Periodic Reporting for period 2 - CerebralHominoids (Evolutionary biology of human and great ape brain development in cerebral organoids)
Reporting period: 2020-01-01 to 2021-06-30
In order to gain a better understanding of developmental events unique to the human brain, we are using cerebral organoids, or brain organoids, as an in vitro model of the human developing brain. We are using this system and applying it to other ape cells as well, to compare early brain development across these species. So far, our comparisons among apes have revealed striking differences very early in brain development in terms of tissue morphogenesis and cell shape. Over the final period of this project, we will investigate the molecular mechanism honing in on genetic and epigenetic differences that explain key differences in timing.
Overall, we aim to discover the key genetic differences and the cellular mechanisms they govern that give rise to our uniquely expanded brain.
1. Improvement of cerebral organoids to enable modeling further events in human brain development and evolution.
We have established a method to culture organoids at the air-liquid interface, enabling longer term maturation and the formation of long-range bundles with functional output (Nature Neuroscience 2019).
We have established a human organoid model of the choroid plexus, the brain regions responsible for generation of cerebrospinal fluid (Science 2020). This enables the investigation of this understudied brain region, as well as the fluid it produces, which will be an important future direction.
2. Investigation of events during brain development that determine brain size.
We have performed comparisons of human and other ape organoids and identified an early difference in tissue size and cell shape that relates to timing of a transition from proliferation to differentiation. This change in timing in humans leads to an increased founder stem cell pool and can account for a large proportion of the difference in brain size between humans and other great apes. We have also performed comparative RNA-seq as planned and identified a number of differentially expressed factors involved in these human-specific differences.