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Dirk and Kelly, Kathleen and Khajouei, Farzaneh and Kharchenko, Peter V. and Kim, Gukhan and Ko, Andrew L. and Kobak, Dmitry and Konwar, Kishori and Kramer, Daniel J. and Krienen, Fenna M. and Kroll, Matthew and Kuang, Xiuli and Kuo, Hsien-Chi and Lake, Blue B. and Larsen, Rachael and Lathia, Kanan and Laturnus, Sophie and Lee, Angus Y. and Lee, Cheng-Ta and Lee, Kuo-Fen and Lein, Ed S. and Lesnar, Phil and Li, Anan and Li, Xiangning and Li, Xu and Li, Yang Eric and Li, Yaoyao and Li, Yuanyuan and Lim, Byungkook and Linnarsson, Sten and Liu, Christine S. and Liu, Hanqing and Liu, Lijuan and Lucero, Jacinta D. and Luo, Chongyuan and Luo, Qingming and Macosko, Evan Z. and Mahurkar, Anup and Martone, Maryann E. and Matho, Katherine S. and McCarroll, Steven A. and McCracken, Carrie and McMillen, Delissa and Miranda, Elanine and Mitra, Partha P and Miyazaki, Paula Assakura and Mizrachi, Judith and Mok, Stephanie and Mukamel, Eran A. and Mulherkar, Shalaka and Nadaf, Naeem M. and Naeemi, Maitham and Narasimhan, Arun and Nery, Joseph R. and Ng, Lydia and Ngai, John and Nguyen, Thuc Nghi and Nickel, Lance and Nicovich, Philip R. and Niu, Sheng-Yong and Ntranos, Vasilis and Nunn, Michael and Olley, Dustin and Orvis, Joshua and Osteen, Julia K. and Osten, Pavel and Owen, Scott F. and Pachter, Lior and Palaniswamy, Ramesh and Palmer, Carter R. and Pang, Yan and Peng, Hanchuan and Pham, Thanh and Pinto-Duarte, Antonio and Plongthongkum, Nongluk and Poirion, Olivier and Preissl, Sebastian and Purdom, Elizabeth and Qu, Lei and Rashid, Mohammad and Reed, Nora M. and Regev, Aviv and Ren, Bing and Ren, Miao and Rimorin, Christine and Risso, Davide and Rivkin, Angeline C. and Muñoz-Castañeda, Rodrigo and Romanow, William J. and Ropelewski, Alexander J. and Roux de Bézieux, Hector and Ruan, Zongcai and Sandberg, Rickard and Savoia, Steven and Scala, Federico and Schor, Michael and Shen, Elise and Siletti, Kimberly and Smith, Jared B. and Smith, Kimberly and Somasundaram, Saroja and Song, Yuanyuan and Sorensen, Staci A. and Stafford, David A. and Street, Kelly and Sulc, Josef and Sunkin, Susan and Svensson, Valentine and Tan, Pengcheng and Tan, Zheng Huan and Tasic, Bosiljka and Thompson, Carol and Tian, Wei and Tickle, Timothy L. and Tieu, Michael and Ting, Jonathan T. and Tolias, Andreas Savas and Torkelson, Amy and Tung, Herman and Vaishnav, Eeshit Dhaval and Van den Berge, Koen and van Velthoven, Cindy T.J. and Vanderburg, Charles R. and Veldman, Matthew B. and Vu, Minh and Wakeman, Wayne and Wang, Peng and Wang, Quanxin and Wang, Xinxin and Wang, Yimin and Wang, Yun and Welch, Joshua D. and White, Owen and Williams, Elora and Xie, Fangming and Xie, Peng and Xiong, Feng and Yang, X. William and Yanny, Anna Marie and Yao, Zizhen and Yin, Lulu and Yu, Yang and Yuan, Jing and Zeng, Hongkui and Zhang, Kun and Zhang, Meng and Zhang, Zhuzhu and Zhao, Sujun and Zhao, Xuan and Zhou, Jingtian and Zhuang, Xiaowei and Zingg, Brian (2020) A multimodal cell census and atlas of the mammalian primary motor cortex. . (Unpublished) https://resolver.caltech.edu/CaltechAUTHORS:20201027-075126222
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Abstract
