Author Kuramoto T, Kuwamura M, Serikawa T.
Title Rat neurological mutations cerebellar vermis defect and hobble are caused by mutations in the netrin-1 receptor gene Unc5h3.
Journal Brain Res. Mol. Brain Res.
Abstract Rats homozygous for the spontaneous cerebellar vermis defect mutation (cvd) or hobble mutation (hob) exhibit cerebellar and midbrain defects, possibly as a result of abnormal neuronal migration. Both mutant rats demonstrate laminar structure abnormalities in the fused cerebellar hemispheres and ectopic cerebellar tissues in the cerebello-pontine junction. Previous genetic studies showed that cvd and hob were allelic and suggested that Unc5h3, the causative gene of the mouse rostral cerebellar malformation (rcm) mutation, was a strong candidate for both cvd and hob. Unc5h3 encodes a receptor mediating the repulsive action for Netrin-1 and has an important role during cell migration in the developing murine cerebellum. Here, we describe positional candidate cloning of cvd and hob, and identified cvd and hob mutations in the rat Unc5h3. The cvd mutation is a nucleotide conversion of G to T resulting in a premature termination at codon 451 of the UNC5H3 protein. The hob mutation is a 2-bp insertion resulting in a frame shift from codon 312 and a premature termination at codon 385 of the UNC5H3 protein. Both cvd and hob mutations are predicted to lead to truncated UNC5H3 proteins lacking their cytoplasmic region required for Netrin-Unc5h3 signaling pathway. Therefore, we conclude that Unc5h3 is causative gene of both cvd and hob mutant phenotypes. Rats homozygous for Unc5h3cvd or Unc5h3hob are the first mammalian Unc5h3 mutant model other than Unc5h3rcm/rcm mice, and will provide a useful tool for further understanding of the biological function of Unc5h3.
Volume 122(2)
Pages 103-8
Published 2004-3-30
DOI 10.1016/j.molbrainres.2003.12.003
PII S0169328X03005503
PMID 15010202
MeSH Animals Cell Movement / genetics* Cerebellum / abnormalities* Cerebellum / metabolism Codon, Nonsense / genetics DNA, Complementary / analysis DNA, Complementary / genetics Frameshift Mutation / genetics Gene Expression Regulation, Developmental / genetics Mice Molecular Sequence Data Molecular Weight Mutation / genetics Nerve Growth Factors / metabolism* Nerve Tissue Proteins / biosynthesis Nerve Tissue Proteins / genetics* Nerve Tissue Proteins / isolation & purification Nervous System Malformations / genetics* Nervous System Malformations / metabolism Nervous System Malformations / physiopathology Netrin Receptors Netrin-1 Protein Structure, Tertiary / genetics Rats Rats, Mutant Strains Receptors, Cell Surface / biosynthesis Receptors, Cell Surface / genetics* Receptors, Cell Surface / isolation & purification Sequence Homology, Amino Acid Sequence Homology, Nucleic Acid Signal Transduction / genetics Tumor Suppressor Proteins
Rats F344.CVD-Unc5ccvd/Kyo(strainID=153)