Retinal Ganglion Cells with Distinct Directional Preferences Differ in Molecular Identity, Structure, and Central Projections

The retina contains ganglion cells (RGCs) that respond selectively to objects moving in particular directions. Individual members of a group of ON-OFF direction-selective RGCs (ooDSGCs) detect stimuli moving in one of four directions: ventral, dorsal, nasal, or temporal. Despite this physiological diversity, little is known about subtype-specific differences in structure, molecular identity, and projections. To seek such differences, we characterized mouse transgenic lines that selectively mark ooDSGCs preferring ventral or nasal motion as well as a line that marks both ventral- and dorsal-preferring subsets. We then used the lines to identify cell surface molecules, including Cadherin 6, CollagenXXVα1, and Matrix metalloprotease 17, that are selectively expressed by distinct subsets of ooDSGCs. We also identify a neuropeptide, CART (cocaine- and amphetamine-regulated transcript), that distinguishes all ooDSGCs from other RGCs. Together, this panel of endogenous and transgenic markers distinguishes the four ooDSGC subsets. Patterns of molecular diversification occur before eye opening and are therefore experience independent. They may help to explain how the four subsets obtain distinct inputs. We also demonstrate differences among subsets in their dendritic patterns within the retina and their axonal projections to the brain. Differences in projections indicate that information about motion in different directions is sent to different destinations.

[1]  H. Barlow,et al.  Retinal ganglion cells responding selectively to direction and speed of image motion in the rabbit , 1964, The Journal of physiology.

[2]  H. Barlow,et al.  The mechanism of directionally selective units in rabbit's retina. , 1965, The Journal of physiology.

[3]  H B Barlow,et al.  Direction-Selective Units in Rabbit Retina: Distribution of Preferred Directions , 1967, Science.

[4]  M Imbert,et al.  Prenatal and postnatal development of retinogeniculate and retinocollicular projections in the mouse , 1984, The Journal of comparative neurology.

[5]  E. Buhl,et al.  Retinal ganglion cells projecting to the accessory optic system in the rat , 1987, The Journal of comparative neurology.

[6]  F. Amthor,et al.  Dendritic architecture of ON-OFF direction-selective ganglion cells in the rabbit retina , 1993, Vision Research.

[7]  F. Amthor,et al.  Spatial organization of retinal information about the direction of image motion. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[8]  J R Sanes,et al.  Lamina-specific connectivity in the brain: regulation by N-cadherin, neurotrophins, and glycoconjugates. , 1997, Science.

[9]  G. Feng,et al.  Imaging Neuronal Subsets in Transgenic Mice Expressing Multiple Spectral Variants of GFP , 2000, Neuron.

[10]  M. Takeichi,et al.  Differential expression of cadherin adhesion receptors in neural retina of the postnatal mouse. , 2000, Investigative ophthalmology & visual science.

[11]  C. Li,et al.  Model-based analysis of oligonucleotide arrays: expression index computation and outlier detection. , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[12]  R. Masland The fundamental plan of the retina , 2001, Nature Neuroscience.

[13]  I. Kanazawa,et al.  CLAC: a novel Alzheimer amyloid plaque component derived from a transmembrane precursor, CLAC‐P/collagen type XXV , 2002, The EMBO journal.

[14]  Wenzhi Sun,et al.  Large‐scale morphological survey of mouse retinal ganglion cells , 2002, The Journal of comparative neurology.

[15]  G. Feng,et al.  Genetic evidence that relative synaptic efficacy biases the outcome of synaptic competition , 2003, Nature.

[16]  J. Nathans,et al.  Quantitative analysis of neuronal morphologies in the mouse retina visualized by using a genetically directed reporter , 2004, The Journal of comparative neurology.

[17]  E. Turner,et al.  Brn3a-Expressing Retinal Ganglion Cells Project Specifically to Thalamocortical and Collicular Visual Pathways , 2005, The Journal of Neuroscience.

[18]  D. I. Vaney,et al.  Gap‐junction communication between subtypes of direction‐selective ganglion cells in the developing retina , 2005, The Journal of comparative neurology.

[19]  J. Sanes,et al.  Labeled lines in the retinotectal system: Markers for retinorecipient sublaminae and the retinal ganglion cell subsets that innervate them , 2006, Molecular and Cellular Neuroscience.

[20]  L. Chalupa,et al.  Morphological properties of mouse retinal ganglion cells , 2006, Neuroscience.

