in the homozygous knockin embryos, although the γ-secretase components appeared to have been properly assembled to a 360 kDa complex. Based on previous studies, it appears that the disturbance in Notch1 processing represents the primary cause of the premature death that we observed 16,35 . Compared to PS1 knockout, the embryonic lethality of PS1-R278I knockin mice occurs at a slightly later stage.…”

Section: Discussionmentioning

confidence: 60%

Potent amyloidogenicity and pathogenicity of Aβ43

et al. 2011

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Aβ42 is known to be a primary amyloidogenic and pathogenic agent in Alzheimer's disease. However, the role of Aβ43, found just as frequently in patient brains, remains unresolved. We generated knockin mice containing a pathogenic presenilin-1 R278I mutation that causes overproduction of Aβ43. Homozygous mice exhibited embryonic lethality, indicating that the mutation involves loss of function. Crossing amyloid precursor protein transgenic mice with heterozygous mutant mice resulted in elevation of Aβ43 levels, impairment of short-term memory, and acceleration of Aβ pathology, accompanying pronounced accumulation of Aβ43 in plaque cores similar to the biochemical composition observed in patient brains. Consistently, Aβ43 showed a higher propensity to aggregate and was more neurotoxic than Aȕ42. Other pathogenic presenilin mutations also caused overproduction of Aβ43 in a manner correlating with Aβ42 and with age of disease onset. These findings indicate that Aβ43, an overlooked species, is potently amyloidogenic, neurotoxic, and abundant in vivo. 3 Alzheimer's disease, the most common form of dementia, is characterized by two pathological features in the brain, extracellular senile plaques and intracellular neurofibrillary tangles. Senile plaques consist of amyloid-β peptide (Aβ) generated from amyloid precursor protein (APP) through sequential proteolytic processing by β-secretase and γ-secretase. Two major forms of Aβ exist, Aβ40 and Aβ42, with Aβ42 being more neurotoxic due to its higher hydrophobicity, which results in faster oligomerization and aggregation 1 . A number of mutations associated with early-onset familial Alzheimer's disease (FAD) have been identified in the APP, PSEN1 and PSEN2 genes, and these mutations lead to accelerated production of Aβ42 or an increase in the Aβ42/Aβ40 ratio. Together these findings indicate that Aβ42 plays an essential role in the initiation of pathogenesis. However, the possible involvement of longer Aβ species that also exist in Alzheimer's disease brains has not yet been fully investigated.Thus far, various longer Aβ species, such as Aβ43, Aβ45, Aβ48, Aβ49 and Aβ50, have been qualitatively described in Alzheimer's disease brains 2 . Similar Aβ species have also been found in transgenic mice that overexpress APP carrying FAD-linked mutations 3 . Further quantitative studies have revealed that Aβ43 is deposited more frequently than Aβ40 in both sporadic Alzheimer's disease (SAD) and FAD [4][5][6][7] .How these Aβ species with different C-terminal ends are generated from the precursor has mainly been investigated by cell biological and biochemical methods. A number of studies 8,9 demonstrated that γ/ε-cleavage by γ-secretase activity controls the fate of the C-terminal end. Aβ43, generated from Aβ49 via Aβ46, is subsequently converted to Aβ40 by γ-secretase whereas Aβ42 is independently generated from Aβ48 via Aβ45. It has also been reported that the FAD-associated I213T mutation in the PSEN1 gene increases the generation of longer Aβ species, such as Aβ43, Aβ45 a...

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Section: Discussionmentioning

confidence: 60%

Potent amyloidogenicity and pathogenicity of Aβ43

et al. 2011

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“…2e–g). Interestingly, Notch1-KO cells expressing TMD-ICD harboring a point mutation that prevents cleavage of the ICD (V1754G 19 , Extended Data Fig. 6b) failed to rescue barrier function (Fig.…”

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confidence: 98%

A non-canonical Notch complex regulates adherens junctions and vascular barrier function

Polacheck

Kutys

Yang

et al. 2017

Nature

282

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The vascular barrier that separates blood from tissues is actively regulated by the endothelium and is essential for transport, inflammation, and hemostasis1. Hemodynamic shear stress plays a critical role in maintaining endothelial barrier function2, but how this occurs remains unknown. Here, using an engineered organotypic model of perfused microvessels and confirming in mouse models, we identify that activation of the Notch1 transmembrane receptor directly regulates vascular barrier function through a non-canonical, transcription independent signaling mechanism that drives adherens junction assembly. Shear stress triggers Dll4-dependent proteolytic activation of Notch1 to reveal the Notch1 transmembrane domain – the key domain that mediates barrier establishment. Expression of the Notch1 transmembrane domain is sufficient to rescue Notch1 knockout-induced defects in barrier function, and does so by catalyzing the formation of a novel receptor complex in the plasma membrane consisting of VE-cadherin, the transmembrane protein tyrosine phosphatase LAR, and the Rac1 GEF Trio. This complex activates Rac1 to drive adherens junction assembly and establish barrier function. Canonical Notch transcriptional signaling is highly conserved throughout metazoans and is required for many processes in vascular development, including arterial-venous differentiation3, angiogenesis4, and remodeling5; here, we establish the existence of a previously unappreciated non-canonical cortical signaling pathway for Notch1 that regulates vascular barrier function, and thus provide a mechanism by which a single receptor might link transcriptional programs with adhesive and cytoskeletal remodeling.

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“…For example, gene deletion studies in both zebra fish and mice have demonstrated a potential role for Notch signaling in hematopoietic and endothelial development. [4][5][6]8,9,25,39 In addition, both Notch1 and Jagged1 are implicated in the induction of definitive over primitive hematopoiesis. 4,16,25 Notch1-deficient mouse embryonic stem cells contribute to primitive yolk-sac hematopoiesis in chimeric mice but are incapable of adult blood development, 4 whereas Jagged1 is required for the establishment of definitive mouse hematopoietic precursors.…”

Section: Discussionmentioning

confidence: 99%

“…[6][7][8][9][10][11] In the hematopoietic system, Jagged1 25 and Delta1 14,26 are key regulators of Notch signaling. Accordingly, to understand the role of Notch signaling in human, we examined whether Jagged1 (Jag1) and Delta1 (Dll1) contribute to hematopoietic development from hPSCs.…”

Section: Notch Ligands Via Hes1 Induce Hematopoietic Differentiationmentioning

confidence: 99%

“…4,5 Perturbation of Notch signaling has deleterious effects on embryonic hematopoiesis and vascular development. [6][7][8][9][10][11] In mouse models, Notch1 was shown to be required for generation of hematopoietic cells from bipotent hemogenic endothelial precursors, known as hemangioblasts. 7 In humans, a critical role for Notch signaling, through the Notch ligand Jagged1, has been demonstrated in the proliferation and differentiation of normal primitive human hematopoietic progenitors.…”

Section: Introductionmentioning

confidence: 99%

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