Transcriptional code and disease map for adult retinal cell types

Siegert, Sandra; Cabuy, Erik; Scherf, Brigitte Gross; Kohler, Hubertus; Panda, Satchidananda; Le, Yun-Zheng; Fehling, Hans Jörg; Gaidatzis, Dimos; Stadler, Michael; Roska, Botond

doi:10.1038/nn.3032

Cited by 229 publications

(301 citation statements)

References 49 publications

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“…Microarray analysis of purified populations of retinal neurons in development and maturity, however, confirms moderate Pttg1 expression within the cholinergic amacrine cells (3,15). Most compelling, microarray data, using a probe to Pttg1.2 (Fig.…”

Section: Pttg1 Is the Most Promising Candidate Gene At The Chromosome 11mentioning

confidence: 83%

“…Perhaps the very cell types that use tangential dispersion during development to produce this regularity become dependent on a Pttg1 signaling pathway to maintain it. Pttg1 is expressed throughout retinal development (14) and by multiple types of retinal cells in maturity and at postnatal day 7 (3,15), with cholinergic amacrine cells being one of the most heavily expressing cells. Because Pttg1 differentially regulates gene expression through its interaction with different cofactors (13), the specificity in its biological role at a particular postnatal stage, and within only particular types of retinal cells, may be due to the temporally restricted presence of these cofactors in selective cell types.…”

Section: Discussionmentioning

confidence: 99%

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Pituitary tumor-transforming gene 1 regulates the patterning of retinal mosaics

Keeley

Zhou

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Neurons are commonly organized as regular arrays within a structure, and their patterning is achieved by minimizing the proximity between like-type cells, but molecular mechanisms regulating this process have, until recently, been unexplored. We performed a forward genetic screen using recombinant inbred (RI) strains derived from two parental A/J and C57BL/6J mouse strains to identify genomic loci controlling spacing of cholinergic amacrine cells, which is a subclass of retinal interneuron. We found conspicuous variation in mosaic regularity across these strains and mapped a sizeable proportion of that variation to a locus on chromosome 11 that was subsequently validated with a chromosome substitution strain. Using a bioinformatics approach to narrow the list of potential candidate genes, we identified pituitary tumortransforming gene 1 (Pttg1) as the most promising. Expression of Pttg1 was significantly different between the two parental strains and correlated with mosaic regularity across the RI strains. We identified a seven-nucleotide deletion in the Pttg1 promoter in the C57BL/6J mouse strain and confirmed a direct role for this motif in modulating Pttg1 expression. Analysis of Pttg1 KO mice revealed a reduction in the mosaic regularity of cholinergic amacrine cells, as well as horizontal cells, but not in two other retinal cell types. Together, these results implicate Pttg1 in the regulation of homotypic spacing between specific types of retinal neurons. The genetic variant identified creates a binding motif for the transcriptional activator protein 1 complex, which may be instrumental in driving differential expression of downstream processes that participate in neuronal spacing.L ike many other CNS structures, the retina is composed of recurring modular microcircuits. Distinct neuronal populations are each distributed across the tissue and establish stereotypic patterns of connectivity with one another. To ensure a complete functional coverage by these microcircuits, individual neuronal populations are arranged in regular arrays across the entire retina (1). The regularity of these arrays is achieved by the presence of a zone of exclusion surrounding each cell, minimizing proximity between like-type cells, and although several developmental mechanisms, such as selective cell death and tangential migration, have been shown to mediate formation of such exclusion zones (2), the molecular underpinnings of these processes have received little attention. Recently, however, the EGF-like transmembrane receptor Megf10, which is expressed in only two neuronal populations of the retina, has been shown to mediate recognition and repulsion between like-type cells (3). In another retinal neuronal population, the anti-and proapoptotic factors Bcl2 and Bax have been shown to modulate programmed cell death, a process that yields increased regularity of this mosaic (4, 5). Aside from these examples, relatively little is known about the genetic determinants that coordinate these retinal cell biological processes.In the pre...

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Section: Pttg1 Is the Most Promising Candidate Gene At The Chromosome 11mentioning

confidence: 83%

Section: Discussionmentioning

confidence: 99%

Pituitary tumor-transforming gene 1 regulates the patterning of retinal mosaics

Keeley

Zhou

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…An Agilent 7890/5975C GC/MS system (Agilent Technologies, Santa Clara, CA) with an Agilent HP-5MS column (30 m ϫ 0.25 mm ϫ 0.25 m film) column was used for GC separation and analysis of metabolites, and the settings for this system have been published previously (23,24). Labeled metabolite data were presented as relative ion abundances or as percent 13 C-labeled metabolites, which was calculated by dividing the labeled ions with total ion intensity. Calibration of ␤-HB was performed using various concentrations of 2,4-13 C 2 ␤-HB.…”

Section: Methodsmentioning

confidence: 99%

“…The natural abundance of the tracers and derivatization reagents was corrected using IsoCor software. [U- 13 C]sodium lactate (catalog no. 485926) and 2,4-13 C 2 ␤-HB (catalog no.…”

Section: Methodsmentioning

confidence: 99%

“…The transporter for ␤-HB was identified recently in the zebrafish model to be monocarboxylate transporter isoform 7 (MCT7, encoded by Slc16a6) (12). MCT7 expression in the RPE and retina has not been reported, but a search of microarray data published recently of individual mouse retina cell types (from the work of Siegert et al (13)) revealed that MCT7 is expressed in photoreceptor cells, suggesting that photoreceptor cells can take up and metabolize ␤-HB. Consistent with this notion, Northern blot analysis showed that MCT7 (previously known as MCT6) transcript is particularly enriched in the brain (14), where the role of ketones as energy substrates is well established.…”

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confidence: 99%

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The Retinal Pigment Epithelium Utilizes Fatty Acids for Ketogenesis

Adijanto

Moffat

et al. 2014

Journal of Biological Chemistry

134

126

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Background: RPE cells derive fatty acids from phagocytized photoreceptor outer segments. Results: RPE cells metabolize palmitate to produce ␤-hydroxybutyrate (␤-HB), a ketone body the retina can use as a metabolic substrate. Conclusion: RPE cells produce ␤-HB as a potential substrate for photoreceptor cells in the outer retina. Significance: This is a novel form of RPE-retina interaction that may be important for retinal cell health and function.

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