GENETIC ANALYSIS OF THE NOTCH SIGNALING PATHWAY

Summary

Principal Investigator: THOMAS H GRIDLEY
Abstract: The long-term goal of this proposal is to understand the multiple roles that the Notch signaling pathway plays during embryonic development in mammals, and the connections between this pathway and the development of congenital human disease syndromes. The components of the Notch signaling pathway are essential for proper embryonic development in numerous organisms, and mutations in Notch pathway genes cause several inherited human disease syndromes. In mammals, four Notch family receptors have been described, encoded by the Notch1 - Notch4 genes. Notch receptors interact with membrane-bound ligands that are encoded by the Jagged (Jag1 and Jag2) and Delta-like (Dlll, Dll3, and Dll4) gene families. We have been performing a comprehensive genetic analysis of the requirements for Notch pathway components during embryonic development in mice. The aims of this proposal are to: 1) determine the role of the Dll4 gene and of other Notch pathway components in the development of the cardiovascular system; 2) test whether the PDZ Iigand domains at the carboxy termini of the JAG1 and DLL4 proteins are essential for function; 3) test whether the intracellular domains of the four different Notch receptors transmit equivalent signals by constructing single copy conditional gain of function alleles at the same genetic locus; 4) test whether Notch signaling plays an evolutionarily-conserved role during oocyte development. These studies will further our understanding of the roles of the Notch signaling pathway in mammalian development, and will be applicable to the study of both normal development and birth defects in humans.
Funding Period: 1996-09-09 - 2008-06-30
more information: NIH RePORT

Top Publications

  1. ncbi Notch signaling coordinates the patterning of striatal compartments
    Heather A Mason
    Developmental Genetics Program and the Department of Cell Biology, The Skirball Institute of Biomolecular Medicine, New York University Medical Center, New York, NY 10016, USA
    Development 132:4247-58. 2005
  2. pmc Smooth muscle Notch1 mediates neointimal formation after vascular injury
    Yuxin Li
    Vascular Medicine Research, Brigham and Women s Hospital and Harvard Medical School, Cambridge, MA 02139, USA
    Circulation 119:2686-92. 2009
  3. pmc Notch signaling regulates bile duct morphogenesis in mice
    Julie Lozier
    The Jackson Laboratory, Bar Harbor, Maine, United States of America
    PLoS ONE 3:e1851. 2008
  4. pmc Notch2 is required for maintaining sustentacular cell function in the adult mouse main olfactory epithelium
    Steve Rodriguez
    Department of Biomedical Sciences, Cornell University, Ithaca, NY 14853, USA
    Dev Biol 314:40-58. 2008
  5. pmc Genetic background modifies inner ear and eye phenotypes of jag1 heterozygous mice
    Amy E Kiernan
    The Jackson Laboratory, Bar Harbor, Maine 04609, USA
    Genetics 177:307-11. 2007
  6. pmc Direct regulation of Gata3 expression determines the T helper differentiation potential of Notch
    Derk Amsen
    Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA
    Immunity 27:89-99. 2007
  7. ncbi Notch1 expression and ligand interactions in progenitor cells of the mouse olfactory epithelium
    Gerald A Schwarting
    Shriver Center UMMS, 200 Trapelo Road, Waltham, MA 02452, USA
    J Mol Histol 38:543-53. 2007
  8. ncbi Bile duct proliferation in liver-specific Jag1 conditional knockout mice: effects of gene dosage
    Kathleen M Loomes
    Division of Gastroenterology, Hepatology and Nutrition, Children s Hospital of Philadelphia, Philadelphia, PA 19104, USA
    Hepatology 45:323-30. 2007
  9. ncbi The long and short of it: somite formation in mice
    Thomas Gridley
    The Jackson Laboratory, Bar Harbor, Maine, USA
    Dev Dyn 235:2330-6. 2006
  10. pmc Jag2-Notch1 signaling regulates oral epithelial differentiation and palate development
    Liam M Casey
    Center for Oral Biology and Department of Biomedical Genetics, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642, USA
    Dev Dyn 235:1830-44. 2006

Scientific Experts

  • THOMAS H GRIDLEY
  • GERALD SCHWARTING
  • KATHLEEN MARY LOOMES
  • Derk Amsen
  • Amy E Kiernan
  • Heather A Mason
  • Julie Lozier
  • Brent McCright
  • Keli Xu
  • Yuxin Li
  • Steve Rodriguez
  • Achim Gossler
  • Liam M Casey
  • Gord Fishell
  • Staci M Rakowiecki
  • Chi chung Hui
  • Sean E Egan
  • Geoff G Hicks
  • John G Sled
  • Tino D Piscione
  • R Mark Henkelman
  • Erica Nieuwenhuis
  • Megan Y J Wu
  • Lisa X Yu
  • Brenda L Cohen
  • Leigh Coultas
  • Wei Wang
  • Jayne S Danska
  • Andras Nagy
  • Janet Rossant
  • Angelo J Canty
  • Luke Krebs
  • Michael I Kotlikoff
  • Ping Yen Liu
  • James K Liao
  • Yasushi Mukai
  • Naotsugu Oyama
  • Kyosuke Takeshita
  • Freddy Radtke
  • Michael T Chin
  • Minoru Satoh
  • Chris Deleonardis
  • David M Lin
  • Ana Alcaraz
  • Heather M Sickles
  • Renhua Li
  • Gary A Churchill
  • Norman L Hawes
  • Eui Sic Cho
  • Rulang Jiang
  • Jingxia Xu
  • Yu Lan
  • Kathleen M Maltby
  • Yuanyuan Huang
  • Ralf Cordes
  • Myrto Raftopoulou
  • Susana Nery
  • Raphael Kopan

