International Mammalian Genome Society

The 16th International Mouse Genome Conference (2002)

Plenary Presentations * Oral Presentations *
Poster Presentations: Complex Genetics and Disease Modifiers * Developmental Genetics * Functional Genomics * Gene Discovery * Genetic Manipulations to Alter Gene Function * Mouse Models: Human Disease and Pharmacogenetics * Sequence Annotation and Comparative Analysis of Genomes *
Attendees * Sponsors * Table of Contents * Photographs * Awards

Oral Presentation

Tuesday 19 November

10:30 - 10:45 HRS

NEURODEGENERATION AND PIGMENTATION DEFECTS IN ATTRACTIN AND MAHOGANOID MUTANTS

TM Gunn
Cornell University

Co-Authors: He L, Barsh GS
Institutions: Stanford University

As with many classical pigmentation genes, mutations in Attractin (Atrn; formerly mahogany) and mahoganoid (md) have pleiotropic effects. Both of these mutants were originally recognized because they suppress Agouti pigment-type switching. More recently, we have identified additional, Agouti-independent phenotypes in Atrn mutants, including hyperactivity and reduced body weight, associated with abnormal myelination and widespread spongy degeneration of the central nervous system (CNS). Mice homozygous for a null allele of md have the same epistatic interactions as Atrn mutants and examination of their CNS also reveals widespread neurodegeneration. Atrn encodes a widely expressed type I transmembrane protein containing multiple plexin and EGF repeats. In the skin, it acts as an accessory receptor required for Agouti signalling, but its role in the CNS is Agouti-independent and not yet understood. We have now identified the md gene by positional cloning. It encodes Mahogunin (Mgn), a widely expressed RING-finger-containing protein with ubiquitin ligase activity. Like Atrn, it has homologs in fruit flies and nematodes. The similarity in Agouti-dependent and Agouti-independent phenotypes and pattern of evolutionary conservation suggests that Atrn and Mgn act in the same signalling pathway and that this pathway has an evolutionarily conserved role in neuronal survival. Identification of mutations in Mgn, a ubiquitin ligase, in md mutants implicates defects in protein ubiquitination in the pathology of neurodegeneration in Atrn and md mutants.