Single-cell analysis reveals transcriptional heterogeneity of neural progenitors in human cortex

Abstract

The human cerebral cortex depends for its normal development and size on a precisely controlled balance between self-renewal and differentiation of diverse neural progenitor cells. Specialized progenitors that are common in humans, but virtually absent in rodents, called ‘outer radial glia’ (ORG), have been suggested to be crucial to the evolutionary expansion of the human cortex. We combined progenitor subtype-specific sorting with transcriptome-wide RNA-sequencing to identify genes enriched in human ORG, which included targets of the transcription factor Neurogenin and previously uncharacterized, evolutionarily dynamic long noncoding RNAs. We show that activating the Neurogenin pathway in ferret progenitors promotes delamination and outward migration. Finally, single-cell transcriptional profiling in human, ferret, and mouse revealed more cells co-expressing proneural Neurogenin targets in human compared to other species, suggesting greater neuronal lineage commitment and differentiation of self-renewing progenitors. Thus, we find that the abundance of human ORG is paralleled by increased transcriptional heterogeneity of cortical progenitors.

Single-cell gene expression analysis reveals regulators of distinct cell subpopulations among developing human neurons

“…These data suggest that the developmental potential of the NPCs we patterned in vitro are already lineage restricted. Interestingly, it was recently been reported that WNT5A is highly expressed in apical neural progenitor cells and lowly expressed in nonapical neural progenitor cells in human brain (Johnson et al 2015), indicating that our derived NPC may reflect the heterogeneity of neural progenitor cells in human brain. Therefore, we conclude that the in vitro NPC differentiation process we used mimicked normal developmental processes and thus serves as a useful model.…”

“…To date, many studies have shown the heterogeneity of neural precursor cells (Johnson et al 2015;Llorens-Bobadilla et al 2015) and neurons (Molyneaux et al 2007;Pollen et al 2014;Darmanis et al 2015;Usoskin et al 2015) in mouse and human brain by scRNA-seq. However, due to complexity of data analysis of cellular dynamics, coupled with the biological variability (birth, death, and differentiation) of individual cells, as well as the presence of technical, environmental, and intracellular noise (Kuznetsov 2001(Kuznetsov , 2003Kuznetsov et al 2002;Kim and Marioni 2013;Kharchenko et al 2014;Buettner et al 2015;Daigle et al 2015;Vu et al 2016), it remains a challenge to interpret the heterogeneity and dynamics of NPC to neuron transitions (Camp et al 2015;Bakken et al 2016;Yao et al 2017).…”

Human cerebral organoids recapitulate gene expression programs of fetal neocortex development

“…Single-cell gene expression analysis is a powerful technique to deconstruct tissue heterogeneity and has recently been used to characterize NPC and neurons in the fetal brain (24,(27)(28)(29). Here we applied scRNA-seq to compare cell composition and lineage relationships in fetal and organoid cerebral cortex.…”

Is this a brain which I see before me? Modeling human neural development with pluripotent stem cells

“…From a molecular perspective, a number of genes have been identified recently, mostly through transcriptomics/genomics approaches, that may be involved in human-specific features of brain development Lambert et al, 2011;Pollard et al, 2006;Prabhakar et al, 2006), some of which have been validated functionally (Charrier et al, 2012;Florio et al, 2015;Johnson et al, 2015;Lui et al, 2014). It is likely that human PSC neural development models will constitute the ideal experimental setup to determine the mechanisms of action of such genes, and to identify others.…”