Cell production and cell death in the generation of variation in neuron number

Retinal ganglion cell numbers in adult mice vary from 40,000 to 80, 000. Much of this variation and the prominent bimodality of strain averages are generated by allelic variants at the neuron number control 1 (Nnc1) locus on chromosome 11. The Nnc1 locus may modulate either ganglion cell production or the severity of ganglion cell death. Here we have determined what the relative contributions of these two processes are to variation in adult cell number by estimating total ganglion cell production in 10 strains of mice (A/J, BALB/cJ, BXD32, C57BL/6J, CAST/Ei, CARL/ChGo, CE/J, C3H/HeSnJ, DBA/2J, and LP/J). These strains have adult populations that range from 45,000 to 76,000 (data available at http://qtl.ml.org). We estimated cell production by counting ganglion cell axons after ganglion cell neurogenesis but before the onset of significant cell death. Total cell production ranges from 131,000 to 224,000, and most of the variation in adult ganglion cell number is explained by this significant variation in cell production. In contrast, the percentage of cell death is relatively uniform in most strains (approximately 69% cell loss). The exceptions are BXD32, a strain that has an extremely high adult cell population, and Mus caroli (CARL/ChGo), a wild southeast Asian species that is distantly related to laboratory strains. In BXD32 and M. caroli, approximately 62% of the population dies. Our analysis indicates that substitutions of single alleles at the Nnc1 locus are responsible for production differences of approximately 8000 ganglion cells.