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S41467-019-11854-X.Pdf ARTICLE https://doi.org/10.1038/s41467-019-11854-x OPEN TBR2 coordinates neurogenesis expansion and precise microcircuit organization via Protocadherin 19 in the mammalian cortex Xiaohui Lv1, Si-Qiang Ren1,2, Xin-Jun Zhang1, Zhongfu Shen2, Tanay Ghosh3,4, Anjin Xianyu1,5, Peng Gao1,6, Zhizhong Li1, Susan Lin1,6, Yang Yu1, Qiangqiang Zhang1, Matthias Groszer3 & Song-Hai Shi1,2,5,6 1234567890():,; 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 pro- genitors 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 neurogen- esis expansion and precise microcircuit assembly via PCDH19 in the mammalian cortex. 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. Correspondence and requests for materials should be addressed to S.-H.S. (email: [email protected]) NATURE COMMUNICATIONS | (2019) 10:3946 | https://doi.org/10.1038/s41467-019-11854-x | www.nature.com/naturecommunications 1 ARTICLE NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-019-11854-x he mammalian cerebral cortex is a complex yet highly found that removal of TBR2 leads to a similar and significant loss organized brain structure, consisting of six layers of neu- of both deep and superficial layer excitatory neurons, but not glial T fi rons that form speci c circuits to support all higher-order cells, generated by individual RGPs. Moreover, in the absence of brain functions. The formation of the cerebral cortex depends on TBR2, clonally related excitatory neurons originating from indi- the orderly production of a large number of diverse neurons, vidual RGPs become more laterally dispersed and their pre- which largely occurs during embryonic development. The vast ferential synapse development is impaired. Mechanistically, we majority of cortical excitatory neurons originate from radial glial found that TBR2 binds to the genomic regulatory sequences cells, the predominant population of neural progenitor cells in the upstream and downstream of Protocadherin-19 (Pcdh19), a developing cortex1–8. During cortical development, radial glial member of the Cadherin superfamily that has been implicated in progenitors (RGPs) progress through a cellular program of pro- female infantile-onset epilepsy and cognitive impairment and liferation, neurogenesis, and gliogenesis4,5,9. At the early stage of regulates its expression. Suppression of Pcdh19 expression leads cortical development (e.g., embryonic day (E) 10-11 in mice), to defects in neuronal production and organization by individual RGPs predominantly undergo symmetric proliferative division to RGPs similar to those observed following TBR2 removal. Fur- amplify themselves. As development proceeds, they switch to thermore, simultaneous PCDH19 expression rescues the defects asymmetric neurogenic division to self-renew and, at the same in production, precise spatial organization and synaptic con- time, to produce neurons either directly (direct neurogenesis) or nectivity of cortical excitatory neurons caused by TBR2 loss. indirectly via transit amplifying progenitors (TAPs) that divide Together, these results reveal a critical molecular pathway mostly in the subventricular zone (SVZ) to give rise to neurons involving TBR2 and PCDH19 in coordinating neurogenesis (indirect neurogenesis)8,10–17. expansion and fine-scale circuit organization in the mammalian Indirect neurogenesis via TAPs greatly increases the number of cortex. neurons generated in the cortex. As a consequence, the abundance and diversity of TAPs have been linked to evolutionary expansion of the cortex with higher cognitive functions10,12–14,18–23. A major Results population of TAPs consists of intermediate progenitors (IPs) that TBR2 removal reduces neuronal output by individual RGPs. preferentially express the T-box transcription factor TBR2/ To assess the precise contribution of TBR2+ IPs to cortical his- EOMES16. Upon generation by dividing RGPs at the VZ surface, togenesis, we took advantage of the Tbr2 floxed mutant mice, TBR2+ IPs migrate to the SVZ and mainly divide symmetrically to Tbr2fl/fl39, and performed clonal analysis using MADM40.We produce neurons. Given the clear importance of IPs in cortical introduced the Emx1-CreERT2 transgene41 into the MADM neurogenesis, extensive efforts have been made to elucidate the mice9,42 to specifically label RGPs in the dorsal telencephalon in a precise contribution of TBR2+ IPs to the process; yet, the results temporally controlled manner. In particular, Cre recombinase- have been inconsistent. Some studies suggested that TBR2 and IPs driven inter-chromosomal recombination in the G2 phase of the fi in the SVZ predominantly contribute to super cial layer neuron dividing RGPs followed by X-segregation (G2-X) reconstitutes production and supragranular layer expansion23–25.Relatedto one of the two fluorescent markers, enhanced green fluorescent this, TBR2+ IPs and indirect neurogenesis have been linked to protein (EGFP, green) or tandem dimer Tomato (tdTomato, red), distinct morphological and electrophysiological features of super- in each of the two daughter cells (Supplementary Fig. 1a). The ficial layer neurons26. On the other hand, a few studies have shown permanent and distinct labeling of the two daughter cells and that TBR2+ IPs contribute to neuron production across all their respective progeny allows explicit analysis of the division layers27–30. In addition, TBR2 has been suggested to influence pattern (symmetric vs. asymmetric) and potential (the number of neuronal differentiation and laminar fate specification in the cor- neural progeny) of the originally labeled dividing RGPs. tex30. Together, these observations indicate that the precise con- We integrated the Tbr2fl/fl allele with the Emx1-CreERT2/ tribution of TBR2+ IPs to cortical neurogenesis, especially at the MADM system (Supplementary Fig. 1b). As shown previously9, level of individual RGPs, remains nebulous. It calls for an in-depth we optimized the dose of TM to achieve a sparse labeling of quantitative clonal analysis of the exact contribution of TBR2+ IPs individual dividing RGPs and corresponding clones in the cortex. to the neuronal as well as glial output of individual RGPs in the We selectively focused on G2-X green/red fluorescent clones, as developing cortex. they reliably reflect the division pattern and neurogenic potential Notably, the cellular processes of neurogenesis and neuronal of individual dividing RGPs. To examine the contribution of migration critically influence the spatial distribution and func- TBR2+ IPs to cortical neurogenesis by individual RGPs, we tional organization of cortical excitatory neurons. In particular, administered TM to timed pregnant females at the following four clonally related excitatory neurons originating from the same embryonic stages: E10, E11, E12, and E13, performed cesarean neurogenic RGP (e.g., labeled at E12-13 in mice) migrate along section and rescue at ~E19, and collected the brain for analysis at their mother radial glial fiber and form an ontogenetic radial postnatal day (P) 21 (Supplementary Fig. 1b). As expected, TM neuronal cluster spanning across both deep and superficial administration triggered reliable sparse labeling of individual layers2,9,31–33. Moreover, radially situated clonally related exci- green/red fluorescent clonal clusters as well as effective removal of tatory neurons preferentially develop specific synapses with each TBR2 in the mutant embryonic cortex compared with the other than with nearby non-clonally related excitatory neurons littermate control cortex (Supplementary Fig. 1c, d). and share similar physiological properties34–38. While TBR2+ IPs To reveal all labeled cells in the cortex, we performed serial play an essential role in expanding cortical neurogenesis, it sectioning, immunohistochemistry, and three-dimensional (3D) remains unclear whether TBR2 regulates the spatial organization reconstruction
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