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Analysis of transcriptional regulatory pathways of photoreceptor genes by expression profiling of the Otx2-deficient retina.

Omori Y, Katoh K, Sato S, Muranishi Y, Chaya T, Onishi A, Minami T, Fujikado T, Furukawa T - PLoS ONE (2011)

Bottom Line: We observed that expression of 101- and 1049-probe sets significantly decreased in the Otx2 CKO retina at P1 and P12, respectively, whereas, expression of 3- and 4149-probe sets increased at P1 and P12, respectively.We found that expression of genes encoding transcription factors involved in photoreceptor development, including Crx, Nrl, Nr2e3, Esrrb, and NeuroD, was markedly down-regulated in the Otx2 CKO at both P1 and P12.Furthermore, we identified three human retinal disease loci mapped in close proximity to certain down-regulated genes in the Otx2 CKO retina including Ccdc126, Tnfsf13 and Pitpnm1, suggesting that these genes are possibly responsible for these diseases.

View Article: PubMed Central - PubMed

Affiliation: Department of Developmental Biology, Osaka Bioscience Institute, Osaka, Japan.

ABSTRACT
In the vertebrate retina, the Otx2 transcription factor plays a crucial role in the cell fate determination of both rod and cone photoreceptors. We previously reported that Otx2 conditional knockout (CKO) mice exhibited a total absence of rods and cones in the retina due to their cell fate conversion to amacrine-like cells. In order to investigate the entire transcriptome of the Otx2 CKO retina, we compared expression profile of Otx2 CKO and wild-type retinas at P1 and P12 using microarray. We observed that expression of 101- and 1049-probe sets significantly decreased in the Otx2 CKO retina at P1 and P12, respectively, whereas, expression of 3- and 4149-probe sets increased at P1 and P12, respectively. We found that expression of genes encoding transcription factors involved in photoreceptor development, including Crx, Nrl, Nr2e3, Esrrb, and NeuroD, was markedly down-regulated in the Otx2 CKO at both P1 and P12. Furthermore, we identified three human retinal disease loci mapped in close proximity to certain down-regulated genes in the Otx2 CKO retina including Ccdc126, Tnfsf13 and Pitpnm1, suggesting that these genes are possibly responsible for these diseases. These transcriptome data sets of the Otx2 CKO retina provide a resource on developing rods and cones to further understand the molecular mechanisms underlying photoreceptor development, function and disease.

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Comparison gene expression profiles with the Otx2-CKO retina.(A-C) Microarray analysis datasets from Crx (A), Nrl (B), Nr2e3 (C) KO retinas were compared with that from the Otx2 CKO retina at P12. We identified 367 down-regulated probes in the Otx2 CKO retina (signal log ratio ≤−2.0, signal intensity ≥74). We used datasets from previous microarray analysis of the Crx, Nrl and Nr2e3- retinas at P21 with the following results: 154 probes down-regulated in the Crx KO retina (signal log ratio ≤−2.0, signal intensity ≥352), 63 probes up-regulated in the Crx KO retina (signal log ratio ≥+2.0, signal intensity ≥345), 95 probes down-regulated in the Nrl KO retina (signal log ratio ≤−2.0, signal intensity ≥354), 186 probes up-regulated in the Nrl KO retina (signal log ratio ≥+2.0, signal intensity ≥347), 9 probes down-regulated in the Nr2e3- (rd7) retina (signal log ratio ≤−2.0, signal intensity ≥354), 37 probes up-regulated in the Nr2e3- retina (signal log ratio ≥+2.0, signal intensity ≥358). The numbers of probes in each category were indicated.
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pone-0019685-g004: Comparison gene expression profiles with the Otx2-CKO retina.(A-C) Microarray analysis datasets from Crx (A), Nrl (B), Nr2e3 (C) KO retinas were compared with that from the Otx2 CKO retina at P12. We identified 367 down-regulated probes in the Otx2 CKO retina (signal log ratio ≤−2.0, signal intensity ≥74). We used datasets from previous microarray analysis of the Crx, Nrl and Nr2e3- retinas at P21 with the following results: 154 probes down-regulated in the Crx KO retina (signal log ratio ≤−2.0, signal intensity ≥352), 63 probes up-regulated in the Crx KO retina (signal log ratio ≥+2.0, signal intensity ≥345), 95 probes down-regulated in the Nrl KO retina (signal log ratio ≤−2.0, signal intensity ≥354), 186 probes up-regulated in the Nrl KO retina (signal log ratio ≥+2.0, signal intensity ≥347), 9 probes down-regulated in the Nr2e3- (rd7) retina (signal log ratio ≤−2.0, signal intensity ≥354), 37 probes up-regulated in the Nr2e3- retina (signal log ratio ≥+2.0, signal intensity ≥358). The numbers of probes in each category were indicated.

