title: Notch3 Arg170Cys knock-in mice display pathologic and clinical features of the neurovascular disorder cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy.
abstract: OBJECTIVE
  Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an adult-onset neurovascular disorder caused by stereotyped mutations in the NOTCH3 receptor. Elucidation of its pathobiology is still incomplete and remains a challenge, in part because the available preclinical mouse models to date do not reproduce the full spectrum of CADASIL pathology and clinical disease.
  
  
  RESULTS
  Here, we report a novel knock-in mouse with Arg170Cys substitution in murine Notch3, corresponding to the prevalent Arg169Cys substitution in CADASIL. The Notch3(Arg170Cys) mice displayed late-onset, dominant CADASIL arteriopathy with typical granular osmiophilic material deposition and developed brain histopathology including thrombosis, microbleeds, gliosis, and microinfarction. Furthermore, Notch3(Arg170Cys) mice experienced neurological symptoms with motor defects such as staggering gait and limb paresis.
  
  
  CONCLUSIONS
  This model, for the first time, phenocopies the arteriopathy and the histopathologic as well as clinical features of CADASIL and may offer novel opportunities to investigate disease pathogenesis.
authors.affiliation: Vesalius Research Center, Flanders Institute for Biotechnology (VIB), Leuven, Belgium.
authors.forename: Goedele
authors.initials: G
authors.lastname: Wallays
authors.forename: Dieter
authors.initials: D
authors.lastname: Nuyens
authors.forename: Robert
authors.initials: R
authors.lastname: Silasi-Mansat
authors.forename: Joris
authors.initials: J
authors.lastname: Souffreau
authors.forename: Zsuzsanna
authors.initials: Z
authors.lastname: Callaerts-Vegh
authors.forename: An
authors.initials: A
authors.lastname: Van Nuffelen
authors.forename: Lieve
authors.initials: L
authors.lastname: Moons
authors.forename: Rudi
authors.initials: R
authors.lastname: D'Hooge
authors.forename: Florea
authors.initials: F
authors.lastname: Lupu
authors.forename: Peter
authors.initials: P
authors.lastname: Carmeliet
authors.forename: Désiré
authors.initials: D
authors.lastname: Collen
authors.forename: Mieke
authors.initials: M
authors.lastname: Dewerchin
mesh_terms: D000818:Animals; D001120:Arginine; D001921:Brain / Q000473:pathology; D046589:CADASIL / Q000235:genetics* / Q000473:pathology* / Q000503:physiopathology; D002196:Capillaries / Q000473:pathology; D003553:Cystine; D004195:Disease Models, Animal; D005298:Fertility / Q000502:physiology; D055879:Gene Knock-In Techniques; D051379:Mice; D009043:Motor Activity / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000473:pathology; D009154:Mutation / Q000235:genetics; D000071656:Receptor, Notch3; D051880:Receptors, Notch / Q000235:genetics*
chemical_list: C499373:Notch3 protein, mouse; D000071656:Receptor, Notch3; D051880:Receptors, Notch; D003553:Cystine; D001120:Arginine