International Mammalian Genome Society

The 15th International Mouse Genome Conference (2001)


NEURODEGENERATION AND COAT COLOR DEFECTS IN THE ATTRACTIN PATHWAY

Teresa Gunn
Department of Biomedical Sciences
T4 018 VRT
Cornell University
Ithaca, NY USA

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

Mutations of the mouse Attractin (Atrn; formerly mahogany) gene, which encodes a widely expressed type I transmembrane protein containing multiple plexin and EGF repeats, were originally recognized because they suppress Agouti pigment type-switching. Surprisingly, homologs of Atrn are found in fruit flies and nematodes, even though Agouti and/or Agouti-related protein are found only in vertebrates. Insight into this apparent paradox now comes from studies of different Atrn alleles, in which we find hyperactivity, abnormal myelination, and widespread CNS vacuolation whose severity is inversely proportional to the amount of normal Atrn mRNA. Neurodegeneration is also caused by the classical coat color mutation mahoganoid, whose effects on pigment type-switching and epistatic interactions are nearly identical to Atrn. We have now positionally cloned mahoganoid, and find that it predicts a 54 kD intracellular protein whose pattern of evolutionary conservation is similar to Atrn. Taken together with studies of invertebrate Atrn homologs, these results suggest that Atrn and mahoganoid function as closely linked components of a metazoan pathway required to maintain normal neuronal architecture, that mahoganoid lies downstream of Atrn, and that this pathway was recruited during vertebrate evolution by the Agouti-melanocortin system to control coat color.


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