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Nat Commun. 2019 Sep 2;10(1):3946. doi: 10.1038/s41467-019-11854-x.

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

Lv X1, Ren SQ1,2, Zhang XJ1, Shen Z2, Ghosh T3,4, Xianyu A1,5, Gao P1,6, Li Z1, Lin S1,6, Yu Y1, Zhang Q1, Groszer M3, Shi SH7,8,9,10.

Author information

1
Developmental Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA.
2
IDG/McGovern Institute for Brain Research, Tsinghua-Peking Joint Center for Life Sciences, Beijing Frontier Research Center of Biological Structures, School of Life Sciences, Tsinghua University, Beijing, 100084, China.
3
Inserm, UMR-S839, Sorbonne Université, Institut du Fer à Moulin, Paris, 75005, France.
4
Department of Clinical Neurosciences, Wellcome Trust-Medical Research Council- Cambridge Stem Cell Institute, University of Cambridge, Cambridge, CB2 0AH, UK.
5
Graduate Program in Biophysics, Weill Cornell Medical College, 1300 York Avenue, New York, NY, 10065, USA.
6
Graduate Program in Neuroscience, Weill Cornell Medical College, 1300 York Avenue, New York, NY, 10065, USA.
7
Developmental Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA. shis@mskcc.org.
8
IDG/McGovern Institute for Brain Research, Tsinghua-Peking Joint Center for Life Sciences, Beijing Frontier Research Center of Biological Structures, School of Life Sciences, Tsinghua University, Beijing, 100084, China. shis@mskcc.org.
9
Graduate Program in Biophysics, Weill Cornell Medical College, 1300 York Avenue, New York, NY, 10065, USA. shis@mskcc.org.
10
Graduate Program in Neuroscience, Weill Cornell Medical College, 1300 York Avenue, New York, NY, 10065, USA. shis@mskcc.org.

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.

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