2024 BNA Scholars announced
15th March 2024
Background:
Loss of function mutations in chromatin modifier proteins are a prominent cause of neurodevelopmental disorders (NDDs). MBD5-associated neurodevelopmental disorder (MAND) is rare human NDD associated with intellectual disability (ID), motor deficits, seizures and autism1. MAND is caused by mutations in the MBD5 gene, the protein product of which associates with ASXL1,2 or 3 and BAP1 to form the polycomb repressive deubiquitinase (PR-DUB) complex. In mouse ES cells, PR-DUB has been shown to regulate gene expression by controlling global H2A ubiquitination levels2. Despite this mechanistic insight, and an expanding repertoire of causal MBD5 mutations; how mutations in MBD5 give rise to MAND phenotypes is currently unknown.
Rationale & hypothesis:
The formation of the human brain requires a balance between the expansion and differentiation of neural stem cells. This is coordinated, in part, by chromatin modifiers that control developmental gene expression programmes. We hypothesise that the gross developmental deficits associated with MBD5 mutations arise due to defective control of neural stem cell populations. To test this hypothesis, the student will establish and characterise cerebral organoids bearing MAND causal mutations.
Aims:
Use these complementary approaches in genomics3 and neurodevelopmental biology to advance our understanding of the molecular basis of MBD5-associated neurodevelopmental disorder.
Training outcomes: