Autism spectrum disorder (ASD) is a neurodevelopmental disorder whose underlying genetic basis has started to be revealed through the use of advanced genetic tools. Animal and human stem-cell-based studies have largely focused on the cerebral cortex because of its essential higher cognitive function. However, recent studies based on human brain imaging studies have revealed that individuals with ASD also display abnormal microstructures in the thalamus and alterations in thalamocortical connectivity. Despite its importance in higher cognitive functions, including emotion, cognition and attention, how thalamic development and thalamocortical connectivity are regulated by ASD genes is unclear.
In-Hyun Park’s laboratory recently developed regionally defined human brain organoids from human embryonic stem cells that reproduce the developing human cortex (human cortical organoids; hCO)1 and thalamus2 (human thalamic organoids; hThO). Further, fusion of hCO and hThO recapitulates the reciprocal thalamocortical and corticothalamic connections2. Using these innovative tools, Park has begun to address how ASD genes are involved in human cortical and thalamic development, and in corticothalamic connectivity.
In this proposal, Park and colleagues will investigate the function of DEAF1 in corticothalamic development and connectivity. DEAF1 is a transcriptional regulator that is highly enriched in hCO and hThO neurons. Mutations in DEAF1 have been repeatedly reported in ASD and intellectual disability, emphasizing the importance of investigating its role in brain development. Using human brain organoids, genomics tools and neurophysiological approaches, Park’s team will identify the molecular regulatory pathways by which DEAF1 regulates corticothalamic development and connectivity, thereby laying a molecular foundation to further our understanding of how thalamocortical function and connectivity becomes compromised in ASD.