Notch3 signaling in small-artery-diseases

Summary

Principal Investigator: Anne Joutel
Abstract: Small-vessel-diseases are a leading cause of Vascular Dementia. Our long-term goal is to elucidate the signaling pathways that control the structural and functional integrity of small arteries and understand the connections between these pathways and the development of small-vessel-diseases, as a prerequisite to the development of therapeutics. The research we propose is focused on the NotchS signaling pathway. Notch signaling is an evolutionary conserved pathway that plays a central role in the development and maturation of most vertebrate organs. We identified NotchS as the causative gene of CADASIL, an increasingly recognized autosomal dominant form of systemic small-vessel-disease causing stroke and dementia. We previously showed that 1[unreadable]) CADASIL patients carry highly stereotyped missense mutations leading to an odd number of cysteine residues within the extracellular domain of NotchS;2[unreadable]) NotchS expression is largely confined to small arteries and vascular Smooth Muscle Cells (vSMC) and 3[unreadable]) Mice expressing an archetypal CADASIL mutation (R90C) targeted in vSMC develop features of the CADASIL arteriopathy. Our specific hypothesis is that appropriate level of NotchS activity is critical for structural and functional integrity of small arteries by modulating an RBP-JK dependent, Hes/HEY independent pathway. That hypothesis is supported by our recent findings: 1 [unreadable]) In adult NotchS null mice, small arteries exhibit structural defects and cerebrovascular reactivity is strongly defective. Notably, NotchS null and CADASIL phenotypes are very different;2[unreadable]) RBP-JK dependent activity is abolished in arteries of NotchS null mice but expression level of Hes/HEY genes is unaffected. Here we propose three specific aims to further our understanding of NotchS- dependent small-vessel-diseases and NotchS signaling and address a major unresolved issue: the extent to which CADASIL mutations impair NotchS activity. We will construct and analyze NotchS gain-of-function mutant mice to determine effect of increasing NotchS activity in small arteries (Aim #1). We will determine the gene expression signature of loss and gain-of-function alleles of NotchS and identify direct target genes of NotchS by microarray analysis on isolated small arteries (Aim # 2). We will investigate effect of the archetypal R90C CADASIL mutation on NotchS wildtype activity in vivo using our Notch3R90C mice, NotchS null mice as a "rescue" system and transgenic RBP-JK reporter mice (Aim # 3).
Funding Period: 2006-02-01 - 2010-01-31
more information: NIH RePORT

Top Publications

  1. pmc Abnormal recruitment of extracellular matrix proteins by excess Notch3 ECD: a new pathomechanism in CADASIL
    Marie Monet-Leprêtre
    INSERM, U740, Paris, F 75010, France
    Brain 136:1830-45. 2013
  2. pmc Transcriptome analysis for Notch3 target genes identifies Grip2 as a novel regulator of myogenic response in the cerebrovasculature
    Charles Fouillade
    INSERM, U740, Paris, France
    Arterioscler Thromb Vasc Biol 33:76-86. 2013
  3. pmc Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy syndrome mutations increase susceptibility to spreading depression
    Katharina Eikermann-Haerter
    Stroke and Neurovascular Regulation Laboratory, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, USA
    Ann Neurol 69:413-8. 2011
  4. ncbi Pathogenesis of CADASIL: transgenic and knock-out mice to probe function and dysfunction of the mutated gene, Notch3, in the cerebrovasculature
    Anne Joutel
    INSERM U740, Paris, France
    Bioessays 33:73-80. 2011
  5. pmc Cerebrovascular dysfunction and microcirculation rarefaction precede white matter lesions in a mouse genetic model of cerebral ischemic small vessel disease
    Anne Joutel
    INSERM U740, Paris, France
    J Clin Invest 120:433-45. 2010
  6. pmc Distinct phenotypic and functional features of CADASIL mutations in the Notch3 ligand binding domain
    Marie Monet-Leprêtre
    INSERM U740, Faculté de Médecine Paris 7, Site Villemin, 10 Avenue de Verdun, Paris, France
    Brain 132:1601-12. 2009
  7. pmc Congruence between NOTCH3 mutations and GOM in 131 CADASIL patients
    Saara Tikka
    Protein Chemistry Unit, Institute of Biomedicine Anatomy, University of Helsinki, Finland
    Brain 132:933-9. 2009
  8. pmc Notch3 is a major regulator of vascular tone in cerebral and tail resistance arteries
    E J Belin de Chantemèle
    INSERM U 771, Angers, France
    Arterioscler Thromb Vasc Biol 28:2216-24. 2008
  9. ncbi Activating NOTCH3 mutation in a patient with small-vessel-disease of the brain
    Charles Fouillade
    INSERM, U740, Paris, F 75010, France
    Hum Mutat 29:452. 2008
  10. ncbi The archetypal R90C CADASIL-NOTCH3 mutation retains NOTCH3 function in vivo
    Marie Monet
    INSERM U740, Paris F 75010, France
    Hum Mol Genet 16:982-92. 2007

