An early cell shape transition drives evolutionary expansion of the human forebrain

Silvia Benito-Kwiecinski,Stefano L Giandomenico,Magdalena Sutcliffe,Erlend S Riis,Paula Freire-Pritchett,Iva Kelava,Stephanie Wunderlich,Ulrich Martin,Gregory A Wray,Kate Mcdole,Madeline A Lancaster

doi:10.1016/j.cell.2021.02.050

Abstract

SummaryThe human brain has undergone rapid expansion since humans diverged from other great apes, but the mechanism of this human-specific enlargement is still unknown. Here, we use cerebral organoids derived from human, gorilla, and chimpanzee cells to study developmental mechanisms driving evolutionary brain expansion. We find that neuroepithelial differentiation is a protracted process in apes, involving a previously unrecognized transition state characterized by a change in cell shape. Furthermore, we show that human organoids are larger due to a delay in this transition, associated with differences in interkinetic nuclear migration and cell cycle length. Comparative RNA sequencing (RNA-seq) reveals differences in expression dynamics of cell morphogenesis factors, including ZEB2, a known epithelial-mesenchymal transition regulator. We show that ZEB2 promotes neuroepithelial transition, and its manipulation and downstream signaling leads to acquisition of nonhuman ape architecture in the human context and vice versa, establishing an important role for neuroepithelial cell shape in human brain expansion.

Highlights

One of the most distinctive features of humans as a species is an enlarged brain
We found that during early NE expansion, the NE to RG transition in human and ape is a gradual process, taking place over the course of several days, unlike the rapid differentiation of NE to RG cells described in mouse, and it involves an intermediate cell morphology state we named transitioning NE cells
RNA sequencing analysis captures dynamics of gene expression across multiple early time points To identify what factors might be controlling these changes in cell shape, we examined the transcriptome profile of human and gorilla organoids

Summary

Introduction

One of the most distinctive features of humans as a species is an enlarged brain. The human brain exhibits a 1,000-fold increase in total neuron number compared with mice (Herculano-Houzel et al, 2006) and is the largest of all primates, roughly 3-fold larger than that of our closest living relatives, chimpanzees and gorillas (Herculano-Houzel, 2012). A number of studies have examined differences in brain development between human, mouse, and other distantly related model organisms (Bae et al, 2015; Lui et al, 2011; Sousa et al, 2017), highlighting divergence in neural progenitor behavior (Florio et al, 2015), neurogenesis (O’Neill et al, 2018), and cytoarchitecture (Dehay et al, 2015; Fietz et al, 2010; Hansen et al, 2010). Comparisons of the human brain to that of other apes reveal a general increase in size without an expansion in particular layers of the cerebral cortex (Donahue et al, 2018, de Sousa et al, 2010; Hutsler et al, 2005), suggesting that while primate expansion may have been governed by both early and late changes, human-specific differences likely take place prior to the generation of cortical layer neurons. Without being able to examine and manipulate early progenitor cell behavior in apes and humans, these observations have remained correlative

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