Mentions: Expression profiles of Crx, Nrl, and Nr2e3- retinas were reported previously [42], [43], [44], [45]. We compared datasets of the Otx2 CKO retina with those of the Crx, Nrl, and Nr2e3- retinas (Fig. 4, Text S1). We found that the expression of 84 probes was strongly decreased in both the Otx2 CKO and Crx KO retinas (signal log ratio ≤−2.0, Fig. 4A). This group includes both rod and cone photoreceptor genes such as Rhodopsin (Rho) and S-opsin (Opn1sw). The expression of 48 probes was markedly decreased in both the Otx2 CKO and Nrl KO retinas (signal log ratio ≤−2.0, Fig. 4B). These genes include rod-specific genes such as Pde6b and Rho. We identified 18 probes that were down-regulated in the Otx2 CKO retina but up-regulated in the Nrl KO retina, including cone photoreceptor genes such as Opn1sw, cone arrestin (Arr3) and Pde6c (Fig. 4B). Five of six genes down-regulated in the Otx2 CKO retina but up-regulated in the Nr2e3- retina overlapped with the probes down-regulated in the Otx2 CKO and up-regulated in the Nrl KO retina (Fig. 4C).


Analysis of transcriptional regulatory pathways of photoreceptor genes by expression profiling of the Otx2-deficient retina.

Omori Y, Katoh K, Sato S, Muranishi Y, Chaya T, Onishi A, Minami T, Fujikado T, Furukawa T - PLoS ONE (2011)

Comparison gene expression profiles with the Otx2-CKO retina.(A-C) Microarray analysis datasets from Crx (A), Nrl (B), Nr2e3 (C) KO retinas were compared with that from the Otx2 CKO retina at P12. We identified 367 down-regulated probes in the Otx2 CKO retina (signal log ratio ≤−2.0, signal intensity ≥74). We used datasets from previous microarray analysis of the Crx, Nrl and Nr2e3- retinas at P21 with the following results: 154 probes down-regulated in the Crx KO retina (signal log ratio ≤−2.0, signal intensity ≥352), 63 probes up-regulated in the Crx KO retina (signal log ratio ≥+2.0, signal intensity ≥345), 95 probes down-regulated in the Nrl KO retina (signal log ratio ≤−2.0, signal intensity ≥354), 186 probes up-regulated in the Nrl KO retina (signal log ratio ≥+2.0, signal intensity ≥347), 9 probes down-regulated in the Nr2e3- (rd7) retina (signal log ratio ≤−2.0, signal intensity ≥354), 37 probes up-regulated in the Nr2e3- retina (signal log ratio ≥+2.0, signal intensity ≥358). The numbers of probes in each category were indicated.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3094341&req=5

