In the eye, complex retinal circuits are wired together for precise neural computation. The diverse but precise wiring between interneurons and retinal ganglion cells serve as the structural basis for circuit processing of different visual features. These parallel circuits are wired up precisely, as defects may lead to several eye diseases and neurological disorders. To investigate the mechanisms behind how diverse neuronal types precisely integrate into distinct parallel retinal circuits, we developed methods that allow for targeted genetic access of the unique On-Off direction-selective circuit, which conveys direction-selectivity signals, as the ideal model system. Our previous studies now position us to examine the role of Type II Cadherins (Cdhs) in assembling this circuit as individual proteins or in combinations. We showed that two Cdhs, Cdh9 and Cdh8, instruct parallel ON and OFF bipolar cell input to ON vs. OFF sublaminae of the ON-OFF direction-selective circuit, thus allowing precise segregation of ON and OFF channels. However, the molecular mechanisms underlying this assembly remain elusive. To investigate the molecular mechanisms underlying the differential functions of Cdh9 vs. Cdh8, we will perform a series of anatomical and functional analyses. We will identify the specific portion of the cadherin molecule, extracellular versus intracellular domains, that are responsible for their distinct functions, as well as the specific timing of their actions in forming synapses between bipolar cells and ganglion cells. We also found that Cdh9 from bipolar neurons heterophilically recognizes the two closely-related Cdhs, Cdh6 and Cdh10, from postsynaptic Ventral-pointing ON-OFF direction-selective ganglion cells (ooDSGCs) and starburst amacrine cells (SACs). We will use this established genetic system to reveal how combinatorial Cdhs act together to wire up parallel direction-selective circuits. We will examine genetically and functionally how Cdh6-9-10 single, double, and triple combinations pattern the Ventral-ooDSGC interaction with SACs. To further expand our understanding of the combinatorial cadherin code in neuronal patterning, we will test the role of Cdh11, which is identified as a Nasal-pointing ooDSGC enriched gene through molecular profiling. Thus, we will generate new molecularly and genetically targeted methods to examine the roles of Cdh11 and its closely related Cdh8 in the wiring of Nasal-pointing direction-selective circuits. Furthermore, we established an in utero injection system to ectopically introduce individual Type II Cdhs onto Ventral-ooDSGCs or Nasal-ooDSGCs to pinpoint combinatorial Cdhs in regulating DS-circuit patterning. Collectively, our studies seek to reveal how Cdh combinations control the formation of parallel but distinct DS circuits. Comprehensive studies on Type II Cdh function would be a major advance for a long-standing question in mammalian neural development. These studies will be a major step forward in understanding how multiple genes interact to specify the wiring of complex neural circuits. The identified mechanisms will have significant relevance to selective circuit wiring throughout the central nervous system.

Public Health Relevance

The central nervous system comprises numerous neuronal subtypes that form specific connections, allowing for complex computations, such as the detection of various visual features by the retina. Using the retina as a model system, we intend to utilize innovative genetic techniques to investigate the role of the cadherin family of cell-recognition molecules in the process of retinal direction-selective circuit wiring. Our ultimate goal is to understand the principles underlying cadherin-mediated connectivity in the retina as a gateway to understand neuronal patterning in the central nervous system, and to offer new cures for various diseases in the eye and the brain.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Neurodifferentiation, Plasticity, and Regeneration Study Section (NDPR)
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Greenwell, Thomas
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University of California San Francisco
Schools of Medicine
San Francisco
United States
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