Neurodevelopmental Disorders (NDD), including intellectual disability and autism spectrum disorder, are a common group of conditions, affecting up to 3% of the general population, with significant societal impact. Yet, the molecular and cellular mechanisms disrupting the tightly regulated orchestration of brain development and function remain unclear. The broad and dynamic complexity of human brain development has been a challenge in addressing these issues. More recent cell culture techniques have attempted to reproduce the three-dimensional complexity of brain development and have provided important insights into cytoarchitecture. However, the heterogeneity and limited reproducibility and scalability of these models has hampered the dissection of intricate molecular mechanisms underlying many NDDs and restricted the development of therapeutic strategies to address those. Bioengineering tools have enabled the development of on-chip models that biomimic targeted aspects of cell growth and morphology, thus allowing the intricate dissection of the underlying processes governing those.
In the present project, we propose the investigate an important group of proteins, the Chromatin remodeller complex BAF swi/snf, that regulates transcription at key timepoints and is involved in NDDs. Using microfabricated devices and on-chip modelling techniques developed in the Serio lab together with iPSC and stem cell lines generated within the Dias lab we will create an in vitro bioengineered model of neurodevelopmental niche, where we will be able to control the establishment, migration and differentiation of neural progenitors niches and systematically study the effects of BAF swi/snf complex mutations on these key phases of development using live imaging techniques.