Spatiotemporal gene expression trajectories reveal developmental hierarchies of the human cortex
Tomasz J. Nowakowski,Aparna Bhaduri,Alex A. Pollen,Beatriz Alvarado,Mohammed A. Mostajo-Radji,Elizabeth Di Lullo,Maximilian Haeussler,Carmen Sandoval-Espinosa,Siyuan John Liu,Dmitry Velmeshev,Johain Ryad Ounadjela,Joe Shuga,Xiaohui Wang,Daniel A. Lim,Jay A. A. West,Anne A. Leyrat,W. James Kent,Arnold R. Kriegstein +17 more
TLDR
The results support a mixed model of topographical, typological, and temporal hierarchies governing cell-type diversity in the developing human telencephalon, including distinct excitatory lineages emerging in rostral and caudal cerebral cortex.Abstract:
Systematic analyses of spatiotemporal gene expression trajectories during organogenesis have been challenging because diverse cell types at different stages of maturation and differentiation coexist in the emerging tissues. We identified discrete cell types as well as temporally and spatially restricted trajectories of radial glia maturation and neurogenesis in developing human telencephalon. These lineage-specific trajectories reveal the expression of neurogenic transcription factors in early radial glia and enriched activation of mammalian target of rapamycin signaling in outer radial glia. Across cortical areas, modest transcriptional differences among radial glia cascade into robust typological distinctions among maturing neurons. Together, our results support a mixed model of topographical, typological, and temporal hierarchies governing cell-type diversity in the developing human telencephalon, including distinct excitatory lineages emerging in rostral and caudal cerebral cortex.read more
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An Integrative Model of Cellular States, Plasticity, and Genetics for Glioblastoma
Cyril Neftel,Julie Laffy,Mariella G. Filbin,Toshiro Hara,Marni E. Shore,Marni E. Shore,Gilbert J. Rahme,Gilbert J. Rahme,Alyssa R. Richman,Alyssa R. Richman,Dana Silverbush,Dana Silverbush,McKenzie Shaw,Christine M. Hebert,Christine M. Hebert,John M. DeWitt,John M. DeWitt,Simon Gritsch,Simon Gritsch,Elizabeth M. Perez,Elizabeth M. Perez,L. Nicolas Gonzalez Castro,Xiaoyang Lan,Xiaoyang Lan,Nicholas Druck,Christopher Rodman,Danielle Dionne,Alexander Kaplan,Mia Bertalan,Julia L. Small,Kristine Pelton,Sarah Becker,Dennis M. Bonal,Quang-Dé Nguyen,Rachel L. Servis,Jeremy M. Fung,Ravindra Mylvaganam,Lisa Mayr,Johannes Gojo,Christine Haberler,René Geyeregger,Thomas Czech,Irene Slavc,Brian V. Nahed,William T. Curry,Bob S. Carter,Hiroaki Wakimoto,Priscilla K. Brastianos,Tracy T. Batchelor,Anat Stemmer-Rachamimov,Maria Martinez-Lage,Matthew P. Frosch,Ivan Stamenkovic,Nicolo Riggi,Esther Rheinbay,Esther Rheinbay,Michelle Monje,Orit Rozenblatt-Rosen,Daniel P. Cahill,Anoop P. Patel,Tony Hunter,Inder M. Verma,Keith L. Ligon,Keith L. Ligon,David N. Louis,Aviv Regev,Aviv Regev,Bradley E. Bernstein,Bradley E. Bernstein,Itay Tirosh,Mario L. Suvà,Mario L. Suvà +71 more
TL;DR: It is found that malignant cells in glioblastoma exist in four main cellular states that recapitulate distinct neural cell types, are influenced by the tumor microenvironment, and exhibit plasticity.
