Date of this Version
Invest Ophthalmol Vis Sci. 2009 May ; 50(5): pp. 1996–2003. doi:10.1167/iovs.08-2556.
Purpose—The size of neuronal populations is modulated by gene variants that influence cell production and survival, in turn influencing neuronal connectivity, function, and disease risk. The size of the dopaminergic amacrine (DA) cell population is a highly heritable trait exhibiting six-fold variation among inbred strains of mice, and is used here to identify genes that modulate the number of DA cells.
Methods—The entire population was counted in retinal wholemounts from 37 genetically defined lines of mice, including six standard inbred strains, 25 recombinant inbred strains (AXB/BXA), reciprocal F1 hybrids, a chromosome (Chr) 7 consomic line, and three additional genetically modified lines.
Results—We mapped much of this variation to a broad locus on Chr 7 (Dopaminergic amacrine cell number control, Chr 7). The Dacnc7 locus is flanked by two candidate genes known to modulate the number of other types of retinal neuron—the pro-apoptotic gene, Bax, and tyrosinase. The Tyr mutation was shown to modulate DA cell number modestly, although in the direction opposite that predicted. In contrast, Bax deficiency increased the population four-fold. Bax expression was significantly greater in the A/J strain relative to C57BL/6J, an effect that may be due to an SNP in a p53 consensus binding site known to modulate transcription. Finally, we note a strong candidate situated at the peak of the Dacnc7 locus, Lrrk1, a Parkinson’s disease gene exhibiting mis-sense mutations segregating within the AXB/BXA cross.
Conclusions—Multiple polymorphic genes on Chr. 7 modulate the size of the population of DA cells.