Molecular network analysis of postnatal FMCD pathologic model

Abstract

Focal Malformations of Cortical Development (FMCDs) lead to critical postnatal pathologies including drug-resistant pediatric epilepsy. However, although developmental pathologies are well-known, the mechanisms associated with more severe postnatal symptoms of FMCD should be studied further for efficient treatment. Thus, we applied transcription profiling to investigate the molecular networks associated with postnatal pathologies of FMCD. We produced pluripotent stem cell (hiPSC)-derived neural cells (NC) with AKT3 p.E17K, a FMCD-causing genetic mutation, and performed RNA-seq using this cell line. From the sequencing data, we formed the molecular networks of differentially expressed genes (DEGs) by protein-protein interaction. Then we found 1) extracellular matrix (ECM)-associated network and 2) synaptic function-associated network. Interestingly, DEGs from ECM network were highly overlapped with the results of the developmental study, but DEGs from synaptic function network were not. This result suggests that there are stage-specific etiologies, and the synaptic function network might be associated with postnatal pathologies. We will identify the effects of postnatal stage-specific networks to various FMCD pathologies. Then we aim to find possible treatment for specific clinical symptoms. To figure out the results in vivo postnatal model, we also plan to perform transposon system-mediated in utero electroporation in developing cortex. The discovery of postnatal stage-specific mechanisms will provide new therapeutic strategies of FMCD as well as provide key insights to understand the neurodevelopmental disease.