title: Loss of cone cyclic nucleotide-gated channel leads to alterations in light response modulating system and cellular stress response pathways: a gene expression profiling study.
abstract: The cone photoreceptor cyclic nucleotide-gated (CNG) channel is essential for central and color vision and visual acuity. Mutations in the channel subunits CNGA3 and CNGB3 are associated with achromatopsia and cone dystrophy. We investigated the gene expression profiles in mouse retina with CNG channel deficiency using whole genome expression microarrays. As cones comprise only 2 to 3% of the total photoreceptor population in the wild-type mouse retina, the mouse lines with CNG channel deficiency on a cone-dominant background, i.e. Cnga3-/-/Nrl-/- and Cngb3-/-/Nrl-/- mice, were used in our study. Comparative data analysis revealed a total of 105 genes altered in Cnga3-/-/Nrl-/- and 92 in Cngb3-/-/Nrl-/- retinas, relative to Nrl-/- retinas, with 27 genes changed in both genotypes. The differentially expressed genes primarily encode proteins associated with cell signaling, cellular function maintenance and gene expression. Ingenuity pathway analysis (IPA) identified 26 and 9 canonical pathways in Cnga3-/-/Nrl-/- and Cngb3-/-/Nrl-/- retinas, respectively, with 6 pathways being shared. The shared pathways include phototransduction, cAMP/PKA-mediated signaling, endothelin signaling, and EIF2/endoplasmic reticulum (ER) stress, whereas the IL-1, CREB, and purine metabolism signaling were found to specifically associate with Cnga3 deficiency. Thus, CNG channel deficiency differentially regulates genes that affect cell processes such as phototransduction, cellular survival and gene expression, and such regulations play a crucial role(s) in the retinal adaptation to impaired cone phototransduction. Though lack of Cnga3 and Cngb3 shares many common pathways, deficiency of Cnga3 causes more significant alterations in gene expression. This work provides insights into how cones respond to impaired phototransduction at the gene expression levels.
authors.forename: Hongwei
authors.initials: H
authors.lastname: Ma
authors.forename: Arjun
authors.initials: A
authors.lastname: Thapa
authors.forename: Lynsie M
authors.initials: LM
authors.lastname: Morris
authors.forename: Stylianos
authors.initials: S
authors.lastname: Michalakis
authors.forename: Martin
authors.initials: M
authors.lastname: Biel
authors.forename: Mark Barton
authors.initials: MB
authors.lastname: Frank
authors.forename: Melissa
authors.initials: M
authors.lastname: Bebak
authors.forename: Xi-Qin
authors.initials: XQ
authors.lastname: Ding
mesh_terms: D000818:Animals; D054815:Cyclic Nucleotide-Gated Cation Channels / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D055537:Light Signal Transduction; D051379:Mice; D008810:Mice, Inbred C57BL; D046228:Microarray Analysis; D055355:Opsins / Q000235:genetics / Q000378:metabolism; D050638:Receptors, Dopamine D4 / Q000235:genetics / Q000378:metabolism; D012160:Retina / Q000378:metabolism*; D017949:Retinal Cone Photoreceptor Cells / Q000378:metabolism*; D015398:Signal Transduction; D014785:Vision, Ocular / Q000235:genetics*
chemical_list: C532622:CNGB3 protein, mouse; C518237:Cnga3 protein, mouse; D054815:Cyclic Nucleotide-Gated Cation Channels; C493600:Drd4 protein, mouse; D055355:Opsins; D050638:Receptors, Dopamine D4