We report the generation of a multimodal cell census and atlas of the mammalian primary motor cortex (MOp or M1) as the initial product of the BRAIN Initiative Cell Census Network (BICCN). This was achieved by coordinated large-scale analyses of single-cell transcriptomes, chromatin accessibility, DNA methylomes, spatially resolved single-cell transcriptomes, morphological and electrophysiological properties, and cellular resolution input-output mapping, integrated through cross-modal computational analysis. Together, our results advance the collective knowledge and understanding of brain cell type organization: First, our study reveals a unified molecular genetic landscape of cortical cell types that congruently integrates their transcriptome, open chromatin and DNA methylation maps. Second, cross-species analysis achieves a unified taxonomy of transcriptomic types and their hierarchical organization that are conserved from mouse to marmoset and human. Third, cross-modal analysis provides compelling evidence for the epigenomic, transcriptomic, and gene regulatory basis of neuronal phenotypes such as their physiological and anatomical properties, demonstrating the biological validity and genomic underpinning of neuron types and subtypes. Fourth, in situ single-cell transcriptomics provides a spatially-resolved cell type atlas of the motor cortex. Fifth, integrated transcriptomic, epigenomic and anatomical analyses reveal the correspondence between neural circuits and transcriptomic cell types. We further present an extensive genetic toolset for targeting and fate mapping glutamatergic projection neuron types toward linking their developmental trajectory to their circuit function. Together, our results establish a unified and mechanistic framework of neuronal cell type organization that integrates multi-layered molecular genetic and spatial information with multi-faceted phenotypic properties.
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| Additional Information: | The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. This version posted October 21, 2020. We thank additional members of our laboratories and institutions who contributed to the experimental and analytical components of this project. This work was supported by grants from the NIH under: 1U24MH114827, 1U19MH114831, 1U19MH114821, 1U01MH117072, 1U19MH114830, 1U01MH114829, 1U01MH121282, 1U01MH117023, 1U01MH114825, 1U01MH114819, 1U01MH114812, 1U01MH121260, 1U01MH114824, 1U01MH117079, 1U01MH116990, 1U01MH114828, 1R24MH117295, 5R24MH114793, 5R24MH114788, 5R24MH114815. We thank NIH BICCN program officers, in particular Dr. Yong Yao, for their guidance and support throughout this study. Additional support: NIH grants R01NS39600 and R01NS86082 to G.A.A. H.S.B. is a Chan Zuckerberg Biohub Investigator. Deutsche Forschungsgemeinschaft through a Heisenberg Professorship (BE5601/4-1), the Cluster of Excellence “Machine Learning --- New Perspectives for Science” (EXC 2064, project number 390727645) and the Collaborative Research Center 1233 “Robust Vision”’ (project number 276693517), the German Federal Ministry of Education and Research (FKZ 01GQ1601 and 01IS18039A) to P.B. This work was supported in part by the Flow Cytometry Core Facility of the Salk Institute with funding from NIH-NCI CCSG: P30 014195 and Shared Instrumentation Grant S10-OD023689. NIH/NIMH R01MH094360 to H.W.D. We thank Marlene Becerra, Tyler Boesen, Chunru Cao, Marina Fayzullina, Kaelan Cotter, Lei Gao, Luis Gacia, Laura Korobkova, Darrick Lo, Christine Mun, Seita Yamashita, Muye Zhu for their technical and informatics support. Howard Hughes Medical Institute for J.E. This work was supported in part by the NNSFC grant 61890953 to H.G. Hearing Health Foundation Hearing Restoration Project grant to R.H. NIH grant OD010425 to G.D.H. This work is