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Transcriptional code and disease map for adult retinal cell types

Abstract

Brain circuits are assembled from a large variety of morphologically and functionally diverse cell types. It is not known how the intermingled cell types of an individual adult brain region differ in their expressed genomes. Here we describe an atlas of cell type transcriptomes in one brain region, the mouse retina. We found that each adult cell type expressed a specific set of genes, including a unique set of transcription factors, forming a 'barcode' for cell identity. Cell type transcriptomes carried enough information to categorize cells into morphological classes and types. Several genes that were specifically expressed in particular retinal circuit elements, such as inhibitory neuron types, are associated with eye diseases. The resource described here allows gene expression to be compared across adult retinal cell types, experimenting with specific transcription factors to differentiate stem or somatic cells to retinal cell types, and predicting cellular targets of newly discovered disease-associated genes.

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Figure 1: Retinal inventory for cell type comparative transcriptome analysis.
Figure 2: Transcriptome comparisons of cell groups that belong to a cell class.
Figure 3: Transcriptome comparisons of cell groups.
Figure 4: Cell group–specific transcription factors.
Figure 5: Retinal disease-associated genes in adult cell types.

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References

  1. Kim, D.S. et al. Identification of molecular markers of bipolar cells in the murine retina. J. Comp. Neurol. 507, 1795–1810 (2008).

    CAS  Article  Google Scholar 

  2. Trimarchi, J.M. et al. Molecular heterogeneity of developing retinal ganglion and amacrine cells revealed through single cell gene expression profiling. J. Comp. Neurol. 502, 1047–1065 (2007).

    CAS  Article  Google Scholar 

  3. Kay, J.N., Voinescu, P.E., Chu, M.W. & Sanes, J.R. Neurod6 expression defines new retinal amacrine cell subtypes and regulates their fate. Nat Neurosci. 14, 965–972 (2011).

    CAS  Article  Google Scholar 

  4. Cherry, T.J., Trimarchi, J.M., Stadler, M.B. & Cepko, C.L. Development and diversification of retinal amacrine interneurons at single cell resolution. Proc. Natl. Acad. Sci. USA 106, 9495–9500 (2009).

    CAS  Article  Google Scholar 

  5. Arlotta, P. et al. Neuronal subtype-specific genes that control corticospinal motor neuron development in vivo. Neuron 45, 207–221 (2005).

    CAS  Article  Google Scholar 

  6. Sugino, K. et al. Molecular taxonomy of major neuronal classes in the adult mouse forebrain. Nat. Neurosci. 9, 99–107 (2006).

    CAS  Article  Google Scholar 

  7. Doyle, J.P. et al. Application of a translational profiling approach for the comparative analysis of CNS cell types. Cell 135, 749–762 (2008).

    CAS  Article  Google Scholar 

  8. Nelson, S.B., Sugino, K. & Hempel, C.M. The problem of neuronal cell types: a physiological genomics approach. Trends Neurosci. 29, 339–345 (2006).

    CAS  Article  Google Scholar 

  9. Son, E.Y. et al. Conversion of mouse and human fibroblasts into functional spinal motor neurons. Cell Stem Cell 9, 205–218 (2011).

    CAS  Article  Google Scholar 

  10. Caiazzo, M. et al. Direct generation of functional dopaminergic neurons from mouse and human fibroblasts. Nature 476, 224–227 (2011).

    CAS  Article  Google Scholar 

  11. Kim, J. et al. Functional integration of dopaminergic neurons directly converted from mouse fibroblasts. Cell Stem Cell 9, 413–419 (2011).

    CAS  Article  Google Scholar 

  12. Roesch, K. et al. The transcriptome of retinal Müller glial cells. J. Comp. Neurol. 509, 225–238 (2008).

    CAS  Article  Google Scholar 

  13. Corbo, J.C., Myers, C.A., Lawrence, K.A., Jadhav, A.P. & Cepko, C.L. A typology of photoreceptor gene expression patterns in the mouse. Proc. Natl. Acad. Sci. USA 104, 12069–12074 (2007).

    CAS  Article  Google Scholar 

  14. Gollisch, T. & Meister, M. Eye smarter than scientists believed: neural computations in circuits of the retina. Neuron 65, 150–164 (2010).

    CAS  Article  Google Scholar 

  15. Sanes, J.R. & Zipursky, S.L. Design principles of insect and vertebrate visual systems. Neuron 66, 15–36 (2010).

    CAS  Article  Google Scholar 

  16. Wässle, H. Parallel processing in the mammalian retina. Nat. Rev. Neurosci. 5, 747–757 (2004).

    Article  Google Scholar 

  17. Masland, R.H. The fundamental plan of the retina. Nat. Neurosci. 4, 877–886 (2001).

    CAS  Article  Google Scholar 

  18. Siegert, S. et al. Genetic address book for retinal cell types. Nat. Neurosci. 12, 1197–1204 (2009).

    CAS  Article  Google Scholar 

  19. Okaty, B.W., Sugino, K. & Nelson, S.B. Cell type-specific transcriptomics in the brain. J. Neurosci. 31, 6939–6943 (2011).

