Multiple genes on chromosome 7 regulate dopaminergic amacrine cell number in the mouse retina.
OBJECTIVE
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 sixfold 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
Much of this variation was mapped to a broad locus on Chr 7 (Dopaminergic amacrine cell number control, Chr 7 [Dacnc7]). The Dacnc7 locus is flanked by two candidate genes known to modulate the number of other types of retinal neuron-the proapoptotic gene, Bax, and tyrosinase. The Tyr mutation was shown to modulate DA cell number modestly, though in the direction opposite that predicted. In contrast, Bax deficiency increased the population fourfold. Bax expression was significantly greater in the A/J than in the C57BL/6J strain, an effect that may be attributed 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 missense mutations segregating within the AXB/BXA cross.


CONCLUSIONS
Multiple polymorphic genes on Chr 7 modulate the size of the population of DA cells.
Whitney
Irene E
IE
Neuroscience Research Institute and Department of Psychology, University of California, Santa Barbara, California 93106-5060, USA.
Raven
Mary A
MA
Ciobanu
Daniel C
DC
Williams
Robert W
RW
Reese
Benjamin E
BE
D025042:Amacrine Cells / Q000166:cytology* / Q000378:metabolism; D000818:Animals; D002452:Cell Count; D002875:Chromosomes / Q000235:genetics*; D003433:Crosses, Genetic; D051379:Mice; D008805:Mice, Inbred A; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D014442:Monophenol Monooxygenase / Q000235:genetics; D016133:Polymerase Chain Reaction; D040641:Quantitative Trait Loci / Q000502:physiology*; D019655:Quantitative Trait, Heritable; D011954:Receptors, Dopamine / Q000378:metabolism*; D012160:Retina / Q000166:cytology; D014446:Tyrosine 3-Monooxygenase / Q000276:immunology
D011954:Receptors, Dopamine; D014446:Tyrosine 3-Monooxygenase; D014442:Monophenol Monooxygenase