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Cell Reports, Volume 42, Issue 1, 31 January 2023 | https://doi.org/10.1016/j.celrep.2023.112003 Reversibility and developmental neuropathology of linear nevus sebaceous syndrome caused by dysregulation of the RAS pathway

Ye Eun Kim ^1,7, Yong-Seok Kim^2,3,7, Hee-Eun Lee¹, Ki Hurn So ¹, Youngshik Choe ², Byung-Chang Suh³, Joung-Hun Kim ¹, Sang Ki Park ¹, Gary W. Mathern ^4,5, Joseph G. Gleeson ⁶, Jong-Cheol Rah^2,3, Seung Tae Baek ^1,8

¹Department of Life Sciences, Pohang University of Science and Technology (POSTECH), 7 Cheongam-Ro, Nam-Gu, Pohang 37673, Republic of Korea
²Korea Brain Research Institute (KBRI), 61 Choemdan-Ro, Dong-Gu, Daegu 41062, Republic of Korea
³Department of Brain Sciences, Daegu Gyeongbuk Institute of Science and Technology (DGIST), Daegu 42988, Republic of Korea
⁴Department of Neurosurgery, Mattel Children’s Hospital, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA
⁵Department of Psychiatry and Biobehavioral Sciences, Mattel Children’s Hospital, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA
⁶Department of Neurosciences, University of California, San Diego (UCSD), La Jolla, CA, USA
⁷These authors contributed equally.
⁸Lead contact

Corresponding authors: Jong-Cheol Rah, Seung Tae Baek

Abstract

Linear nevus sebaceous syndrome (LNSS) is a neurocutaneous disorder caused by somatic gain-of-function mutations in KRAS or HRAS. LNSS brains have neurodevelopmental defects, including cerebral defects and epilepsy; however, its pathological mechanism and potentials for treatment are largely unclear. We show that introduction of KRAS^G12V in the developing mouse cortex results in subcortical nodular heterotopia and enhanced excitability, recapitulating major pathological manifestations of LNSS. Moreover, we show that decreased firing frequency of inhibitory neurons without KRAS^G12V expression leads to disrupted excitation and inhibition balance. Transcriptional profiling after destabilization domain-mediated clearance of KRAS^G12V in human neural progenitors and differentiating neurons identifies reversible functional networks underlying LNSS. Neurons expressing KRAS^G12V show molecular changes associated with delayed neuronal maturation, most of which are restored by KRAS^G12V clearance. These findings provide insights into the molecular networks underlying the reversibility of some of the neuropathologies observed in LNSS caused by dysregulation of the RAS pathway.

논문정보

형식Research article
게재일2023년 01월 (BRIC 등록일 2023-02-07)
연구진국내(교신)+국외 연구진
분야 생명과학 > 신경생물학

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