    CAS  Article  Google Scholar 

  20. Okaty, B.W., Sugino, K. & Nelson, S.B. A quantitative comparison of cell-type-specific microarray gene expression profiling methods in the mouse brain. PLoS ONE 6, e16493 (2011).

    CAS  Article  Google Scholar 

  21. Jeon, C.J., Strettoi, E. & Masland, R.H. The major cell populations of the mouse retina. J. Neurosci. 18, 8936–8946 (1998).

    CAS  Article  Google Scholar 

  22. Livesey, F.J. & Cepko, C.L. Vertebrate neural cell-fate determination: lessons from the retina. Nat. Rev. Neurosci. 2, 109–118 (2001).

    CAS  Article  Google Scholar 

  23. Agathocleous, M. & Harris, W.A. From progenitors to differentiated cells in the vertebrate retina. Annu. Rev. Cell Dev. Biol. 25, 45–69 (2009).

    CAS  Article  Google Scholar 

  24. Dasen, J.S. & Jessell, T.M. Hox networks and the origins of motor neuron diversity. Curr. Top. Dev. Biol. 88, 169–200 (2009).

    CAS  Article  Google Scholar 

  25. Arendt, D. Evolution of eyes and photoreceptor cell types. Int. J. Dev. Biol. 47, 563–571 (2003).

    PubMed  Google Scholar 

  26. Koyanagi, M., Kubokawa, K., Tsukamoto, H., Shichida, Y. & Terakita, A. Cephalochordate melanopsin: evolutionary linkage between invertebrate visual cells and vertebrate photosensitive retinal ganglion cells. Curr. Biol. 15, 1065–1069 (2005).

    CAS  Article  Google Scholar 

  27. Isoldi, M.C., Rollag, M.D., Castrucci, A.M.D. & Provencio, I. Rhabdomeric phototransduction initiated by the vertebrate photopigment melanopsin. Proc. Natl. Acad. Sci. USA 102, 1217–1221 (2005).

    CAS  Article  Google Scholar 

  28. Hardie, R.C. Phototransduction in Drosophila melanogaster. J. Exp. Biol. 204, 3403–3409 (2001).

    CAS  PubMed  Google Scholar 

  29. Lee, Y.J. et al. The Drosophila Dgq gene encodes a Gα-protein that mediates phototransduction. Neuron 13, 1143–1157 (1994).

    CAS  Article  Google Scholar 

  30. Terakita, A., Hariyama, T., Tsukahara, Y., Katsukura, Y. & Tashiro, H. Interaction of GTP-binding protein Gq with photoactivated rhodopsin in the photoreceptor-membranes of crayfish. FEBS Lett. 330, 197–200 (1993).

    CAS  Article  Google Scholar 

  31. Sekaran, S. et al. 2-Aminoethoxydiphenylborane is an acute inhibitor of directly photosensitive retinal ganglion cell activity in vitro and in vivo. J. Neurosci. 27, 3981–3986 (2007).

    CAS  Article  Google Scholar 

  32. Briggman, K.L., Helmstaedter, M. & Denk, W. Wiring specificity in the direction-selectivity circuit of the retina. Nature 471, 183–188 (2011).

    CAS  Article  Google Scholar 

  33. Yoshida, K. et al. A key role of starburst amacrine cells in originating retinal directional selectivity and optokinetic eye movement. Neuron 30, 771–780 (2001).

    CAS  Article  Google Scholar 

  34. Tarpey, P. et al. Mutations in FRMD7, a newly identified member of the FERM family, cause X-linked idiopathic congenital nystagmus. Nat. Genet. 38, 1242–1244 (2006).

    CAS  Article  Google Scholar 

  35. Geng, R. et al. Usher syndrome IIIA gene clarin-1 is essential for hair cell function and associated neural activation. Hum. Mol. Genet. 18, 2748–2760 (2009).

    CAS  Article  Google Scholar 

  36. Chen, J., Connor, K.M. & Smith, L.E. Overstaying their welcome: defective CX3CR1 microglia eyed in macular degeneration. J. Clin. Invest. 117, 2758–2762 (2007).

    CAS  Article  Google Scholar 

  37. Klein, R.J. et al. Complement factor H polymorphism in age-related macular degeneration. Science 308, 385–389 (2005).

