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

Abstract

<jats:title>Abstract</jats:title><jats:p>The 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 the differentiation of neuroepithelial cells to neurogenic radial glia 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. Temporally resolved RNA-seq from human and gorilla organoids reveals differences in gene expression patterns associated with cell morphogenesis, and in particular highlights <jats:italic>ZEB2</jats:italic>, a known regulator of epithelial-mesenchymal transition and cell shape. We show, through loss- and gain-of-function experiments, that <jats:italic>ZEB2</jats:italic> promotes the progression of neuroepithelial differentiation, and its ectopic overexpression in human is sufficient to trigger a premature transition. Thus, by mimicking the nonhuman ape expression in human organoids, we are able to force the acquisition of nonhuman ape architecture, establishing for the first time, an instructive role of neuroepithelial cell shape in human brain expansion.</jats:p>

CHD8 haploinsufficiency alters the developmental trajectories of human excitatory and inhibitory neurons linking autism phenotypes with transient cellular defects

“…ZEB2 encodes a transcription factor recently described to promote neuroepithelial differentiation into radial glia, thus determining the initial number of proliferating cells and thereby controlling cortical tissue expansion. For this reason, the delayed increase in ZEB2 levels in humans versus apes has been proposed to underlie human neocortical expansion 34 . Consistently, we found enrichment for ZEB2 ChIPseq-defined targets among the DEGs of multiple clusters at day 20 (Fig.…”

From stem and progenitor cells to neurons in the developing neocortex: key differences among hominids

“…All rights reserved A recent preprint provides further evidence suggesting a fundamental link between developmental timing and NSPC proliferation potential among hominids. Specifically, very early forebrain organoid APs of human remained longer in a more neuroepithelial (NE)-like state than those of gorilla, as suggested by morphological features [41]. This NE-like morphology included shorter apicobasal processes and a larger apical contact with the surface of the ventricle-like structures of the organoids.…”

“…The switch to an aRGlike state occurred earlier in gorilla than human organoid APs, being accompanied by a down-regulation of certain epithelial features such as lower and more apically restricted levels of the tight junction marker occludin. The transcription factor ZEB2 was proposed as a driver of this switch, as it was expressed earlier in gorilla than human organoid APs, and its overexpression in human organoid APs mimicked the gorilla organoid phenotype [41]. These findings are of interest in light of the notion that NECs exhibit greater proliferative capacity than aRG [14][15][16].…”

Role of NDE1 in the Development and Evolution of the Gyrified Cortex

“…The latter would be facilitated by using a mutation identified by Monda and Cheeseman (2018) that abolishes the interaction between NDE1 and the 26S proteasome. An even more exciting possibility is emerging with the advent of multispecies organoids, which allow modeling of cortical development across evolution (Mora-Bermúdez et al, 2016;Pollen et al, 2018;Kanton et al, 2019;Muchnik et al, 2019;Benito-Kwiecinski et al, 2020;Eze et al, 2020) and may hold insight into the specific contributions of NDE1 to cortical development. Although most multispecies organoid studies have sought to compare human and non-human primate cortical development, it is exciting to consider expanding this technology to other lineages with substantial rates of gyrification to study mechanistic overlap in the development and evolution of the gyrencephalic brain.…”

“…Expansion of the cortex and gyrification emerged from changes in brain development, which requires tight coordination of proliferation and differentiation within a limited gestational window. For instance, experimental and cross-species comparative studies indicate that extension of the proliferative period early in cortical development, or lengthening of the neurogenic period itself, can drive cortical expansion (Finlay and Darlington, 1995;Geschwind and Rakic, 2013;Mora-Bermúdez et al, 2016;Benito-Kwiecinski et al, 2020;Eze et al, 2020;Stepien et al, 2020). The precise mechanisms underlying cortical expansion are complex, involving both the regulation of progenitor cell division and species-specific heterogeneity of progenitor populations (Reillo et al, 2010;Geschwind and Rakic, 2013;Borrell and Götz, 2014;Kalebic and Huttner, 2020).…”