title: A Single-Cell Roadmap of Lineage Bifurcation in Human ESC Models of Embryonic Brain Development.
abstract: During human brain development, multiple signaling pathways generate diverse cell types with varied regional identities. Here, we integrate single-cell RNA sequencing and clonal analyses to reveal lineage trees and molecular signals underlying early forebrain and mid/hindbrain cell differentiation from human embryonic stem cells (hESCs). Clustering single-cell transcriptomic data identified 41 distinct populations of progenitor, neuronal, and non-neural cells across our differentiation time course. Comparisons with primary mouse and human gene expression data demonstrated rostral and caudal progenitor and neuronal identities from early brain development. Bayesian analyses inferred a unified cell-type lineage tree that bifurcates between cortical and mid/hindbrain cell types. Two methods of clonal analyses confirmed these findings and further revealed the importance of Wnt/β-catenin signaling in controlling this lineage decision. Together, these findings provide a rich transcriptome-based lineage map for studying human brain development and modeling developmental disorders.
authors.affiliation: Allen Institute for Brain Science, Seattle, WA 98109, USA.
authors.forename: Zizhen
authors.initials: Z
authors.lastname: Yao
authors.affiliation: Allen Institute for Brain Science, Seattle, WA 98109, USA.
authors.forename: John K
authors.initials: JK
authors.lastname: Mich
authors.affiliation: Allen Institute for Brain Science, Seattle, WA 98109, USA.
authors.forename: Sherman
authors.initials: S
authors.lastname: Ku
authors.affiliation: Allen Institute for Brain Science, Seattle, WA 98109, USA.
authors.forename: Vilas
authors.initials: V
authors.lastname: Menon
authors.affiliation: Allen Institute for Brain Science, Seattle, WA 98109, USA.
authors.forename: Anne-Rachel
authors.initials: AR
authors.lastname: Krostag
authors.affiliation: Allen Institute for Brain Science, Seattle, WA 98109, USA.
authors.forename: Refugio A
authors.initials: RA
authors.lastname: Martinez
authors.affiliation: Molecular and Cellular Biology Department, Harvard University, Cambridge, MA 02138, USA.
authors.forename: Leon
authors.initials: L
authors.lastname: Furchtgott
authors.affiliation: Allen Institute for Brain Science, Seattle, WA 98109, USA.
authors.forename: Heather
authors.initials: H
authors.lastname: Mulholland
authors.affiliation: Allen Institute for Brain Science, Seattle, WA 98109, USA.
authors.forename: Susan
authors.initials: S
authors.lastname: Bort
authors.affiliation: Allen Institute for Brain Science, Seattle, WA 98109, USA.
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Fuqua
authors.affiliation: Allen Institute for Brain Science, Seattle, WA 98109, USA.
authors.forename: Ben W
authors.initials: BW
authors.lastname: Gregor
authors.affiliation: Allen Institute for Brain Science, Seattle, WA 98109, USA.
authors.forename: Rebecca D
authors.initials: RD
authors.lastname: Hodge
authors.affiliation: Allen Institute for Brain Science, Seattle, WA 98109, USA.
authors.forename: Anu
authors.initials: A
authors.lastname: Jayabalu
authors.affiliation: Allen Institute for Brain Science, Seattle, WA 98109, USA.
authors.forename: Ryan C
authors.initials: RC
authors.lastname: May
authors.affiliation: School of Engineering and Applied Science, Harvard University, Cambridge, MA 02138, USA.
authors.forename: Samuel
authors.initials: S
authors.lastname: Melton
authors.affiliation: Allen Institute for Brain Science, Seattle, WA 98109, USA.
authors.forename: Angelique M
authors.initials: AM
authors.lastname: Nelson
authors.affiliation: Allen Institute for Brain Science, Seattle, WA 98109, USA.
authors.forename: N Kiet
authors.initials: NK
authors.lastname: Ngo
authors.affiliation: Allen Institute for Brain Science, Seattle, WA 98109, USA.
authors.forename: Nadiya V
authors.initials: NV
authors.lastname: Shapovalova
authors.affiliation: Allen Institute for Brain Science, Seattle, WA 98109, USA.
authors.forename: Soraya I
authors.initials: SI
authors.lastname: Shehata
authors.affiliation: Allen Institute for Brain Science, Seattle, WA 98109, USA.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Smith
authors.affiliation: Allen Institute for Brain Science, Seattle, WA 98109, USA.
authors.forename: Leah J
authors.initials: LJ
authors.lastname: Tait
authors.affiliation: Allen Institute for Brain Science, Seattle, WA 98109, USA.
authors.forename: Carol L
authors.initials: CL
authors.lastname: Thompson
authors.affiliation: Allen Institute for Brain Science, Seattle, WA 98109, USA.
authors.forename: Elliot R
authors.initials: ER
authors.lastname: Thomsen
authors.affiliation: Allen Institute for Brain Science, Seattle, WA 98109, USA.
authors.forename: Chaoyang
authors.initials: C
authors.lastname: Ye
authors.affiliation: Division of Genetic Medicine, University of Washington, Seattle Children's Hospital, Seattle, WA 98105, USA.
authors.forename: Ian A
authors.initials: IA
authors.lastname: Glass
authors.affiliation: Allen Institute for Brain Science, Seattle, WA 98109, USA.
authors.forename: Ajamete
authors.initials: A
authors.lastname: Kaykas
authors.affiliation: Allen Institute for Brain Science, Seattle, WA 98109, USA.
authors.forename: Shuyuan
authors.initials: S
authors.lastname: Yao
authors.affiliation: Allen Institute for Brain Science, Seattle, WA 98109, USA.
authors.forename: John W
authors.initials: JW
authors.lastname: Phillips
authors.affiliation: Allen Institute for Brain Science, Seattle, WA 98109, USA. Electronic address: grimley@gmail.com.
authors.forename: Joshua S
authors.initials: JS
authors.lastname: Grimley
authors.affiliation: Allen Institute for Brain Science, Seattle, WA 98109, USA. Electronic address: boazl@alleninstitute.org.
authors.forename: Boaz P
authors.initials: BP
authors.lastname: Levi
authors.affiliation: Allen Institute for Brain Science, Seattle, WA 98109, USA. Electronic address: ywseattle@gmail.com.
authors.forename: Yanling
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Allen Institute for Brain Science, Seattle, WA 98109, USA; Molecular and Cellular Biology Department, Harvard University, Cambridge, MA 02138, USA; School of Engineering and Applied Science, Harvard University, Cambridge, MA 02138, USA. Electronic address: sharad@post.harvard.edu.
authors.forename: Sharad
authors.initials: S
authors.lastname: Ramanathan
mesh_terms: D000818:Animals; D001921:Brain / Q000196:embryology* / Q000378:metabolism; D002460:Cell Line; D019070:Cell Lineage / Q000235:genetics; D002999:Clone Cells; D047108:Embryonic Development / Q000235:genetics; D000066449:Human Embryonic Stem Cells / Q000166:cytology*; D006801:Humans; D051379:Mice; D008954:Models, Biological; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D015203:Reproducibility of Results; D017423:Sequence Analysis, RNA; D059010:Single-Cell Analysis / Q000379:methods*; D014157:Transcription Factors / Q000378:metabolism; D059467:Transcriptome / Q000235:genetics; D060449:Wnt Signaling Pathway / Q000235:genetics
chemical_list: D014157:Transcription Factors
keywords: human embryonic stem cells; lineage; neurogenesis; single cell RNA-seq