Trans-Seq maps a selective mammalian retinotectal synapse instructed by Nephronectin

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Abstract
The mouse visual system serves as an accessible model to understand mammalian circuit wiring. Despite rich knowledge in retinal circuits, the long-range connectivity map from distinct retinal ganglion cell (RGC) types to diverse brain neuron types remains unknown. In this study, we developed an integrated approach, called Trans-Seq, to map RGCs to superior collicular (SC) circuits. Trans-Seq combines a fluorescent anterograde trans-synaptic tracer, consisting of codon-optimized wheat germ agglutinin fused to mCherry, with single-cell RNA sequencing. We used Trans-Seq to classify SC neuron types innervated by genetically defined RGC types and predicted a neuronal pair from αRGCs to Nephronectin-positive wide-field neurons (NPWFs). We validated this connection using genetic labeling, electrophysiology and retrograde tracing. We then used transcriptomic data from Trans-Seq to identify Nephronectin as a determinant for selective synaptic choice from αRGC to NPWFs via binding to Integrin α8β1. The Trans-Seq approach can be broadly applied for post-synaptic circuit discovery from genetically defined pre-synaptic neurons.
Funding Information
  • U.S. Department of Health & Human Services | NIH | National Eye Institute (F30EY033201)
  • U.S. Department of Health & Human Services | National Institutes of Health (RO1DK118032, 1R01MH08188, 1RF1MH116989, P30EY002162, R01EY030138)
  • U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (R01NS123912)
  • Glaucoma Research Foundation (CFC3)
  • E. Matilda Ziegler Foundation for the Blind (Research Award)
  • Esther A. and Joseph Klingenstein Fund (Neuroscience Fellowship)
  • Research to Prevent Blindness (CDA)
  • Whitehall Foundation (Research Grant)

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