Journal ArticleDOI
Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism
F. Kyle Satterstrom,F. Kyle Satterstrom,Jack A. Kosmicki,Jiebiao Wang,Michael S. Breen,Silvia De Rubeis,Joon Yong An,Joon Yong An,Minshi Peng,Ryan Collins,Jakob Grove,Jakob Grove,Lambertus Klei,Christine Stevens,Jennifer Reichert,Maureen Mulhern,Mykyta Artomov,Sherif Gerges,Brooke Sheppard,Xinyi Xu,Aparna Bhaduri,Utku Norman,Harrison Brand,Grace Schwartz,Rachel Nguyen,Elizabeth E. Guerrero,Caroline Dias,Branko Aleksic,Richard Anney,Mafalda Barbosa,Somer L. Bishop,Alfredo Brusco,Jonas Bybjerg-Grauholm,Angel Carracedo,Marcus C.Y. Chan,Andreas G. Chiocchetti,Brian H.Y. Chung,Hilary Coon,Michael L. Cuccaro,Aurora Currò,Bernardo Dalla Bernardina,Ryan N. Doan,Enrico Domenici,Shan Dong,Chiara Fallerini,Montserrat Fernández-Prieto,Giovanni Battista Ferrero,Christine M. Freitag,Menachem Fromer,J. Jay Gargus,Daniel H. Geschwind,Elisa Giorgio,Javier González-Peñas,Stephen J. Guter,Danielle Halpern,Emily Hansen-Kiss,Xin He,Gail E. Herman,Irva Hertz-Picciotto,David M. Hougaard,Christina M. Hultman,Iuliana Ionita-Laza,Suma Jacob,Jesslyn Jamison,Astanand Jugessur,Miia Kaartinen,Gun Peggy Knudsen,Alexander Kolevzon,Itaru Kushima,So Lun Lee,Terho Lehtimäki,Elaine T. Lim,Carla Lintas,W. Ian Lipkin,Diego Lopergolo,Fátima Lopes,Yunin Ludena,Patrícia Maciel,Per Magnus,Behrang Mahjani,Nell Maltman,Dara S. Manoach,Gal Meiri,Idan Menashe,Judith Miller,Nancy J. Minshew,Eduarda Montenegro M. de Souza,Danielle de Paula Moreira,Eric M. Morrow,Ole Mors,Preben Bo Mortensen,Matthew W. Mosconi,Pierandrea Muglia,Benjamin M. Neale,Merete Nordentoft,Norio Ozaki,Aarno Palotie,Mara Parellada,Maria Rita Passos-Bueno,Margaret A. Pericak-Vance,Antonio M. Persico,Isaac N. Pessah,Kaija Puura,Abraham Reichenberg,Alessandra Renieri,Evelise Riberi,Elise B. Robinson,Elise B. Robinson,Kaitlin E. Samocha,Sven Sandin,Sven Sandin,Susan L. Santangelo,Susan L. Santangelo,Gerry Schellenberg,Stephen W. Scherer,Sabine Schlitt,Rebecca J. Schmidt,Lauren M. Schmitt,Isabela Maya Wahys Silva,Tarjinder Singh,Tarjinder Singh,Paige M. Siper,Moyra Smith,Gabriela Soares,Camilla Stoltenberg,Pål Surén,Ezra Susser,John A. Sweeney,Peter Szatmari,Lara Tang,Flora Tassone,Karoline Teufel,Elisabetta Trabetti,Maria del Pilar Trelles,Christopher A. Walsh,Lauren A. Weiss,Thomas Werge,Donna M. Werling,Emilie M. Wigdor,Emilie M. Wigdor,Emma Wilkinson,A. Jeremy Willsey,Timothy W. Yu,Mullin H.C. Yu,Ryan Yuen,Elaine Cristina Zachi,Esben Agerbo,Thomas Damm Als,Vivek Appadurai,Marie Bækvad-Hansen,Rich Belliveau,Alfonso Buil,Caitlin E. Carey,Felecia Cerrato,Kimberly Chambert,Claire Churchhouse,Claire Churchhouse,Søren Dalsgaard,Ditte Demontis,Ashley Dumont,Jacqueline I. Goldstein,Christine Søholm Hansen,Mads E. Hauberg,Mads E. Hauberg,Mads E. Hauberg,Mads V. Hollegaard,Daniel P. Howrigan,Hailiang Huang,Julian Maller,Alicia R. Martin,Joanna Martin,Manuel Mattheisen,Jennifer L. Moran,Jonatan Pallesen,Duncan S. Palmer,Carsten Bøcker Pedersen,Marianne Giørtz Pedersen,Timothy Poterba,Jesper Buchhave Poulsen,Stephan Ripke,Andrew J. Schork,Wesley K. Thompson,Patrick Turley,Raymond K. Walters,Catalina Betancur,Edwin H. Cook,Louise Gallagher,Michael Gill,James S. Sutcliffe,Audrey Thurm,Michael E. Zwick,Anders D. Børglum,Matthew W. State,A. Ercument Cicek,A. Ercument Cicek,Michael E. Talkowski,David J. Cutler,Bernie Devlin,Stephen Sanders,Kathryn Roeder,Mark J. Daly,Joseph D. Buxbaum +201 more
TL;DR: The largest exome sequencing study of autism spectrum disorder (ASD) to date, using an enhanced analytical framework to integrate de novo and case-control rare variation, identifies 102 risk genes at a false discovery rate of 0.1 or less, consistent with multiple paths to an excitatory-inhibitory imbalance underlying ASD.
