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Transmembrane semaphorin signalling controls laminar stratification in the mammalian retina

Nature volume 470, pages 259–263 (2011)Cite this article

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Abstract

In the vertebrate retina, establishment of precise synaptic connections among distinct retinal neuron cell types is critical for processing visual information and for accurate visual perception. Retinal ganglion cells (RGCs), amacrine cells and bipolar cells establish stereotypic neurite arborization patterns to form functional neural circuits in the inner plexiform layer (IPL)1,2,3, a laminar region that is conventionally divided into five major parallel sublaminae1,2. However, the molecular mechanisms governing distinct retinal subtype targeting to specific sublaminae within the IPL remain to be elucidated. Here we show that the transmembrane semaphorin Sema6A signals through its receptor PlexinA4 (PlexA4) to control lamina-specific neuronal stratification in the mouse retina. Expression analyses demonstrate that Sema6A and PlexA4 proteins are expressed in a complementary fashion in the developing retina: Sema6A in most ON sublaminae and PlexA4 in OFF sublaminae of the IPL. Mice with null mutations in PlexA4 or Sema6A exhibit severe defects in stereotypic lamina-specific neurite arborization of tyrosine hydroxylase (TH)-expressing dopaminergic amacrine cells, intrinsically photosensitive RGCs (ipRGCs) and calbindin-positive cells in the IPL. Sema6A and PlexA4 genetically interact in vivo for the regulation of dopaminergic amacrine cell laminar targeting. Therefore, neuronal targeting to subdivisions of the IPL in the mammalian retina is directed by repulsive transmembrane guidance cues present on neuronal processes.

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Figure 1: PlexinA4 directs lamina-specific neurite arborization of dopaminergic amacrine cells and calbindin-positive cells in the IPL in vivo.
Figure 2: PlexinA4 controls dendritic targeting of M1-type ipRGCs within the IPL, but not co-localization of dopaminergic amacrine cell and ipRGC processes.
Figure 3: PlexinA4 and Sema6A exhibit complementary protein expression in the developing mouse retina.
Figure 4: Sema6A signalling through the PlexinA4 receptor directs retinal sublaminar targeting.

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  • 10 February 2011

    Three labels were corrected in Fig. 4.

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Acknowledgements

We thank K.-W. Yau for the C-terminal melanopsin antibody, F. Suto for the PlexA4 antibody, B. Howell for the Dab-1 antibody, Y. Yoshida for the PlexA1−/− eyes, P. Mombaerts for the PlexB1−/− and PlexB3−/− mice (unpublished), C. Gu for the PlexD1-/flox ;nestin cre (unpublished) eyes and M. Tessier-Lavigne for the PlexA4−/− mice. We also thank J. Nathans, S. Hattar, K. Mandai and M. Riccomagno for comments on the manuscript and discussions, and members of the Kolodkin laboratory for assistance. This work was supported by R01 NS35165 to A.L.K., a predoctoral fellowship from the Nakajima Foundation to R.L.M., the Fondation pour la Recherche Médicale (Programme équipe FRM) to A.C., the Fondation Retina France to K.T.N.-B.-C., and a PhD fellowship from the Paris School of Neuroscience (ENP) to A.P. A.L.K. is an investigator of the Howard Hughes Medical Institute.

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Author notes

  1. Tudor C. Badea

    Present address: Present address: Retinal Circuit Development & Genetics Unit, Neurobiology-Neurodegeneration and Repair Laboratory, National Eye Institute, Bethesda, Maryland 20892, USA .,

Authors and Affiliations

  1. The Solomon H. Snyder Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, 21205, Maryland, USA

    Ryota L. Matsuoka & Alex L. Kolodkin

  2. Department of Molecular Biology and Genetics, The Johns Hopkins University School of Medicine, Baltimore, 21205, Maryland, USA

    Tudor C. Badea

  3. Howard Hughes Medical Institute, The Johns Hopkins University School of Medicine, Baltimore, 21205, Maryland, USA

    Ryota L. Matsuoka, Tudor C. Badea & Alex L. Kolodkin

  4. Institut National de la Santé et de la Recherche Médicale (INSERM), UMR S968, Institut de la Vision, F-75012 Paris, France ,

    Kim T. Nguyen-Ba-Charvet, Aijaz Parray & Alain Chédotal

  5. Université Pierre et Marie Curie (UPMC) Paris VI, UMR S968, Institut de la Vision, F-75012 Paris, France ,

    Kim T. Nguyen-Ba-Charvet, Aijaz Parray & Alain Chédotal

  6. Centre National de la Recherche Scientifique (CNRS) UMR 7210, Institut de la Vision, F-75012 Paris, France ,

    Kim T. Nguyen-Ba-Charvet, Aijaz Parray & Alain Chédotal

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Contributions

R.L.M., A.C. and A.L.K. conceived and designed the experiments; R.L.M. performed most of the experiments and data analysis; K.T.N.-B.-C., A.P. and A.C. participated in the phenotypic analyses of Sema6A mutant mice and provided PlexA2−/− and PlexB2−/− mutants; T.C.B. performed cholera toxin injections and provided suggestions and reagents; R.L.M. and A.L.K. wrote the paper.

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Correspondence to Alex L. Kolodkin.

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The authors declare no competing financial interests.

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Matsuoka, R., Nguyen-Ba-Charvet, K., Parray, A. et al. Transmembrane semaphorin signalling controls laminar stratification in the mammalian retina. Nature 470, 259–263 (2011). https://doi.org/10.1038/nature09675

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