Dysregulation of KRAS during cortical development leads to subcortical heterotopia and hyperexcitability

Abstract

RAS/MAPK pathway involves not only biological processes such as differentiation, proliferation, and migration but also many diseases such as cancer. RASopathies, which are a group of developmental disorder caused by mutation of RAS/MAPK pathway component, suggest crucial role of this pathway in normal development. Sebaceous nevus syndrome (SNS) is, one of the RASopathies, is caused by somatic gain-of-function mutation of HRAS or KRAS. The symptoms of SNS includes central-nervous system related defects such as cerebral defects, intellectual disability and epilepsy, however, the pathological mechanism are poorly understood. Here, we show that dysregulation of KRAS during cortical development leads to several pathological phenotype of SNS in mice. We generated SNS disease model in mouse by overexpression of KRAS p.G12V in developing cortex using in utero electroporation. Dysregulation of KRAS during cortical development led to abnormal neuronal differentiation, severe neuronal migration defects and heterotopia formation in the adult stage. Also, neuronal dysmorphogenesis was observed. However, BrdU labeling experiment showed that neuronal proliferation was not affected by dysregulation of KRAS, despite the oncogenic role of KRAS p.G12V in the other tissues. We also characterized neuronal activity in the disease model using whole cell path clamp in adult mice, and difference of neuronal activity was observed. These pathological phenotypes suggest the role of RAS/MAPK pathway in focal cortical dysplasia and severe epilepsy observed in the SNS patient with KRAS p.G12V. In the current study, we characterize transcriptomic changes using dox-inducible KRAS expressing hPSC-derived neuronal progenitor cells and neurons. Taken together, we will identify molecular mechanism underlying pathogenesis of SNS and suggest therapeutic strategies of SNS.