INVESTIGATING THE ROLE OF FEZ1 IN EARLY HUMAN BRAIN DEVELOPMENT USING CEREBRAL ORGANOIDS

Abstract

Perturbations in quantity and localization of multiple neuronal cells generated from progenitors during early cortical development contribute to neuropsychiatric disorders. Genetic interventions are known to cause these disorders but underlying mechanism remains unclear. Human FEZ1 gene is associated with a few mental diseases. In this thesis, we seek to determine function of FEZ1 during early brain development by human cerebral organoids model and loss of function study. Transcriptome analysis revealed genes associated with neuronal development and synaptic function were differentially expressed in FEZ1 knockout organoids, suggesting FEZ1 participated in early forebrain development. Differences in cell sub-population generation during cortical stratification were identified in FEZ1-null organoids when compared with wild type. In addition, subtle spatial-temporal changes were observed in early synaptogenesis within the FEZ1-null organoids. Thus, we uncover FEZ1’s importance during early forebrain development. These findings potentially contribute to the understanding of neural developmental pathologies and origins of neuropsychiatric disorders.