A Single-Cell Roadmap of Lineage Bifurcation in Human ESC Models of Embryonic Brain Development

Publication date: Available online 27 October 2016
Source:Cell Stem Cell
Author(s): Zizhen Yao, John K. Mich, Sherman Ku, Vilas Menon, Anne-Rachel Krostag, Refugio A. Martinez, Leon Furchtgott, Heather Mulholland, Susan Bort, Margaret A. Fuqua, Ben W. Gregor, Rebecca D. Hodge, Anu Jayabalu, Ryan C. May, Samuel Melton, Angelique M. Nelson, N. Kiet Ngo, Nadiya V. Shapovalova, Soraya I. Shehata, Michael W. Smith, Leah J. Tait, Carol L. Thompson, Elliot R. Thomsen, Chaoyang Ye, Ian A. Glass, Ajamete Kaykas, Shuyuan Yao, John W. Phillips, Joshua S. Grimley, Boaz P. Levi, Yanling Wang, Sharad Ramanathan
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.

Graphical abstract

Teaser

Yao et al. perform single-cell RNA-seq during neural differentiation of hESCs. They identify many classes of neural progenitors and neurons that map to early human brain cells, computationally infer and experimentally confirm lineage relationships between them, and show that Wnt signaling influences the bifurcation between forebrain and mid/hindbrain lineages in vitro.


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