PUBLICATION

The autism susceptibility gene met regulates zebrafish cerebellar development and facial motor neuron migration

Authors
Elsen, G.E., Choi, L.Y., Prince, V.E., and Ho, R.K.
ID
ZDB-PUB-090914-33
Date
2009
Source
Developmental Biology   335(1): 78-92 (Journal)
Registered Authors
Choi, Louis, Elsen, Gina, Ho, Robert K., Prince, Victoria E.
Keywords
Autism, Met, Hgf, Zebrafish, Hindbrain, Cerebellum, Facial motor neuron, Migration, Morphogenesis, Proliferation
MeSH Terms
  • Humans
  • Zebrafish Proteins*/genetics
  • Zebrafish Proteins*/metabolism
  • Cell Proliferation
  • Mice
  • Facial Nerve/cytology*
  • Ligands
  • Signal Transduction/physiology
  • Oligonucleotides, Antisense/genetics
  • Oligonucleotides, Antisense/metabolism
  • Motor Neurons/cytology
  • Motor Neurons/physiology*
  • Animals, Genetically Modified
  • Autistic Disorder/genetics*
  • Autistic Disorder/metabolism
  • Zebrafish*/anatomy & histology
  • Zebrafish*/embryology
  • Zebrafish*/genetics
  • Child
  • Cerebellum*/anatomy & histology
  • Cerebellum*/embryology
  • Proto-Oncogene Proteins c-met*/genetics
  • Proto-Oncogene Proteins c-met*/metabolism
  • Animals
  • Cell Movement/physiology*
(all 25)
PubMed
19732764 Full text @ Dev. Biol.
Abstract
During development, Met signaling regulates a range of cellular processes including growth, differentiation, survival and migration. The Met gene encodes a tyrosine kinase receptor, which is activated by Hgf (hepatocyte growth factor) ligand. Altered regulation of human MET expression has been implicated in autism. In mouse, Met signaling has been shown to regulate cerebellum development. Since abnormalities in cerebellar structure have been reported in some autistic patients, we have used the zebrafish to address the role of Met signaling during cerebellar development and thus further our understanding of the molecular basis of autism. We find that zebrafish met is expressed in the cerebellar primordium, later localizing to the ventricular zone (VZ), with the hgf1 and hgf2 ligand genes expressed in surrounding tissues. Morpholino knockdown of either Met or its Hgf ligands leads to a significant reduction in the size of the cerebellum, primarily as a consequence of reduced proliferation. Met signaling knockdown disrupts specification of VZ-derived cell types, and also reduces granule cell numbers, due to an early effect on cerebellar proliferation and/or as an indirect consequence of loss of signals from VZ-derived cells later in development. These patterning defects preclude analysis of cerebellar neuronal migration, but we have found that Met signaling is necessary for migration of hindbrain facial motor neurons. In summary, we have described roles for Met signaling in coordinating growth and cell type specification within the developing cerebellum, and in migration of hindbrain neurons. These functions may underlie the correlation between altered MET regulation and Autism Spectrum Disorders.
Genes / Markers
Figures
Figure Gallery (13 images) / 2
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Expression
Phenotype
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
jh1TgTransgenic Insertion
    knu3TgTransgenic Insertion
      rw0TgTransgenic Insertion
        1 - 3 of 3
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        Human Disease / Model
        No data available
        Sequence Targeting Reagents
        Target Reagent Reagent Type
        hgfaMO1-hgfaMRPHLNO
        hgfaMO2-hgfaMRPHLNO
        hgfbMO1-hgfbMRPHLNO
        metMO1-metMRPHLNO
        metMO2-metMRPHLNO
        metMO6-metMRPHLNO
        1 - 6 of 6
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        Fish
        Antibodies
        Orthology
        No data available
        Engineered Foreign Genes
        Marker Marker Type Name
        EGFPEFGEGFP
        GFPEFGGFP
        1 - 2 of 2
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        Mapping
        No data available