Dysregulation of KRAS during cortical development leads to subcortical heterotopia and hyperexcitability
- Title
- Dysregulation of KRAS during cortical development leads to subcortical heterotopia and hyperexcitability
- Authors
- BAEK, SEUNG TAE; KIM, YEEUN; KIM, JOUNG HUN; RAH, JONG-CHEOL; KIM, YONGSEOK
- Date Issued
- 2020-11-16
- Publisher
- 한국뇌신경과학회
- 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.
- URI
- https://oasis.postech.ac.kr/handle/2014.oak/109785
- Article Type
- Conference
- Citation
- KSBNS 2020, 2020-11-16
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