Patterned cPCDH expression regulates the fine organization of the neocortex

Xiaohui Lv, Shuo Li, Jingwei Li, Xiang-Yu Yu, Xiao Ge, Bo Li, Shuhan Hu, Yang Lin, Songbo Zhang, Jiajun Yang, Xiuli Zhang, Jie Yan, Alexandra L. Joyner, Hang Shi, Qiang Wu and Song-Hai Shi ()
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Xiaohui Lv: Tsinghua University
Shuo Li: Tsinghua University
Jingwei Li: Shanghai Jiao Tong University
Xiang-Yu Yu: Tsinghua University
Xiao Ge: Shanghai Jiao Tong University
Bo Li: Tsinghua University
Shuhan Hu: Tsinghua University
Yang Lin: Tsinghua University
Songbo Zhang: Tsinghua University
Jiajun Yang: Tsinghua University
Xiuli Zhang: Tsinghua University
Jie Yan: Tsinghua University
Alexandra L. Joyner: Memorial Sloan Kettering Cancer Centre
Hang Shi: Tsinghua University
Qiang Wu: Shanghai Jiao Tong University
Song-Hai Shi: Tsinghua University

Nature, 2022, vol. 612, issue 7940, 503-511

Abstract: Abstract The neocortex consists of a vast number of diverse neurons that form distinct layers and intricate circuits at the single-cell resolution to support complex brain functions1. Diverse cell-surface molecules are thought to be key for defining neuronal identity, and they mediate interneuronal interactions for structural and functional organization2–6. However, the precise mechanisms that control the fine neuronal organization of the neocortex remain largely unclear. Here, by integrating in-depth single-cell RNA-sequencing analysis, progenitor lineage labelling and mosaic functional analysis, we report that the diverse yet patterned expression of clustered protocadherins (cPCDHs)—the largest subgroup of the cadherin superfamily of cell-adhesion molecules7—regulates the precise spatial arrangement and synaptic connectivity of excitatory neurons in the mouse neocortex. The expression of cPcdh genes in individual neocortical excitatory neurons is diverse yet exhibits distinct composition patterns linked to their developmental origin and spatial positioning. A reduction in functional cPCDH expression causes a lateral clustering of clonally related excitatory neurons originating from the same neural progenitor and a significant increase in synaptic connectivity. By contrast, overexpression of a single cPCDH isoform leads to a lateral dispersion of clonally related excitatory neurons and a considerable decrease in synaptic connectivity. These results suggest that patterned cPCDH expression biases fine spatial and functional organization of individual neocortical excitatory neurons in the mammalian brain.

Date: 2022
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DOI: 10.1038/s41586-022-05495-2

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