RRC ID 12105
Author Elsen GE, Choi LY, Prince VE, Ho RK.
Title The autism susceptibility gene met regulates zebrafish cerebellar development and facial motor neuron migration.
Journal 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.
Volume 335(1)
Pages 78-92
Published 2009-11-1
DOI 10.1016/j.ydbio.2009.08.024
PII S0012-1606(09)01142-7
PMID 19732764
PMC PMC2784935
MeSH Animals Animals, Genetically Modified Autistic Disorder / genetics* Autistic Disorder / metabolism Cell Movement / physiology* Cell Proliferation Cerebellum* / anatomy & histology Cerebellum* / embryology Child Facial Nerve / cytology* Humans Ligands Mice Motor Neurons / cytology Motor Neurons / physiology* Oligonucleotides, Antisense / genetics Oligonucleotides, Antisense / metabolism Proto-Oncogene Proteins c-met* / genetics Proto-Oncogene Proteins c-met* / metabolism Signal Transduction / physiology Zebrafish* / anatomy & histology Zebrafish* / embryology Zebrafish* / genetics Zebrafish Proteins* / genetics Zebrafish Proteins* / metabolism
IF 3.262
Resource
Zebrafish rw0(Tg(CM-isl1:GFP))