C57BLKS/J-Map1a^m1J/SlacJ

Stock number: 007724
Research areas: Neurobiology Research

Description

This recessive spontaneous mutation causes disruption of the microtubule organization in the somatodendritic domain of Purkinje cells and subsequent late-onset Purkinje cell degeneration in homozygotes, which presents as mild ataxia and tremors at approximately 1 year of age.

Detailed description

Mice homozygous for this spontaneous mutation develop mild ataxia and tremors at one year of age due to late-onset degeneration of cerebellar Purkinje cells. Map1a disruption causes changes in the microtubule networks in Purkinje cells, but not other cells. Mice homozygous for the null allele Map1a^{tm1.2(KOMP)Mbp} were found to have reductions in beta tubulin, and acetylated, polyglutamylated, and delta 2 alpha tubulin, but not tyrosinated alpha tubulin, in Purkinje cells at 18 days of age, and reduction of alpha and beta tubulin along the dendritic shaft and soma. Further immunohistochemistry showed MAP1B and MAP1B light chain greatly diminished in Purkinje cell soma, increased in distal dendritic segments, but normal in the dendritic shaft at 6 weeks of age in the Map1a^{tm1.2(KOMP)Mbp} homozygotes, although expression levels of MAP1B heavy chain, light chain, and MAP2 by Western blot analysis of cerebellar extracts are normal in both Map1a^{tm1.2(KOMP)Mbp} homozygotes and Map1a^m1J homozygotes. DLG2 is a membrane-associated guanylate kinase expressed in Purkinje cells. At five weeks of age DLG2 levels are decreased in the cerebellum of Map1a^m1J homozygotes and immunohistochemistry revealed greatly decreased DLG2 expression in the soma and dendritic shafts of Purkinje cells and moderately decreased expression in areas of the molecular layer surrounding the Purkinje cell dendritic shafts. Beginning at six weeks of age axonal torpedos are found in cerebellum Purkinje cells of Map1a^m1J homozygotes, but loss of Purkinje cell soma is not found before three months of age. Also at six weeks of age focal swellings of Purkinje cell dendrites, containing accumulated MAP1B, MAP1B light chain, and alpha and beta tubulin, are found and become more widespread by three months of age. At 2 months of age the axonal initial segment of Purkinje cells are hypertrophic or have abnormal blebs and transgenic expression of Map1a light chain is inadequate to rescue this phenotype, indicating an essential role for the full heavy chain. At seven months of age some Purkinje cell loss is found and by 18 months of age there is significant Purkinje cell degeneration in the cerebellum and the molecular layer is an average of 34% thinner than normal. Heterozygotes do not show Purkinje cell loss or any phenotypic abnormality and homozygotes were not found to have neuronal death or reactive gliosis in non-cerebellar regions. (Liu et al., 2015.)

Development

The Map1a^m1J mutation arose spontaneously at The Jackson Laboratory in the C57BLKS/J-Npc1^spm/J strain and was initially characterized by The Mouse Mutant Resource. The Npc1^spm mutation was bred out by a series of backcrosses to C57BLKS/J and sperm was later cryopreserved from homozygous males.

Allele

Symbol: Map1a^m1J
Name: mutation 1, Jackson
MGI accession ID: MGI:5774956
Generation method: Spontaneous
Marker symbol: Map1a
Marker name: microtubule-associated protein 1 A
Chromosome: 2
Strain of origin: C57BLKS/J-Npc1^spm/J
Molecular note: A spontaneous mutation results in a 8 bp deletion and 1 bp insertion. This mutation results in a frame shift, deleting 297 amino acids from the C terminus of the heavy chain sand loss of the entire LC2 light chain. Western blot analysis confirmed production of a truncated heavy chain.