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The Journal of Neuroscience, January 1, 1998, 18(1):138-146
Natural Variation in Neuron Number in Mice Is Linked to a Major
Quantitative Trait Locus on Chr 11
Robert W.
Williams,
Richelle C.
Strom, and
Dan
Goldowitz
Center for Neuroscience, Department of Anatomy and
Neurobiology, University of Tennessee, Memphis, Tennessee 38163
Common genetic polymorphisms as opposed to rare
mutationsgenerate almost all heritable differences in the size and
structure of the CNS. Surprisingly, these normal variants have not
previously been mapped or cloned in any vertebrate species. In a recent
paper (), we suggested that much of the variation in retinal ganglion cell number in mice, and the striking bimodality of
strain averages, are caused by one or two quantitative trait loci
(QTLs). To test this idea, and to map genes linked to this variable and
highly heritable quantitative trait, we have counted ganglion cells in
38 recombinant inbred strains (BXD and BXH) derived from parental
strains that have high and low cell numbers. A genome-wide search using
simple and composite interval-mapping techniques revealed a major QTL
on chromosome (Chr) 11 in a 3 cM interval between Hoxb
and Krt1 (LOD = 6.8; genome-wide p = 0.001)
and possible subsidiary QTLs on Chr 2 and Chr 8. The Chr 11 locus,
neuron number control 1 (Nnc1), accounts for
one third of the genetic variance among BXH strains and more than half
of that among BXD strains, but Nnc1 has no known effects
on brain weight, eye weight, or total retinal cell number. Three strong candidate genes have been mapped previously to the same region as
Nnc1. These genesRara,
Thra, and Erbb2 encode receptors for retinoic acid, thyroxine, and neuregulin, respectively. Each receptor is expressed in the retina during development, and their ligands affect
the proliferation or survival of retinal cells.
Key words:
brain evolution; brain weight; composite interval
mapping; gene polymorphism; inner nuclear layer; linkage analysis; mouse chromosome 11; natural variation; neuron number; optic nerve; outer nuclear layer; quantitative trait locus; recombinant inbred
strains; regression analysis; retinal ganglion cell
Copyright © 1998 Society for Neuroscience 0270-6474/98/181138-09$05.00/0
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