Investigation of the molecular mechanisms of intellectual disability using human-brain organoids

Intellectual disability (ID) is a condition characterized by significant limitation in cognitive ability and adaptive behaviours with disease onset before adulthood. ID affects 1-2% of children worldwide resulting in a high social burden. Due to recent advances in high-throughput sequencing technology, genetic studies identified more than 2500 genes associated with ID, and autosomal-recessive ID counts more than 50 % of the genetic causes of ID. A significant portion of ID cases shows an anatomical abnormality in the brain such as microcephaly and lissencephaly, suggesting a neurodevelopmental origin of the disorder. However, little is known about the molecular mechanisms underlying ID, which limits possible interventions and therapeutics of the disease.
The goal of the project is to investigate the molecular mechanisms of ID using human-brain organoids. We have identified a group of ID-associated genes that encode proteins involved in RNA processing and modifications, and ID Patients with mutations in these genes have microcephaly.
In this project, the function of those genes on cortical development will be investigated with the following specific objectives.
Objective 1. To investigate the role of ID-associated genes in neural stem cell behaviour and neuronal migration and maturation in human forebrain organoids
Objective 2. To determine transcriptomic changes upon genetic insults using single-cell RNA sequencing and identify target RNAs
Objective 3. To identify the molecular mechanism of RNA processing involved in cortical development, and validate its functionality in cortical development
The student will obtain fundamental concepts of brain development including neural stem cell behaviour and neuronal maturation during human cortical development and neurodevelopmental disorders. Technically, the student will learn how to culture human stem cells and brain organoids and assess neural development using immunohistochemistry, imaging, and computational analyses. Also, the student will have opportunities to learn molecular biology for genetic manipulation of ID genes and a biochemical approach to understand the RNA process