[21]  Jonathan B Demb,et al.  Cellular Mechanisms for Direction Selectivity in the Retina , 2007, Neuron.

[22]  N. Yoshida,et al.  Establishment of an MT4‐MMP‐deficient mouse strain representing an efficient tracking system for MT4‐MMP/MMP‐17 expression in vivo using β‐galactosidase , 2007, Genes to cells : devoted to molecular & cellular mechanisms.

[23]  Allan R. Jones,et al.  Genome-wide atlas of gene expression in the adult mouse brain , 2007, Nature.

[24]  David G. Melvin,et al.  A recombineering based approach for high-throughput conditional knockout targeting vector construction , 2007, Nucleic acids research.

[25]  D. Klein,et al.  Localization and regulation of dopamine receptor D4 expression in the adult and developing rat retina. , 2008, Experimental eye research.

[26]  Seunghoon Lee,et al.  Synaptic physiology of direction selectivity in the retina , 2008, The Journal of physiology.

[27]  E. Chichilnisky,et al.  Direction Selectivity in the Retina Is Established Independent of Visual Experience and Cholinergic Retinal Waves , 2008, Neuron.

[28]  M. Bernardo,et al.  MT4-(MMP17) and MT6-MMP (MMP25), A unique set of membrane-anchored matrix metalloproteinases: properties and expression in cancer , 2008, Cancer and Metastasis Reviews.

[29]  M. Kuhar,et al.  CART peptides: regulators of body weight, reward and other functions , 2008, Nature Reviews Neuroscience.

[30]  Keisuke Yonehara,et al.  Expression of SPIG1 Reveals Development of a Retinal Ganglion Cell Subtype Projecting to the Medial Terminal Nucleus in the Mouse , 2008, PloS one.

[31]  J. Sanes,et al.  Molecular identification of a retinal cell type that responds to upward motion , 2008, Nature.

[32]  M. Feller,et al.  Genetic Identification of an On-Off Direction- Selective Retinal Ganglion Cell Subtype Reveals a Layer-Specific Subcortical Map of Posterior Motion , 2009, Neuron.

[33]  B. Roska,et al.  Genetic address book for retinal cell types , 2009, Nature Neuroscience.

[34]  Wade G. Regehr,et al.  Linking Genetically Defined Neurons to Behavior through a Broadly Applicable Silencing Allele , 2009, Neuron.

[35]  B. Völgyi,et al.  Tracer coupling patterns of the ganglion cell subtypes in the mouse retina , 2009, The Journal of comparative neurology.

[36]  H. Wässle,et al.  Expression analysis of green fluorescent protein in retinal neurons of four transgenic mouse lines , 2009, Neuroscience.

[37]  K. Hoffmann,et al.  Comparative Neurobiology of the Optokinetic Reflex , 2009, Annals of the New York Academy of Sciences.

[38]  H. Wässle,et al.  Cone Contacts, Mosaics, and Territories of Bipolar Cells in the Mouse Retina , 2009, The Journal of Neuroscience.

[39]  Hiroshi Ishikane,et al.  Identification of Retinal Ganglion Cells and Their Projections Involved in Central Transmission of Information about Upward and Downward Image Motion , 2009, PloS one.

[40]  J. Sanes,et al.  Design Principles of Insect and Vertebrate Visual Systems , 2010, Neuron.

[41]  J. Sanes,et al.  Laminar Restriction of Retinal Ganglion Cell Dendrites and Axons: Subtype-Specific Developmental Patterns Revealed with Transgenic Markers , 2010, The Journal of Neuroscience.

[42]  Seunghoon Lee,et al.  Role of ACh-GABA Cotransmission in Detecting Image Motion and Motion Direction , 2010, Neuron.

[43]  Allan R. Jones,et al.  A robust and high-throughput Cre reporting and characterization system for the whole mouse brain , 2009, Nature Neuroscience.

[44]  J. N. Kay,et al.  NEUROD6 EXPRESSION DEFINES NOVEL RETINAL AMACRINE CELL SUBTYPES AND REGULATES THEIR FATE , 2011, Nature Neuroscience.

[45]  J. Sanes,et al.  Stereotyped axonal arbors of retinal ganglion cell subsets in the mouse superior colliculus , 2011, The Journal of comparative neurology.

[46]  Marla B. Feller,et al.  Development of asymmetric inhibition underlying direction selectivity in the retina , 2011, Nature.