TBR2 coordinates neurogenesis expansion and precise microcircuit organization via Protocadherin 19 in the mammalian cortex

Xiaohui Lv,Yang Yu,Matthias Groszer,Peng Gao,Zhongfu Shen,Susan Lin,Song-Hai Shi,Zhizhong Li,Qiangqiang Zhang,Tanay Ghosh,Si-Qiang Ren,Xin-Jun Zhang,Anjin Xianyu

doi:10.1038/s41467-019-11854-x

Abstract

Cerebral cortex expansion is a hallmark of mammalian brain evolution; yet, how increased neurogenesis is coordinated with structural and functional development remains largely unclear. The T-box protein TBR2/EOMES is preferentially enriched in intermediate progenitors and supports cortical neurogenesis expansion. Here we show that TBR2 regulates fine-scale spatial and circuit organization of excitatory neurons in addition to enhancing neurogenesis in the mouse cortex. TBR2 removal leads to a significant reduction in neuronal, but not glial, output of individual radial glial progenitors as revealed by mosaic analysis with double markers. Moreover, in the absence of TBR2, clonally related excitatory neurons become more laterally dispersed and their preferential synapse development is impaired. Interestingly, TBR2 directly regulates the expression of Protocadherin 19 (PCDH19), and simultaneous PCDH19 expression rescues neurogenesis and neuronal organization defects caused by TBR2 removal. Together, these results suggest that TBR2 coordinates neurogenesis expansion and precise microcircuit assembly via PCDH19 in the mammalian cortex.

Highlights

Cerebral cortex expansion is a hallmark of mammalian brain evolution; yet, how increased neurogenesis is coordinated with structural and functional development remains largely unclear
While TBR2+ intermediate progenitors (IPs) play an essential role in expanding cortical neurogenesis, it remains unclear whether TBR2 regulates the spatial organization and synapse development of excitatory neurons in the cortex
We quantitatively examined the contribution of TBR2+ IPs to the neuronal and glial output of individual radial glial progenitors (RGPs) by performing mosaic analysis with double markers (MADM)

Summary

Introduction

Cerebral cortex expansion is a hallmark of mammalian brain evolution; yet, how increased neurogenesis is coordinated with structural and functional development remains largely unclear. TBR2 has been suggested to influence neuronal differentiation and laminar fate specification in the cortex[30] Together, these observations indicate that the precise contribution of TBR2+ IPs to cortical neurogenesis, especially at the level of individual RGPs, remains nebulous. We found that removal of TBR2 leads to a similar and significant loss of both deep and superficial layer excitatory neurons, but not glial cells, generated by individual RGPs. in the absence of TBR2, clonally related excitatory neurons originating from individual RGPs become more laterally dispersed and their preferential synapse development is impaired. Simultaneous PCDH19 expression rescues the defects in production, precise spatial organization and synaptic connectivity of cortical excitatory neurons caused by TBR2 loss Together, these results reveal a critical molecular pathway involving TBR2 and PCDH19 in coordinating neurogenesis expansion and fine-scale circuit organization in the mammalian cortex

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Conclusion