Natural Variation in Neuron Number in Mice Is Linked to a Major Quantitative Trait Locus on Chr 11

Common genetic polymorphisms—as opposed to rare mutations—generate 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 (Williams et al., 1996a), 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 betweenHoxbandKrt1(LOD = 6.8; genome-widep= 0.001) and possible subsidiary QTLs on Chr 2 and Chr 8. The Chr 11 locus,neuron number control1 (Nnc1), accounts for one third of the genetic variance among BXH strains and more than half of that among BXD strains, butNnc1has 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 asNnc1. These genes—Rara,Thra, andErbb2— 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.