The Michele Jacob Lab
The Jacob Lab studies focus on beta-catenin: an essential protein for typical nervous system development, maturation and function. It plays key roles in cadherin-based synaptic adhesion complexes and as a transcription co-factor in the Wnt signal transduction pathway. Beta-catenin is encoded by CTNNB1, a high significance risk gene for intellectual disability and autism.
We are currently investigating the neurodevelopmental disorder CTNNB1 syndrome, characterized by developmental delays (language, motor), intellectual disability, spasticity and autism. It is caused by sporadic loss-of-function pathogenic variants in one allele of CTNNB1. The core molecular pathology is insufficient levels of beta-catenin. We use preclinical Ctnnb1 germline heterozygote mice and human central nervous system (CNS) models derived from CTNNB1 syndrome patient pluripotent stem cells (iPSCs) harboring distinct mutations that span the gene. We are defining underlying molecular and functional pathophysiological changes. Most important, we have identified a potential efficacious therapeutic by showing a small molecule treatment normalizes the aberrant beta-catenin protein levels and associated behavioral changes (Alexander, et. al, EMBO Molec Med, 2024) and we are currently advancing our therapeutic studies to patient derived CNS cell models.
