Using Stem Cells to Study Human Origins

Since the split of Homo sapiens from the last common nonhuman primate (NHP) ancestor, the human brain has substantially altered its size, structure and connectivity. The human brain has a larger mass with respect to body weight, increased cortical neurons with respect to size, an expanded proliferative zone, and unique connectivity patterns.

Human-specific neurodevelopment is not only marked by physical differences, but also by temporal changes. Human neurons, during both prenatal neurodevelopment and adult neurogenesis, exhibit an exceptionally delayed time course, a characteristic termed neoteny. It is hypothesized that this longer developmental period plays a role in the aforementioned structural and connectivity differences. It has long been proposed that the phenotypic differences between closely related species may be driven, in part, by divergent transcriptional regulation rather than by novel protein-coding sequence. However, how these regulatory mechanisms play a role in the protracted maturation process in human neurons remains largely unknown.

Signatures of human-specific neoteny have been observed and reproduced across different systems including induced pluripotent stem cell (iPSC) and brain organoids models. To examine the evolutionary constraints on the rate of neuronal maturation, we compared neurogenesis across iPSC-derived cells from five primate species - Macaca mulatta (rhesus), Gorilla gorilla (gorilla), Pan paniscus (bonobo), Pan troglodytes (chimpanzee), and Homo sapiens (human) - and assessed the differences in transcriptional dynamics. While the neural progenitor cells of humans, chimpanzees, and bonobos were highly similar, we found that transcriptional differences increased between all species throughout neuronal differentiation and maturation. We identified a pioneer transcription factor, GATA3, that exhibited elevated neuronal expression only in humans. Strikingly, down-regulation of GATA3 increased the rate of physiological maturity in human neurons, indicating that the species-specific rate of physiological maturity is cell intrinsic and can be modulated by perturbing a single, conserved transcription factor. This finding provides evidence for the divergence of gene regulation as a contributor to human neoteny.