Genes Expressed in Specific Areas of the Human Fetal Cerebral Cortex Display Distinct Patterns of Evolution

Abstract

The developmental mechanisms through which the cerebral cortex increased in size and complexity during primate evolution are essentially unknown. To uncover genetic networks active in the developing cerebral cortex, we combined three-dimensional reconstruction of human fetal brains at midgestation and whole genome expression profiling. This novel approach enabled transcriptional characterization of neurons from accurately defined cortical regions containing presumptive Broca and Wernicke language areas, as well as surrounding associative areas. We identified hundreds of genes displaying differential expression between the two regions, but no significant difference in gene expression between left and right hemispheres. Validation by qRTPCR and in situ hybridization confirmed the robustness of our approach and revealed novel patterns of area- and layer-specific expression throughout the developing cortex. Genes differentially expressed between cortical areas were significantly associated with fast-evolving non-coding sequences harboring human-specific substitutions that could lead to divergence in their repertoires of transcription factor binding sites. Strikingly, while some of these sequences were accelerated in the human lineage only, many others were accelerated in chimpanzee and/or mouse lineages, indicating that genes important for cortical development may be particularly prone to changes in transcriptional regulation across mammals. Genes differentially expressed between cortical regions were also enriched for transcriptional targets of FoxP2, a key gene for the acquisition of language abilities in humans. Our findings point to a subset of genes with a unique combination of cortical areal expression and evolutionary patterns, suggesting that they play important roles in the transcriptional network underlying human-specific neural traits.

Lateralization of gene expression in human language cortex

“…This is also consistent with data from human embryonic and fetal material, where little evidence for lateralization has been detected in four post mortem studies, with the possible exception of a small number of genes in the first trimester of gestation (Johnson et al, 2009;Lambert et al, 2011;Pletikos et al, 2014;Sun, Collura, Ruvolo, & Walsh, 2006). However, those embryonic data may also benefit from the kinds of analyses that we have applied here, and the results could then be compared to the adult genetic lateralization that we have identified.…”

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.…”

Comparative Anatomy of Marmoset and Mouse Cortex from Genomic Expression

“…and what is the function of these differentially expressed genes? Recent observations that may help to answer these questions indicate that noncoding genes can control the area and timing of coding gene expression (Ohshima and Okada, 2005;Pollard et al, 2006;Goodier and Kazazian, 2008;Britten, 2010) of signaling molecules to regulate patterning, neuronal growth rate, and DNA damage repair (Goodier and Kazazian, 2008;Sasaki et al, 2008;Lambert et al, 2011). The generation of transgenic marmosets for enhancer activity assays will be a very powerful tool to test this hypothesis (Sasaki et al, 2009).…”