Detail Information

Publications15

  1. ncbi Notch signaling coordinates the patterning of striatal compartments
    Heather A Mason
    Developmental Genetics Program and the Department of Cell Biology, The Skirball Institute of Biomolecular Medicine, New York University Medical Center, New York, NY 10016, USA
    Development 132:4247-58. 2005
    ..These results indicate that Notch signaling is required in neural progenitor cells to control cell fate in the striatum, but is dispensable during subsequent phases of neuronal migration and differentiation...
  2. pmc Smooth muscle Notch1 mediates neointimal formation after vascular injury
    Yuxin Li
    Vascular Medicine Research, Brigham and Women s Hospital and Harvard Medical School, Cambridge, MA 02139, USA
    Circulation 119:2686-92. 2009
    ..However, the pathophysiological role of Notch1 in the postnatal period is not known. We hypothesize that Notch1 signaling in vascular smooth muscle cells (SMCs) may contribute to neointimal formation after vascular injury...
  3. pmc Notch signaling regulates bile duct morphogenesis in mice
    Julie Lozier
    The Jackson Laboratory, Bar Harbor, Maine, United States of America
    PLoS ONE 3:e1851. 2008
    ..However, our previous study did not establish whether bile duct paucity in Jag1/Notch2 double heterozygous mice resulted from impaired differentiation of bile duct precursor cells, or from defects in bile duct morphogenesis...
  4. pmc Notch2 is required for maintaining sustentacular cell function in the adult mouse main olfactory epithelium
    Steve Rodriguez
    Department of Biomedical Sciences, Cornell University, Ithaca, NY 14853, USA
    Dev Biol 314:40-58. 2008
    ....
  5. pmc Genetic background modifies inner ear and eye phenotypes of jag1 heterozygous mice
    Amy E Kiernan
    The Jackson Laboratory, Bar Harbor, Maine 04609, USA
    Genetics 177:307-11. 2007
    ..Genome scans of N2 backcross mice identified a significant modifier locus on chromosome 7, as well as a suggestive locus on chromosome 14. We also analyzed modifiers of an eye defect in Jag1del1 heterozygous mice from this same cross...
  6. pmc Direct regulation of Gata3 expression determines the T helper differentiation potential of Notch
    Derk Amsen
    Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA
    Immunity 27:89-99. 2007
    ..Moreover, absence of GATA-3 turned Notch from a Th2 inducer into a powerful inducer of Th1 differentiation. Therefore, Gata3 is a critical element determining inductive Th2 differentiation and limiting Th1 differentiation by Notch...
  7. ncbi Notch1 expression and ligand interactions in progenitor cells of the mouse olfactory epithelium
    Gerald A Schwarting
    Shriver Center UMMS, 200 Trapelo Road, Waltham, MA 02452, USA
    J Mol Histol 38:543-53. 2007
    ..Taken together, these results further support a role for Notch signaling in the regulation of olfactory neurogenesis and cell diversity...
  8. ncbi Bile duct proliferation in liver-specific Jag1 conditional knockout mice: effects of gene dosage
    Kathleen M Loomes
    Division of Gastroenterology, Hepatology and Nutrition, Children s Hospital of Philadelphia, Philadelphia, PA 19104, USA
    Hepatology 45:323-30. 2007
    ..When Jag1 conditional mice were crossed with mice carrying the Jag1 null allele, the adult progeny exhibited striking bile duct proliferation...
  9. ncbi The long and short of it: somite formation in mice
    Thomas Gridley
    The Jackson Laboratory, Bar Harbor, Maine, USA
    Dev Dyn 235:2330-6. 2006
    ....
  10. pmc Jag2-Notch1 signaling regulates oral epithelial differentiation and palate development
    Liam M Casey
    Center for Oral Biology and Department of Biomedical Genetics, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642, USA
    Dev Dyn 235:1830-44. 2006
    ....
  11. ncbi Loss of notch activity in the developing central nervous system leads to increased cell death
    Heather A Mason
    Developmental Genetics Program and the Department of Cell Biology, The Skirball Institute of Biomolecular Medicine, New York University Medical Center, New York, NY 10016, USA
    Dev Neurosci 28:49-57. 2006
    ....
  12. pmc The Notch ligand JAG1 is required for sensory progenitor development in the mammalian inner ear
    Amy E Kiernan
    The Jackson Laboratory, Bar Harbor, Maine, USA
    PLoS Genet 2:e4. 2006
    ..These data demonstrate that JAG1-mediated Notch signaling is essential during early development for establishing the prosensory regions of the inner ear...
  13. ncbi Generation of new Notch2 mutant alleles
    Brent McCright
    The Jackson Laboratory, Bar Harbor, Maine 04609, USA
    Genesis 44:29-33. 2006
    ....
  14. ncbi The Notch ligands DLL1 and JAG2 act synergistically to regulate hair cell development in the mammalian inner ear
    Amy E Kiernan
    The Jackson Laboratory, Bar Harbor, ME 04609, USA
    Development 132:4353-62. 2005
    ..Our results demonstrate that the Notch pathway plays a dual role in regulating cellular differentiation and patterning in the cochlea, acting both through lateral inhibition and the control of cellular proliferation...
  15. pmc Lunatic Fringe-mediated Notch signaling is required for lung alveogenesis
    Keli Xu
    Program in Developmental and Stem Cell Biology, The Hospital for Sick Children, 101 College St, East Tower, Rm 14 309, Toronto, Ontario, Canada M5G 1L7
    Am J Physiol Lung Cell Mol Physiol 298:L45-56. 2010
    ..In sum, these results demonstrate that Lfng functions to enhance Notch signaling in myofibroblast precursor cells and thereby to coordinate differentiation and mobilization of myofibroblasts required for alveolar septation...