The transformation of the embryonic forebrain neuroepithelium into the complex adult cerebrum depends on the timely division, migration and differentiation of neural stem cells.

At the Novarino group located at the Institute of Science and Technology Austria, we have a long-standing interest in understanding which factors determine the precise balance between neural stem cell proliferation/self-renewal and differentiation as well as how different types of neurons assemble to construct functionally diverse neuronal networks?

Genetic perturbations of neuro developmental conditions are extremely instructive about intrinsic and extrinsic factors that influence the precise sequences of events which lead to a functional human brain.

In particular we study Autism Spectrum Disorders (ASDs) which are a group of disorders characterized by defects in social interaction and communication skills accompanied by the presence of stereotypic or repetitive behaviors, affecting 1 in 68 children. The core symptoms of ASD are rarely isolated and often coexist with other conditions such as intellectual disability (ID) or epilepsy. ASD are considered neuro developmental disorders of connectivity and have a strong genetic basis, as demonstrated by the recurrent risk in families and twin studies.

Thanks to rapid technological and methodological advancements in genetics and genomics, the last decade has seen an unprecedented identification of mutations underlying ASDs. Specifically, functional genomic studies suggest that ASDs are associated with abnormal development of the cerebral cortex already from early to mid-fetal stages. The Novarino group has made significant contributions to the characterization of a number of ASD-related genes. We have observed that, in several cases, neural stem cell proliferation, differentiation or migration are critically affected.

We are now interested in employing in vivo and in vitro models to systematically assess how mutations in ASD genes affect neural lineage progression. Specifically, we will employ control and ASD-mutant, human embryonic stem cells (hESCs) to study if and how ASD-linked mutations affect neural stem cell progression in human cerebral organoids. In parallel, we will employ mouse models for a key ASD-risk gene to identify specific defects in neural stem cells and understand how these abnormalities contribute to the appearance of ASD-relevant phenotypes.