    CAS  Article  Google Scholar 

  38. Klaver, C.C. et al. Genetic association of apolipoprotein E with age-related macular degeneration. Am. J. Hum. Genet. 63, 200–206 (1998).

    CAS  Article  Google Scholar 

  39. Shibuya, E. et al. Association of Toll-like receptor 4 gene polymorphisms with normal tension glaucoma. Invest. Ophthalmol. Vis. Sci. 49, 4453–4457 (2008).

    Article  Google Scholar 

  40. Tezel, G. TNF-alpha signaling in glaucomatous neurodegeneration. Prog. Brain Res. 173, 409–421 (2008).

    CAS  Article  Google Scholar 

  41. Naj, A.C. et al. Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer's disease. Nat. Genet. 43, 436–441 (2011).

    CAS  Article  Google Scholar 

  42. Hollingworth, P. et al. Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer's disease. Nat. Genet. 43, 429–435 (2011).

    CAS  Article  Google Scholar 

  43. Eiraku, M. et al. Self-organizing optic-cup morphogenesis in three-dimensional culture. Nature 472, 51–56 (2011).

    CAS  Article  Google Scholar 

  44. MacLaren, R.E. et al. Retinal repair by transplantation of photoreceptor precursors. Nature 444, 203–207 (2006).

    CAS  Article  Google Scholar 

  45. Lamba, D.A. et al. Generation, purification and transplantation of photoreceptors derived from human induced pluripotent stem cells. PLoS ONE 5, e8763 (2010).

    Article  Google Scholar 

  46. Lee, E.C. et al. A highly efficient Escherichia coli-based chromosome engineering system adapted for recombinogenic targeting and subcloning of BAC DNA. Genomics 73, 56–65 (2001).

    CAS  Article  Google Scholar 

  47. Liu, P., Jenkins, N.A. & Copeland, N.G. A highly efficient recombineering-based method for generating conditional knockout mutations. Genome Res. 13, 476–484 (2003).

    CAS  Article  Google Scholar 

  48. Caputto, B.L. & Guido, M.E. Immediate early gene expression within the visual system: light and circadian regulation in the retina and the suprachiasmatic nucleus. Neurochem. Res. 25, 153–162 (2000).

    CAS  Article  Google Scholar 

  49. Matsuda, T. & Cepko, C.L. Electroporation and RNA interference in the rodent retina in vivo and in vitro. Proc. Natl. Acad. Sci. USA 101, 16–22 (2004).

    CAS  Article  Google Scholar 

  50. Morrow, E.M., Belliveau, M.J. & Cepko, C.L. Two phases of rod photoreceptor differentiation during rat retinal development. J. Neurosci. 18, 3738–3748 (1998).

    CAS  Article  Google Scholar 

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Acknowledgements

We thank S. Djaffer, J. Jüttner, J. Hall and Y. Shimada for technical assistance, E. Oakeley for comments on the experimental design, D. Balya for providing help with programming, and K. Farrow, S. Rompani, K. Yonehara, V. Busskamp, S. Oakeley, P. King, A. Matus, S. Arber and F. Rijli for comments on the manuscript. We thank Z. Raics for making the webpage, and L. Kus and S. Gong (Rockefeller University) for help and for BACs from the GENSAT project. We thank I. Provencio (University of Virginia) for providing the melanopsin antibody. The study was supported by Friedrich Miescher Institute funds, Alcon award, a National Center of Competence in Research Genetics grant, a European Research Council grant, a Swiss-Hungarian grant, and RETICIRC, TREATRUSH, SEEBETTER and OPTONEURO grants from the European Union to B.R.

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Contributions

S.S. designed experiments; characterized mouse lines with immunohistochemistry and electrophysiology; performed confocal microscopy, image processing and quantification; dissociated retinas; performed fluorescence-activated cell sorting; normalized gene array data; analyzed gene and exon array data; created figures; and wrote the manuscript. E.C. performed RNA isolation, amplification and gene profiling for gene and exon arrays. B.G.S. generated BAC transgenic mouse lines and performed in situ hybridization. H.K. assisted with fluorescence-activated cell sorting. S.P. provided the Opn4-Cre mouse. Y.-Z.L. provided b2-Cre and d4-Cre mice. H.J.F. provided the Rosa26-LSL-RFP reporter mouse. D.G. normalized exon array data. M.B.S. assisted with gene array data analysis and provided scripts for pairwise correlation analysis and hierarchical clustering. B.R. helped with data analysis; designed experiments; and wrote the manuscript.

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Correspondence to Botond Roska.

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Siegert, S., Cabuy, E., Scherf, B. et al. Transcriptional code and disease map for adult retinal cell types. Nat Neurosci 15, 487–495 (2012). https://doi.org/10.1038/nn.3032

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