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Single-cell transcriptomics of the developing lateral geniculate nucleus reveals insights into circuit assembly and refinement

Brian T. Kalish,Brian T. Kalish,Lucas Cheadle,Siniša Hrvatin,M. Nagy,S. Rivera,M. Crow,J. Gillis,Rory D. Kirchner,M. Greenberg

Published 2018 in Proceedings of the National Academy of Sciences of the United States of America

ABSTRACT

Significance Neurons and nonneuronal cells in the developing brain dynamically regulate gene expression as neural connectivity is established. However, the specific gene programs activated in distinct cell populations during the assembly and refinement of many intact neuronal circuits have not been thoroughly characterized. In this study, we take advantage of recent advances in transcriptomic profiling techniques to characterize gene expression in the postnatal developing lateral geniculate nucleus (LGN) at single-cell resolution. Our data reveal that genes involved in brain development are dynamically regulated in all major cell types of the LGN, suggesting that the establishment of neural connectivity depends upon functional collaboration between multiple neuronal and nonneuronal cell types in this brain region. Coordinated changes in gene expression underlie the early patterning and cell-type specification of the central nervous system. However, much less is known about how such changes contribute to later stages of circuit assembly and refinement. In this study, we employ single-cell RNA sequencing to develop a detailed, whole-transcriptome resource of gene expression across four time points in the developing dorsal lateral geniculate nucleus (LGN), a visual structure in the brain that undergoes a well-characterized program of postnatal circuit development. This approach identifies markers defining the major LGN cell types, including excitatory relay neurons, oligodendrocytes, astrocytes, microglia, and endothelial cells. Most cell types exhibit significant transcriptional changes across development, dynamically expressing genes involved in distinct processes including retinotopic mapping, synaptogenesis, myelination, and synaptic refinement. Our data suggest that genes associated with synapse and circuit development are expressed in a larger proportion of nonneuronal cell types than previously appreciated. Furthermore, we used this single-cell expression atlas to identify the Prkcd-Cre mouse line as a tool for selective manipulation of relay neurons during a late stage of sensory-driven synaptic refinement. This transcriptomic resource provides a cellular map of gene expression across several cell types of the LGN, and offers insight into the molecular mechanisms of circuit development in the postnatal brain.

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