The human brain sets us apart as a species, with its size being one of its most striking features. Brain size is largely determined during development as vast numbers of neurons and supportive glia are generated. In an effort to better understand the events that determine the human brain’s cellular makeup, and its size, we use a human model system in a dish, called cerebral organoids. These 3D tissues are generated from pluripotent stem cells through neural differentiation and a supportive 3D microenvironment to generate organoids with the same tissue architecture as the early human fetal brain. Such organoids are allowing us to tackle questions previously impossible with more traditional approaches. Indeed, our recent findings provide insight into regulation of brain size and neuron number across ape species, identifying key stages of early neural stem cell expansion that set up a larger starting cell number to enable the production of increased numbers of neurons. We are also investigating the role of extrinsic regulators in determining numbers and types of neurons produced in the human cerebral cortex. Overall, our findings are pointing to key, human-specific aspects of brain development and function, that have important implications for neurological disease.

The symposium will start with Prof Song-Hai Shi who will present “Assembly of the neocortex”. Then, Dr Lynette Lim will talk about “Shared and Unique Developmental Trajectories of Cortical Inhibitory Neurons”. Dr Alfredo Molina will deal with the “Tuneable progenitor cells to build the cerebral cortex”, and Prof Tomasz Nowakowski will present “Charting the molecular 'protomap' of the human cerebral cortex using single cell genomic”.

Malformations of the human cerebral cortex represent a major cause of developmental disabilities. To date, animal models carrying mutations of genes so far identified in human patients with brain malformations only partially recapitulate the expected phenotypes and therefore do not provide reliable models to entirely understand the molecular and cellular mechanisms responsible for these disorders. Hence, we combine the in vivo mouse model and the human brain organoids in order to better comprehend the mechanisms involved in the migration of neurons during human development and tackle the causes of neurodevelopmental disorders. Our results show that we can model human brain development and disorders using human brain organoids and contribute to open new avenues to bridge the gap of knowledge between human brain malformations and existing animal models.