supported in part by NIH BRAIN Initiative award RF1MH114126 from the National Institute of Mental Health to E.S.L., J.T.T., and B.P.L. This work was supported in part by the NNSFC grant 81827901 to Q.L. This project was supported in part by NIH grants P51OD010425 from the Office of Research Infrastructure Programs (ORIP) and UL1TR000423 from the National Center for Advancing Translational Sciences (NCATS). Its contents are solely the responsibility of the authors and do not necessarily represent the official view of NIH, ORIP, NCATS, the Institute of Translational Health Sciences at the Washington National Primate Research Center. NSFC grant 61871411 and the University Synergy Innovation Program of Anhui Province GXXT-2019-008 to L.Q. Howard Hughes Medical Institute and the Klarman Cell Observatory for A.R. Howard Hughes Medical Institute for X.Z. V.D.B. is a postdoctoral fellow from the Belgian American Educational Foundation, and is supported by the Research Foundation Flanders (FWO), grant number 1246220N. NSFC Grant No. 32071367 and NSF Shanghai Grant No. 20ZR1420100 to Y.W. NIH grants R01EY023173 and U01MH105982 to H.Z. Researchers from Allen Institute for Brain Science wish to thank the Allen Institute founder, Paul G. Allen, for his vision, encouragement, and support. Author contributions: See the consortium author list for full details of author contributions. BICCN Contributing PIs: G.A.A., M.M.B., E.M.C., J.C., H.D., J.R.E., G.F., J.C.G., S.S.G., Y.O.H., M.H., R.H., Z.J.H., E.S.L., B.L., M.E.M., L.N., J.N., P.O., L.P., A.J.R., T.L.T., A.S.T., O.W., X.W.Y., H.Z., K.Z., X.Z. Principal manuscript editors: Z.J.H., E.S.L., H.Z. Manuscript writing and figure generation: G.A.A., T.E.B., P.B., E.M.C., T.L.D., H.D., J.R.E., J.A.H., M.H., Z.J.H., N.L.J., B.E.K., D.K., E.S.L., Y.E.L., H.L., K.S.M., E.A.M., M.N., J.N., P.O., B.R., F.S., P.T., J.T.T., A.S.T., F.X., H.Z., M.Z., Z.Z., J.Z., X.Z., B.Z. Analysis coordination: T.E.B., E.M.C., H.D., J.R.E., J.A.H., M.H., Z.J.H., E.S.L., E.A.M., J.N., P.O., B.R., A.S.T., H.Z., X.Z. Integrated data analysis: E.A., T.E.B., P.B., H.D., J.R.E., J.A.H., Z.J.H., N.L.J., B.E.K., D.K., E.S.L., Y.E.L., H.L., E.A.M., P.O., B.R., F.S., P.T., A.S.T., F.X., Z.Y., H.Z., M.Z., Z.Z., J.Z., X.Z. Sc/snRNA-seq data generation and processing: D.B., T.C., J.C., K.C., N.D., D.D., S.D., W.D., E.L.D., G.F., O.F., M.G., J.G., R.D.H., L.H., C.D.K., F.M.K., M.K., B.B.L., K.L., E.S.L., S.L., C.S.L., E.Z.M., S.A.M., D.M., N.M.N., T.N.N., C.R.P., T.P., N.P., N.M.R., A.R., C.R., W.J.R., S.S., K.S., K.S., J.S., B.T., M.T., A.T., H.T., C.T.V.V., C.R.V., A.M.Y., H.Z., K.Z. ATAC-seq data generation and processing: M.M.B., J.C., D.D., W.D., R.F., X.H., B.B.L., Y.E.L., C.S.L., J.D.L., J.K.O., C.R.P., A.P., N.P., O.P., S.P., B.R., W.J.R., X.W., K.Z. Methylcytosine data production and analysis: A.I.A., A.B., M.M.B., L.B., C.O., R.G.C., H.C., J.R.E., C.F., H.L., J.D.L., C.L., J.R.N., M.N., J.K.O., A.P., A.C.R., W.T., J.Z. Epi-Retro-Seq data generation and processing: A.B., M.M.B., L.B., E.M.C., C.O., R.G.C., B.D., J.R.E., C.F., T.I., M.J., X.J., C.L., K.L., P.A.M., E.A.M., J.R.N., M.N., Y.P., A.P., M.R., A.C.R., J.B.S., P.T., M.V., E.W., Z.Z., J.Z. Omics data analysis: E.A., T.E.B., T.B., A.S.B., M.C., D.D., S.D., J.R.E., R.F., S.F., O.F., J.G., J.G., Q.H., N.L.J., P.V.K., F.M.K., B.B.L., E.S.L., Y.E.L., S.L., H.L., E.Z.M., E.A.M., J.N., S.N., V.N., L.P., O.P., E.P., A.R., D.R., H.R.D.B., K.S., K.S., S.S., K.S., V.S., B.T., W.T., E.D.V., K.V.D.B., C.T.V.V., J.D.W., F.X., Z.Y., H.Z., J.Z. Tracing