title: Transcriptome analysis for Notch3 target genes identifies Grip2 as a novel regulator of myogenic response in the cerebrovasculature.
abstract: OBJECTIVE
  Notch3 is critically important for the structure and myogenic response of distal arteries, particularly of cerebral arteries. However, signaling pathways acting downstream of Notch3 remain largely unknown.
  
  
  RESULTS
  Transcriptome analysis using tail arteries of Notch3-null mice identified a core set of 17 novel Notch3-regulated genes confirmed in tail or brain arteries. Postnatal deletion of RBP-Jκ in smooth muscle cells recapitulated the structural, functional, and molecular defects of brain arteries induced by Notch3 deficiency. Transient in vivo blockade of the Notch pathway with γ-secretase inhibitors uncovered, in addition to Notch3, 6 immediate responders, including the voltage-gated potassium channel Kv1.5, which opposes to myogenic constriction of brain arteries, and the glutamate receptor-interacting protein 2 (Grip2) with no previously established role in the cerebrovasculature. We identified a vascular smooth muscle cell isoform of Grip2. We showed that Notch3-RBP-Jκ specifically regulates this isoform. Finally, we found that cerebral arteries of Grip2 mutant mice, which express an N-terminally truncated Grip2 protein, exhibited selective attenuation of pressure-induced contraction.
  
  
  CONCLUSIONS
  Our data provide insight into how Notch3 signals in the brain arteries, establishing the postnatal requirement of smooth muscle RBP-Jκ in this context. Notch3-regulated transcriptome provides potential for modulating myogenic response in the cerebrovasculature.
authors.affiliation: INSERM, U740, Paris, France.
authors.forename: Charles
authors.initials: C
authors.lastname: Fouillade
authors.forename: Céline
authors.initials: C
authors.lastname: Baron-Menguy
authors.forename: Valérie
authors.initials: V
authors.lastname: Domenga-Denier
authors.forename: Christelle
authors.initials: C
authors.lastname: Thibault
authors.forename: Kogo
authors.initials: K
authors.lastname: Takamiya
authors.forename: Richard
authors.initials: R
authors.lastname: Huganir
authors.forename: Anne
authors.initials: A
authors.lastname: Joutel
mesh_terms: D000409:Alanine / Q000031:analogs & derivatives / Q000494:pharmacology; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D001381:Azepines / Q000494:pharmacology; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002536:Cerebral Arteries / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein / Q000235:genetics / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D051666:Kv1.5 Potassium Channel / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000071656:Receptor, Notch3; D051880:Receptors, Notch / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D014661:Vasoconstriction / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014664:Vasodilation; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D001381:Azepines; D002352:Carrier Proteins; D004791:Enzyme Inhibitors; C485567:Grip2 protein, mouse; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; D047908:Intracellular Signaling Peptides and Proteins; C496982:Kcna5 protein, mouse; D051666:Kv1.5 Potassium Channel; C484278:N2-((2S)-2-(3,5-difluorophenyl)-2-hydroxyethanoyl)-N1-((7S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo(b,d)azepin-7-yl)-L-alaninamide; D009419:Nerve Tissue Proteins; C499373:Notch3 protein, mouse; C497571:Rbpj protein, mouse; D000071656:Receptor, Notch3; D051880:Receptors, Notch; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D053829:Amyloid Precursor Protein Secretases; D000409:Alanine