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A QTL on chromosome 10 modulates cone photoreceptor number in the mouse retina.

ABSTRACT: This investigation examines the genetic sources of marked variation in cone photoreceptor number among inbred lines of mice, identifying candidate genes that may control the proliferation, differentiation, or survival of this neuronal population.Cone photoreceptor populations were counted in C57BL/6J (B6/J) and A/J strains, and 26 recombinant inbred (RI) strains derived from them. Eyes from RI strains were also collected for microarray analysis. Quantitative trait locus (QTL) analysis was carried out by simple and composite interval mapping and validated using a consomic line. Candidate genes were evaluated based on genetic variance between the parental strains and analysis of gene expression. Expression data, deposited in GeneNetwork (www.GeneNetwork.org), were used to generate a coexpression network of established cone photoreceptor genes as a reference standard.B6/J has 70% more cone photoreceptors than A/J. A significant QTL was mapped to chromosome 10 (Chr 10) and confirmed using B6.A<10> mice. Of 19 positional candidate genes, one-the myeloblastosis oncogene (Myb)-stood out. Myb has a potentially damaging missense mutation, high retinal expression, and a known role in cell proliferation. The ectonucleotide pyrophosphatase/phosphodiesterase 1 gene (Enpp1) was a second strong candidate, with an expression pattern that covaried with cone photoreceptors and that was differentially expressed between the parental strains. Enpp1 and several other candidate genes covaried with multiple genes within the cone photoreceptor gene network.The mouse retina shows marked variation in cone photoreceptor number, some of which must be controlled by polymorphisms in a gene or genes on Chr 10.

SUBMITTER: Whitney IE

PROVIDER: S-EPMC3109025 | biostudies-literature | 2011 May

REPOSITORIES: biostudies-literature

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A QTL on chromosome 10 modulates cone photoreceptor number in the mouse retina.

Whitney Irene E IE Raven Mary A MA Lu Lu L Williams Robert W RW Reese Benjamin E BE

Investigative ophthalmology & visual science 20110516 6

<h4>Purpose</h4>This investigation examines the genetic sources of marked variation in cone photoreceptor number among inbred lines of mice, identifying candidate genes that may control the proliferation, differentiation, or survival of this neuronal population.<h4>Methods</h4>Cone photoreceptor populations were counted in C57BL/6J (B6/J) and A/J strains, and 26 recombinant inbred (RI) strains derived from them. Eyes from RI strains were also collected for microarray analysis. Quantitative trait ...[more]

PMID: 21330668

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Project description:Using constitutive GRF1/2 knockout mice, we showed previously that GRF2 is a key regulator of nuclear migration in retinal cone photoreceptors. To evaluate the functional relevance of that cellular process for two putative targets of the GEF activity of GRF2 (RAC1 and CDC42), here we compared the structural and functional retinal phenotypes resulting from conditional targeting of RAC1 or CDC42 in the cone photoreceptors of constitutive GRF2KO and GRF2WT mice. We observed that single RAC1 disruption did not cause any obvious morphological or physiological changes in the retinas of GRF2WT mice, and did not modify either the phenotypic alterations previously described in the retinal photoreceptor layer of GRF2KO mice. In contrast, the single ablation of CDC42 in the cone photoreceptors of GRF2WT mice resulted in clear alterations of nuclear movement that, unlike those of the GRF2KO retinas, were not accompanied by electrophysiological defects or slow, progressive cone cell degeneration. On the other hand, the concomitant disruption of GRF2 and CDC42 in the cone photoreceptors resulted, somewhat surprisingly, in a normalized pattern of nuclear positioning/movement, similar to that physiologically observed in GRF2WT mice, along with worsened patterns of electrophysiological responses and faster rates of cell death/disappearance than those previously recorded in single GRF2KO cone cells. Interestingly, the increased rates of cone cell apoptosis/death observed in single GRF2KO and double-knockout GRF2KO/CDC42KO retinas correlated with the electron microscopic detection of significant ultrastructural alterations (flattening) of their retinal ribbon synapses that were not otherwise observed at all in single-knockout CDC42KO retinas. Our observations identify GRF2 and CDC42 (but not RAC1) as key regulators of retinal processes controlling cone photoreceptor nuclear positioning and survival, and support the notion of GRF2 loss-of-function mutations as potential drivers of cone retinal dystrophies.

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A QTL on chromosome 10 modulates cone photoreceptor number in the mouse retina.

Publications

A QTL on chromosome 10 modulates cone photoreceptor number in the mouse retina.

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