Chiaradia, I. | bioRxiv Science

bioRxiv2025

Human-specific morphoregulatory signatures in basal radial glia characterize neocortex evolution

As the seat of our cognition, the human neocortex is an object of immense fascination. Human neocortex expansion during evolution has been attributed to an increase in the proliferative capacity of neural progenitor cells during development, particularly basal radial glia (bRG). Despite their evolutionary relevance, the genomic changes driving human-specific bRG biology remain uncharacterized. We used comparative chromatin and transcriptional profiling of neural progenitor cells isolated from gorilla, chimpanzee and human cerebral organoids to identify cis-regulatory elements that have gained activity in humans. Focusing specifically on bRG, we discovered that morphoregulatory enhancer activity and gene expression signatures distinguish human bRG from other great apes. Functional analysis of the morphoregulatory genes FAM107A and CNGA3 in human organoids revealed that these genes are required for the morphological complexity of human bRG. Taken together, our interspecies comparison of basal radial glia suggests that human-specific morphoregulatory signatures characterize neocortex evolution.

neuroscience↗

bioRxiv2020

Male sex hormones increase excitatory neuron production in developing human neocortex

The presence of male-female brain differences has long been a controversial topic. Yet simply negating the existence of biological differences has detrimental consequences for all sexes and genders, particularly for the development of accurate diagnostic tools, effective drugs and understanding of disease. The most well-established morphological difference is size, with males having on average a larger brain than females; yet a mechanistic understanding of how this difference arises remains to be elucidated. Here, we use brain organoids to test the roles of sex chromosomes and sex steroids during development. While we show no observable differences between XX and XY brain organoids, sex steroids, namely androgens, increase proliferation of cortical neural progenitors. Transcriptomic analysis reveals effects on chromatin remodelling and HDAC activity, both of which are also implicated in the male-biased conditions autism spectrum disorder and schizophrenia. Finally, we show that higher numbers of progenitors result specifically in increased upper-layer excitatory neurons. These findings uncover a hitherto unknown role for male sex hormones in regulating excitatory neuron number within the human neocortex and represent a first step towards understanding the origin of human sex-related brain differences.

developmental biology↗