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.
|Martersteck, Emily M; Hirokawa, Karla E; Evarts, Mariah et al. (2017) Diverse Central Projection Patterns of Retinal Ganglion Cells. Cell Rep 18:2058-2072|
|Krieger, Brenna; Qiao, Mu; Rousso, David L et al. (2017) Four alpha ganglion cell types in mouse retina: Function, structure, and molecular signatures. PLoS One 12:e0180091|
|Norsworthy, Michael W; Bei, Fengfeng; Kawaguchi, Riki et al. (2017) Sox11 Expression Promotes Regeneration of Some Retinal Ganglion Cell Types but Kills Others. Neuron 94:1112-1120.e4|
|Liu, Jinyue; Sanes, Joshua R (2017) Cellular and Molecular Analysis of Dendritic Morphogenesis in a Retinal Cell Type That Senses Color Contrast and Ventral Motion. J Neurosci 37:12247-12262|
|Peng, Yi-Rong; Tran, Nicholas M; Krishnaswamy, Arjun et al. (2017) Satb1 Regulates Contactin 5 to Pattern Dendrites of a Mammalian Retinal Ganglion Cell. Neuron 95:869-883.e6|
|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|
|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|
|Krishnaswamy, Arjun; Yamagata, Masahito; Duan, Xin et al. (2015) Sidekick 2 directs formation of a retinal circuit that detects differential motion. Nature 524:466-470|
|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|
|Qiao, Mu; Sanes, Joshua R (2015) Genetic Method for Labeling Electrically Coupled Cells: Application to Retina. Front Mol Neurosci 8:81|
Showing the most recent 10 out of 18 publications