Our long-term goal is to find out how axons and dendrites in the vertebrate brain determine when and where to form synapses. We focus on laminar specificity, a fundamental determinant of connectivity throughout the brain, whereby neuronal processes confine their arbors and synapses to specific laminae within a target area. Our object of study is the retinal ganglion cell (RGC), because it is relatively accessible, has a well-defined function, and displays exquisite laminar specificity: axons of distinct RGC subsets synapse in specific retinorecipient sublaminae of the superior colliculus, and their dendrites arborize in specific sublaminae of the inner plexiform layer (IPL), where they receive inputs from lamina-specified subsets of retinal interneurons. In work supported by this grant, we have obtained evidence that four related immunoglobulin superfamily (IgSF) adhesion molecules -Sidekick- 1, Sidekick-2, Dscam and DscamL- are critical determinants of an "IgSF code" that underlies some aspects of sublaminar specificity in the IPL. We will now use genetic methods to map the circuits that express these IgSF genes in mice, assess consequences of deleting them singly and in pairs, and determine whether they act cell-autonomously and/or homophilically. We will also test the possibility that close relatives of Sidekicks and Dscams, the Contactins, are additional components of the IgSF code. Then, we will use electrophysiological methods to relate circuit assembly to circuit function. We will map the receptive fields of IgSF-expressing RGC subsets, identify the interneurons that innervate then, and assess the effects of IgSF gene deletion on their properties. As an exacting test of our hypothesis, we will attempt to "rewire" a retinal circuit by replacing one IgSF gene with another, assessing the structural and functional effects of this "swap." Finally, we will extend our analysis to the laminar targeting of RGC axons in the superior colliculus. We recently generated a map of projections that RGC subsets form in collicular retinorecipient sublaminae, and will now classify the target cells on which axons of these subsets form synapses. With this foundation, we will test our hypothesis, based on results from chick optic tectum, that members of the cadherin superfamily (particularly Type II cadherins) are involved in the targeting of RGCs to sublaminae in the superior colliculus. Together these studies will contribute to elucidation of mechanisms that promote lamina-specific synapse formation and, by extension, synaptic specificity generally.
During development, neurons connect with each other in very specific ways, forming the complex circuits that underlie our mental activities. Conversely, impaired development of these circuits is believed to underlie many behavioral disorders including autism and schizophrenia. Our long-term goal is to find some of the cells and molecules that determine when and where these connections, called synapses, form. To this end, we are focusing on the accessible visual system, in which we can assess the structural and functional consequences of controlled alterions in patterns of synaptic specificity.
|Rousso, David L; Qiao, Mu; Kagan, Ruth D et al. (2016) Two Pairs of ON and OFF Retinal Ganglion Cells Are Defined by Intersectional Patterns of Transcription Factor Expression. Cell Rep 15:1930-44|
|Martell, Jeffrey D; Yamagata, Masahito; Deerinck, Thomas J et al. (2016) A split horseradish peroxidase for the detection of intercellular protein-protein interactions and sensitive visualization of synapses. Nat Biotechnol 34:774-80|
|Qiao, Mu; Sanes, Joshua R (2015) Genetic Method for Labeling Electrically Coupled Cells: Application to Retina. Front Mol Neurosci 8:81|
|Duan, Xin; Qiao, Mu; Bei, Fengfeng et al. (2015) Subtype-specific regeneration of retinal ganglion cells following axotomy: effects of osteopontin and mTOR signaling. Neuron 85:1244-56|
|Krishnaswamy, Arjun; Yamagata, Masahito; Duan, Xin et al. (2015) Sidekick 2 directs formation of a retinal circuit that detects differential motion. Nature 524:466-70|
|Hong, Y Kate; Park, SuHong; Litvina, Elizabeth Y et al. (2014) Refinement of the retinogeniculate synapse by bouton clustering. Neuron 84:332-9|
|SÃ¼mbÃ¼l, Uygar; Song, Sen; McCulloch, Kyle et al. (2014) A genetic and computational approach to structurally classify neuronal types. Nat Commun 5:3512|
|Duan, Xin; Krishnaswamy, Arjun; De la Huerta, Irina et al. (2014) Type II cadherins guide assembly of a direction-selective retinal circuit. Cell 158:793-807|
|De la Huerta, Irina; Kim, In-Jung; Voinescu, P Emanuela et al. (2012) Direction-selective retinal ganglion cells arise from molecularly specified multipotential progenitors. Proc Natl Acad Sci U S A 109:17663-8|
|Zhang, Yifeng; Kim, In-Jung; Sanes, Joshua R et al. (2012) The most numerous ganglion cell type of the mouse retina is a selective feature detector. Proc Natl Acad Sci U S A 109:E2391-8|
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