and connectivity data generation: X.A., H.S.B., I.B., R.K.C., H.D., N.N.F., W.G., H.G., L.G., J.A.H., J.T.H., H.H., K.E.H., Z.J.H., G.K., D.J.K., A.L., X.L., B.L., Q.L., K.S.M., L.N., J.N., R.M., D.A.S., H.Z., B.Z. Morphology data generation and reconstruction: T.L.D., H.D., Z.F., H.G., J.A.H., K.E.H., Z.J.H., X.J., S.J., T.J., X.K., R.L., P.L., X.L., Y.L., Y.L., L.L., Q.L., H.P., L.Q., M.R., Z.R., E.S., Y.S., W.W., P.W., Y.W., Y.W., L.Y., J.Y., H.Z., S.Z., X.Z. OLST/STPT and other data generation: X.A., W.G., J.T.H., Z.J.H., G.K., K.S.M., A.N., P.O., R.P., R.M. Morphology, connectivity and imaging analysis: X.A., G.A.A., S.B., L.D., H.D., Z.F., N.N.F., W.G., H.G., J.A.H., J.T.H., Z.J.H., B.H., X.J., G.K., H.K., S.L., A.L., X.L., K.S.M., P.P.M., J.M., M.N., A.N., L.N., P.O., R.P., H.P., R.M., Q.W., Y.W., Y.W., P.X., F.X., Y.Y., H.Z. Spatially resolved single-cell transcriptomics (MERFISH): H.D., S.W.E., Z.Y., H.Z., M.Z., X.Z., B.Z. Multimodal profiling (PATCH-seq): P.B., J.B., M.B., Y.B., C.R.C., J.R.C., R.D., L.H., G.D.H., X.J., B.E.K., C.D.K., A.L.K., D.K., S.L., E.S.L., E.M., S.M., P.R.N., S.F.O., R.S., F.S., K.S., S.A.S., Z.H.T., J.T.T., A.S.T., H.Z. Transgenic tools: S.A., X.A., H.S.B., R.K.C., T.L.D., W.G., J.T.H., D.H., Z.J.H., G.K., D.J.K., A.Y.L., K.S.M., J.N., D.A.S., B.T., M.B.V., X.W.Y., Z.Y., H.Z. NeMO archive and analytics: R.S.A., S.A.A., H.C.B., R.C., A.C., C.C., J.C., H.C., V.F., M.G., B.R.H., R.H., J.K., A.M., C.M., L.N., D.O., J.O., M.S., O.W. Brain Image Library (BIL) archive: G.H., A.J.R. DANDI archive: B.D., S.S.G., M.G., Y.O.H., B.H. Brain Cell Data Center (BCDC): A.B., N.B., B.C., F.D.D., K.D., J.C.G., T.H.G., M.H., F.K., K.K., M.E.M., L.N., C.T., T.L.T. Project management: P.B., F.D.D., H.G., H.H., K.K., D.K., B.B.L., K.S.M., S.M., M.N., F.S., S.S., C.T. Competing interests: A.B. is a cofounder of SciCrunch, a company devoted to improving scientific communication. J.R.E. is a member of Zymo Research SAB. J.A.H. is currently employed by Cajal Neuroscience. K.E.H. is currently employed by Cajal Neuroscience. P.V.K. serves on the Scientific Advisory Board to Celsius Therapeutics Inc. M.E.M. is a founder and CSO of SciCrunch Inc., a UCSD tech start up that produces tools in support of reproducibility including RRIDs. P.R.N. is currently employed by Cajal Neuroscience. A.R. is a founder and equity holder of Celsius Therapeutics, an equity holder in Immunitas Therapeutics and until August 31, 2020 was an SAB member of Syros Pharmaceuticals, Neogene Therapeutics, Asimov and ThermoFisher Scientific. From August 1, 2020, A.R. is an employee of Genentech. B.R. is shareholder of Arima Genomics, Inc. and Epigenome Technologies, Inc. K.Z is a co-founder, equity holder and serves on the Scientific Advisor Board of Singlera Genomics. X.Z. is a co-founder and consultant of Vizgen. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Official Citation: | A multimodal cell census and atlas of the mammalian primary motor cortex BRAIN Initiative Cell Census Network (BICCN), Ricky S. Adkins, et. al., bioRxiv 2020.10.19.343129; doi: https://doi.org/10.1101/2020.10.19.343129 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| ID Code: | 106288 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Deposited By: | Tony Diaz | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Deposited On: | 27 Oct 2020 17:28 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Last Modified: | 27 Oct 2020 17:28 |
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