pone-0019685-g004: Comparison gene expression profiles with the Otx2-CKO retina.(A-C) Microarray analysis datasets from Crx (A), Nrl (B), Nr2e3 (C) KO retinas were compared with that from the Otx2 CKO retina at P12. We identified 367 down-regulated probes in the Otx2 CKO retina (signal log ratio ≤−2.0, signal intensity ≥74). We used datasets from previous microarray analysis of the Crx, Nrl and Nr2e3- retinas at P21 with the following results: 154 probes down-regulated in the Crx KO retina (signal log ratio ≤−2.0, signal intensity ≥352), 63 probes up-regulated in the Crx KO retina (signal log ratio ≥+2.0, signal intensity ≥345), 95 probes down-regulated in the Nrl KO retina (signal log ratio ≤−2.0, signal intensity ≥354), 186 probes up-regulated in the Nrl KO retina (signal log ratio ≥+2.0, signal intensity ≥347), 9 probes down-regulated in the Nr2e3- (rd7) retina (signal log ratio ≤−2.0, signal intensity ≥354), 37 probes up-regulated in the Nr2e3- retina (signal log ratio ≥+2.0, signal intensity ≥358). The numbers of probes in each category were indicated.
Mentions: Expression profiles of Crx, Nrl, and Nr2e3- retinas were reported previously [42], [43], [44], [45]. We compared datasets of the Otx2 CKO retina with those of the Crx, Nrl, and Nr2e3- retinas (Fig. 4, Text S1). We found that the expression of 84 probes was strongly decreased in both the Otx2 CKO and Crx KO retinas (signal log ratio ≤−2.0, Fig. 4A). This group includes both rod and cone photoreceptor genes such as Rhodopsin (Rho) and S-opsin (Opn1sw). The expression of 48 probes was markedly decreased in both the Otx2 CKO and Nrl KO retinas (signal log ratio ≤−2.0, Fig. 4B). These genes include rod-specific genes such as Pde6b and Rho. We identified 18 probes that were down-regulated in the Otx2 CKO retina but up-regulated in the Nrl KO retina, including cone photoreceptor genes such as Opn1sw, cone arrestin (Arr3) and Pde6c (Fig. 4B). Five of six genes down-regulated in the Otx2 CKO retina but up-regulated in the Nr2e3- retina overlapped with the probes down-regulated in the Otx2 CKO and up-regulated in the Nrl KO retina (Fig. 4C).

Bottom Line: We observed that expression of 101- and 1049-probe sets significantly decreased in the Otx2 CKO retina at P1 and P12, respectively, whereas, expression of 3- and 4149-probe sets increased at P1 and P12, respectively.We found that expression of genes encoding transcription factors involved in photoreceptor development, including Crx, Nrl, Nr2e3, Esrrb, and NeuroD, was markedly down-regulated in the Otx2 CKO at both P1 and P12.Furthermore, we identified three human retinal disease loci mapped in close proximity to certain down-regulated genes in the Otx2 CKO retina including Ccdc126, Tnfsf13 and Pitpnm1, suggesting that these genes are possibly responsible for these diseases.

View Article: PubMed Central - PubMed

Affiliation: Department of Developmental Biology, Osaka Bioscience Institute, Osaka, Japan.

ABSTRACT
In the vertebrate retina, the Otx2 transcription factor plays a crucial role in the cell fate determination of both rod and cone photoreceptors. We previously reported that Otx2 conditional knockout (CKO) mice exhibited a total absence of rods and cones in the retina due to their cell fate conversion to amacrine-like cells. In order to investigate the entire transcriptome of the Otx2 CKO retina, we compared expression profile of Otx2 CKO and wild-type retinas at P1 and P12 using microarray. We observed that expression of 101- and 1049-probe sets significantly decreased in the Otx2 CKO retina at P1 and P12, respectively, whereas, expression of 3- and 4149-probe sets increased at P1 and P12, respectively. We found that expression of genes encoding transcription factors involved in photoreceptor development, including Crx, Nrl, Nr2e3, Esrrb, and NeuroD, was markedly down-regulated in the Otx2 CKO at both P1 and P12. Furthermore, we identified three human retinal disease loci mapped in close proximity to certain down-regulated genes in the Otx2 CKO retina including Ccdc126, Tnfsf13 and Pitpnm1, suggesting that these genes are possibly responsible for these diseases. These transcriptome data sets of the Otx2 CKO retina provide a resource on developing rods and cones to further understand the molecular mechanisms underlying photoreceptor development, function and disease.

Show MeSH
Related in: MedlinePlus