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Aberrant ERK signaling in astrocytes impairs learning and memory in RASopathy-associated BRAF mutant mouse models

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dc.contributor.authorKang, Minkyung-
dc.contributor.authorChoi, Jihye-
dc.contributor.authorHan, Jeongho-
dc.contributor.authorAraki, Toshiyuki-
dc.contributor.authorKim, Soo-Whee-
dc.contributor.authorRyu, Hyun-Hee-
dc.contributor.authorKim, Min-Gyun-
dc.contributor.authorKim, Seoyeon-
dc.contributor.authorJang, Hanbyul-
dc.contributor.authorKim, Sun Yong-
dc.contributor.authorHwang, Kyoung-Doo-
dc.contributor.authorKim, Soobin-
dc.contributor.authorYoo, Myeongjong-
dc.contributor.authorLee, Jaegeon-
dc.contributor.authorKim, Kitae-
dc.contributor.authorPark, Pojeong-
dc.contributor.authorChoi, Ja Eun-
dc.contributor.authorHan, Dae Hee-
dc.contributor.authorKim, Yujin-
dc.contributor.authorKim, Jeongyeon-
dc.contributor.authorChang, Sunghoe-
dc.contributor.authorKaang, Bong-Kiun-
dc.contributor.authorKo, Jung Min-
dc.contributor.authorCheon, Keun-Ah-
dc.contributor.authorAn, Joon-Yong-
dc.contributor.authorKim, Sang Jeong-
dc.contributor.authorPark, Hyungju-
dc.contributor.authorNeel, Benjamin G.-
dc.contributor.authorKim, Chul Hoon-
dc.contributor.authorLee, Yong-Seok-
dc.date.accessioned2025-03-04T07:30:16Z-
dc.date.available2025-03-04T07:30:16Z-
dc.date.issued2025-02-
dc.identifier.issn0021-9738-
dc.identifier.issn1558-8238-
dc.identifier.urihttp://scholarworks.bwise.kr/kbri/handle/2023.sw.kbri/1246-
dc.description.abstractRAS/MAPK pathway mutations often induce RASopathies with overlapping features, such as craniofacial dysmorphology, cardiovascular defects, dermatologic abnormalities, and intellectual disabilities. Although BRAF gene mutations are associated with cardio-facio-cutaneous (CFC) syndrome and Noonan syndrome, it remains unclear how these mutations impair cognition. Here, we investigated the underlying neural mechanisms using several mouse models harboring a gain-of-function BRAF mutation (K499E) discovered in RASopathy patients. We found expressing BRAF K499E (KE) in neural stem cells under the control of a Nestin-Cre promoter (Nestin;BRAFKE/+) induced hippocampal memory deficits, but expressing it in excitatory or inhibitory neurons did not. BRAF KE expression in neural stem cells led to aberrant reactive astrogliosis, increased astrocytic Ca2+ fluctuations, and reduced hippocampal long-term depression (LTD) in mice. Consistently, 3D human cortical spheroids expressing BRAF KE also showed reactive astrogliosis. Astrocyte-specific AAV-BRAF KE delivery induced memory deficits, reactive astrogliosis, and increased astrocytic Ca2+ fluctuations. Notably, reducing ERK activity in astrocytes rescued the memory deficits and altered astrocytic Ca2+ activity of Nestin;BRAFKE/+ mice. Furthermore, reducing astrocyte Ca2+ activity rescued the spatial memory impairments of BRAF KE-expressing mice. Our results demonstrate that ERK hyperactivity contributes to astrocyte dysfunction associated with Ca2+ dysregulation, leading to the memory deficits of BRAF-associated RASopathies.-
dc.language영어-
dc.language.isoENG-
dc.publisherAmerican Society for Clinical Investigation-
dc.titleAberrant ERK signaling in astrocytes impairs learning and memory in RASopathy-associated BRAF mutant mouse models-
dc.typeArticle-
dc.publisher.location미국-
dc.identifier.doi10.1172/jci176631-
dc.identifier.bibliographicCitationJournal of Clinical Investigation-
dc.citation.titleJournal of Clinical Investigation-
dc.description.isOpenAccessN-
dc.description.journalRegisteredClassscie-
dc.description.journalRegisteredClassscopus-
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