Journal ArticleDOI
Individual brain organoids reproducibly form cell diversity of the human cerebral cortex
Silvia Velasco,Amanda J. Kedaigle,Amanda J. Kedaigle,Sean Simmons,Allison Nash,Allison Nash,Marina Rocha,Marina Rocha,Giorgia Quadrato,Giorgia Quadrato,Bruna Paulsen,Bruna Paulsen,Lan Nguyen,Xian Adiconis,Aviv Regev,Aviv Regev,Joshua Z. Levin,Paola Arlotta,Paola Arlotta +18 more
TL;DR: It is shown that an organoid model of the dorsal forebrain can reliably generate a rich diversity of cell types appropriate for the human cerebral cortex, and that establishment of terminal cell identity is a highly constrained process that can emerge from diverse stem cell origins and growth environments.
Journal ArticleDOI
Integrative functional genomic analysis of human brain development and neuropsychiatric risks
Mingfeng Li,Gabriel Santpere,Yuka Imamura Kawasawa,Yuka Imamura Kawasawa,Oleg V. Evgrafov,Forrest O. Gulden,Sirisha Pochareddy,Susan M. Sunkin,Zhen Li,Yurae Shin,Yurae Shin,Ying Zhu,André M. M. Sousa,Donna M. Werling,Robert R. Kitchen,Hyo Jung Kang,Hyo Jung Kang,Mihovil Pletikos,Mihovil Pletikos,Jinmyung Choi,Sydney Muchnik,Xuming Xu,Daifeng Wang,Belen Lorente-Galdos,Shuang Liu,Paola Giusti-Rodríguez,Hyejung Won,Christiaan de Leeuw,Antonio F. Pardiñas,PsychENCODE Developmental Subgroup,Ming Hu,Fulai Jin,Yun Li,Michael John Owen,Michael Conlon O'Donovan,James T.R. Walters,Danielle Posthuma,Mark Reimers,Pat Levitt,Pat Levitt,Daniel R. Weinberger,Thomas M. Hyde,Joel E. Kleinman,Daniel H. Geschwind,Michael Hawrylycz,Matthew W. State,Stephen Sanders,Patrick F. Sullivan,Mark Gerstein,Ed S. Lein,James A. Knowles,Nenad Sestan +51 more
TL;DR: The generation and analysis of a variety of genomic data modalities at the tissue and single-cell levels, including transcriptome, DNA methylation, and histone modifications across multiple brain regions ranging in age from embryonic development through adulthood, reveal insights into neurodevelopment and the genomic basis of neuropsychiatric risks.
Journal ArticleDOI
Single-cell genomics identifies cell type-specific molecular changes in autism.
Dmitry Velmeshev,Lucas Schirmer,Lucas Schirmer,Diane Jung,Maximilian Haeussler,Yonatan Perez,Simone Mayer,Simone Mayer,Aparna Bhaduri,Nitasha Goyal,Nitasha Goyal,David H. Rowitch,Arnold R. Kriegstein +12 more
TL;DR: It is found that synaptic signaling of upper-layer excitatory neurons and the molecular state of microglia are preferentially affected in autism, and results show that dysregulation of specific groups of genes in cortico-cortical projection neurons correlates with clinical severity of autism.
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