Loss of PAX6 alters excitatory/inhibitory neuronal ratio in human cerebral organoids

The transcription factor PAX6 plays a crucial role in the development of the forebrain. In mice, it is known to regulate the differentiation of excitatory and inhibitory neurons in this region. However, there are notable distinctions between human and mouse forebrain, such as the presence of primate-specific progenitor population, outer radial glial cells that expresses PAX6. Due to limited human samples and ethical constraints, our understanding of PAX6 function in humans is lacking. Here, we used human cerebral organoids as a model system to study the role of PAX6 in human neurodevelopment. We generated homozygous PAX6 mutant (PAX6-/-) organoids and found that they are larger and contained inhibitory cells not found in PAX6+/+ organoids. These inhibitory cells were transcriptomically similar to inhibitory cells previously described in Pax6-/- mice and were distributed in a comparable manner. Our data suggest that while the major role of PAX6 is conserved across species, there are signalling variations in progenitor populations that have not been described in mice indicating species-specific mechanistic difference of PAX6 action in humans compared to mice.