Critical periods in neuronal differentiation
We found that human cortical neurons exhibit substantial epigenetic change during differentiation and that this process is disrupted in Tuberous Sclerosis Complex (TSC). Neurons from TSC patient induced pluripotent stem cells display downregulation of the demethylation enzymes TET1 and TET2, and they show they show impaired activity-dependent transcription of EGR1. mTOR is the main signaling molecule disrupted in TSC, and mTOR inhibition later in differentiation is incapable of reversing these processes. Therefore, we are interested in the interplay between demethylation and EGR1 to understand this critical window of neuronal development and how it applies to TSC. Furthermore, we are exploring the relevance of this mechanism to other genetic disorders.
Non-cell autonomous effects in brain malformations
Brain lesions in TSC are known as cortical tubers, and they are a type of brain malformation known as a type II focal cortical dysplasia (FCD). While patients with TSC are heterozygous for variants in TSC1 or TSC2, most manifestations are caused by second hit variants in either gene. We found that second hit variants in TSC2 during the neuroprogenitor stage can alter the differentiation of surrounding heterozygous cells through secreted factors. Furthermore, these abnormal heterozygous neurons display changes that are observed in FCDs. We are investigating the pathways that are perturbed in these surrounding neurons to understand whether they might be novel targets for epilepsy associated with TSC.