International Mammalian Genome Society

17th International Mouse Genome Conference

9-12 November 2003, Braunschweig, Germany


POSTER 88 - MUTATIONS IN DYNEIN LINK MOTOR NEURON DEGENERATION TO DEFECTS IN RETROGRADE TRANSPORT

Fisher E M C
Institute of Neurology, London

Co-Authors: 1) Hafezparast M, Ahmad-Annuar A, 2) Ruhrberg C, Lalli G, Shima D, Toda T, Schiavo G, 3) Ball S, Peters J, 4) Bowen S, Martin J E
Institutions: 1) Institute of Neurology, London, 2) Cancer Research UK, London, 3) MRC Mammalian Genetics Unit, Harwell, 4) Royal London Hospital, London

We set out to phenotypically and genetically analyse a mouse mutant, the Legs at Odd Angles ( Loa) mouse, which has progressive loss of locomotor function in heterozygotes, and is a model for aspects of human motor neuron diseases – common and incurable killers that strike all age groups.

We used a range of methods to define the molecular genetics of the Loa mutation, histopathology, cell biological features including axonal transport, and other aspects of the mutation, including studying neurodevelopmental defects seen in homozygous embryos. On positional cloning of the mutation we identified a single base pair change in the dynein heavy chain gene 1 (Dnchc1). This conservative amino acid change leads to progressive loss of anterior horn cells in the spinal cord of heterozygous mice, and to neurodevelopmental defects in homozygous mice, including deficits in facial motor neuron migration and deficits in nerve branching and elongation. These defects include greatly increased apoptotic cell death in the nervous system, and the appearance of inclusion bodies staining positively for neurofilaments, ubiquitin, CDK5 and SOD1. We find a defect in one component of retrograde transport in the axons of Loa mice. These results, implicating the dynein-dynactin pathways in motor neuron disease were corroborated by other findings in mouse and human.


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