Scientific Experts

  • Anne Joutel
  • Hannu Kalimo
  • Marie Monet-Leprêtre
  • Charles Fouillade
  • Elisabeth Tournier-Lasserve
  • Valérie Domenga-Denier
  • Celine Baron-Menguy
  • Katharina Eikermann-Haerter
  • Saara Tikka
  • Hugues Chabriat
  • Valérie Domenga
  • Barbara Lemaire
  • Michel Cohen-Tannoudji
  • E J Belin de Chantemèle
  • Marie Monet
  • Christelle Thibault
  • Maï Fouillot-Panchal
  • Meriem Riani
  • Kogo Takamiya
  • Joelle Vinh
  • Iman Haddad
  • Claire Dussaule
  • Emmanuel Cognat
  • Richard Huganir
  • Ergin Dilekoz
  • Izumi Yuzawa
  • Michael A Moskowitz
  • Cenk Ayata
  • Robert Bergholm
  • Boris Bardot
  • Kati Mykkänen
  • Marc Baumann
  • Minna Poyhonen
  • Maija Junna
  • Hannele Yki-Jarvinen
  • Marie Magdeleine Ruchoux
  • Ophelia Godin
  • Matti Viitanen
  • Martin Dichgans
  • Florence Riant
  • L Loufrani
  • A Bocquet
  • V Domenga
  • E Vessieres
  • B Lemaire
  • C Baufreton
  • A L Guihot
  • F Pinaud
  • Marie Germaine Bousser
  • Minh Arnoud
  • D Henrion
  • K Retailleau
  • Laurent Magy
  • Manuele Mine
  • Céline Souilhol
  • Francina Langa
  • Thomas Gridley
  • Charles Babinet

Detail Information

Publications10

  1. pmc Abnormal recruitment of extracellular matrix proteins by excess Notch3 ECD: a new pathomechanism in CADASIL
    Marie Monet-Leprêtre
    INSERM, U740, Paris, F 75010, France
    Brain 136:1830-45. 2013
    ..Specifically, our results suggest a dysregulation of TIMP3 activity, which could contribute to mutant Notch3(ECD) toxicity by impairing extracellular matrix homeostasis in small vessels...
  2. pmc Transcriptome analysis for Notch3 target genes identifies Grip2 as a novel regulator of myogenic response in the cerebrovasculature
    Charles Fouillade
    INSERM, U740, Paris, France
    Arterioscler Thromb Vasc Biol 33:76-86. 2013
    ..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...
  3. pmc Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy syndrome mutations increase susceptibility to spreading depression
    Katharina Eikermann-Haerter
    Stroke and Neurovascular Regulation Laboratory, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, USA
    Ann Neurol 69:413-8. 2011
    ..Our results link vascular smooth muscle Notch 3 mutations to enhanced spreading depression susceptibility, implicating the neurovascular unit in the development of migraine aura...
  4. ncbi Pathogenesis of CADASIL: transgenic and knock-out mice to probe function and dysfunction of the mutated gene, Notch3, in the cerebrovasculature
    Anne Joutel
    INSERM U740, Paris, France
    Bioessays 33:73-80. 2011
    ..In this paper, I provide a critical overview of these studies. Moreover, I discuss future directions and further work that needs to be done...
  5. pmc Cerebrovascular dysfunction and microcirculation rarefaction precede white matter lesions in a mouse genetic model of cerebral ischemic small vessel disease
    Anne Joutel
    INSERM U740, Paris, France
    J Clin Invest 120:433-45. 2010
    ..These studies provide in vivo evidence for cerebrovascular dysfunction and microcirculatory failure as key contributors to hypoperfusion and white matter damage in this genetic model of ischemic SVD...
  6. pmc Distinct phenotypic and functional features of CADASIL mutations in the Notch3 ligand binding domain
    Marie Monet-Leprêtre
    INSERM U740, Faculté de Médecine Paris 7, Site Villemin, 10 Avenue de Verdun, Paris, France
    Brain 132:1601-12. 2009
    ....
  7. pmc Congruence between NOTCH3 mutations and GOM in 131 CADASIL patients
    Saara Tikka
    Protein Chemistry Unit, Institute of Biomedicine Anatomy, University of Helsinki, Finland
    Brain 132:933-9. 2009
    ..Detection of GOM requires technically adequate biopsies and distinction of true GOM from fallacious deposits. If GOM is not found in the first vessel or biopsy, other vessels or additional biopsies should be examined...
  8. pmc Notch3 is a major regulator of vascular tone in cerebral and tail resistance arteries
    E J Belin de Chantemèle
    INSERM U 771, Angers, France
    Arterioscler Thromb Vasc Biol 28:2216-24. 2008
    ..Genetic studies in human and mice revealed a critical role for Notch3 in the structural integrity of distal resistance arteries by regulating arterial differentiation and postnatal maturation...
  9. ncbi Activating NOTCH3 mutation in a patient with small-vessel-disease of the brain
    Charles Fouillade
    INSERM, U740, Paris, F 75010, France
    Hum Mutat 29:452. 2008
    ..L1515P mutation falls in a novel mechanistic class of NOTCH3 mutations and that NOTCH3 activating mutations should be further considered for molecular analysis of patients with cerebral small-vessel-disease...
  10. ncbi The archetypal R90C CADASIL-NOTCH3 mutation retains NOTCH3 function in vivo
    Marie Monet
    INSERM U740, Paris F 75010, France
    Hum Mol Genet 16:982-92. 2007
    ..Collectively, these data suggest a model that invokes novel pathogenic roles for the mutant NOTCH3 protein rather than compromised NOTCH3 function as the primary determinant of the CADASIL arteriopathy...