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Evolutionary biology of human and great ape brain development in cerebral organoids

Periodic Reporting for period 3 - CerebralHominoids (Evolutionary biology of human and great ape brain development in cerebral organoids)

Reporting period: 2021-07-01 to 2022-12-31

The human brain is incredibly complex, both in terms of its architecture and its functionality. Indeed, the complex architecture of the brain is thought to lead to its complex functionality and explain our higher cognitive capabilities. However, how this complexity arises during development, and what features of brain development are unique to humans remains to be explained. This question is of fundamental importance for our understanding of both the healthy and diseased brain, for it is often the very same human-specific features that are affected in patients with neurological and mental health conditions. For example, autism spectrum disorder, schizophrenia, and neurodegeneration all affect uniquely human cognitive functions, such as language, logic and reasoning, and complex emotions.

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.
We have made major advances in two key areas:

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.
We will now turn to molecular mechanisms governing the differences observed between human and other ape organoids. We have already identified a protein involved in epithelial-mesenchymal-transition whose expression dynamics can explain the differences in cell shape and tissue growth in human organoids. We will now investigate the upstream regulators responsible for differences in timing of its expression. We also plan to interogate other identified factors and perform functional studies using genetic manipulation to determine their roles.
Comparison of organoids from human and nonhuman ape cells