Excitatory neuron-specific SHP2-ERK signaling network regulates synaptic plasticity and memory
- Authors
- Ryu, Hyun-Hee; Kim, TaeHyun; Kim, Jung-Woong; Kang, Minkyung; Park, Pojeong; Kim, Yong Gyu; Kim, Hyopil; Ha, Jiyeon; Choi, Ja Eun; Lee, Jisu; Lim, Chae-Seok; Kim, Chul-Hong; Kim, Sang Jeong; Silva, Alcino J.; Kaang, Bong-Kiun; Lee, Yong-Seok
- Issue Date
- Mar-2019
- Publisher
- AMER ASSOC ADVANCEMENT SCIENCE
- Citation
- SCIENCE SIGNALING, v.12, no.571
- Journal Title
- SCIENCE SIGNALING
- Volume
- 12
- Number
- 571
- URI
- https://scholarworks.bwise.kr/cau/handle/2019.sw.cau/18123
- DOI
- 10.1126/scisignal.aau5755
- ISSN
- 1945-0877
1937-9145
- Abstract
- Mutations in RAS signaling pathway components cause diverse neurodevelopmental disorders, collectively called RASopathies. Previous studies have suggested that dysregulation in RAS-extracellular signal-regulated kinase (ERK) activation is restricted to distinct cell types in different RASopathies. Some cases of Noonan syndrome (NS) are associated with gain-of-function mutations in the phosphatase SHP2 (encoded by PTPN11); however, SHP2 is abundant in multiple cell types, so it is unclear which cell type(s) contribute to NS phenotypes. Here, we found that expressing the NS-associated mutant SHP2(D61G) in excitatory, but not inhibitory, hippocampal neurons increased ERK signaling and impaired both long-term potentiation (LTP) and spatial memory in mice, although endogenous SHP2 was expressed in both neuronal types. Transcriptomic analyses revealed that the genes encoding SHP2-interacting proteins that are critical for ERK activation, such as GAB1 and GRB2, were enriched in excitatory neurons. Accordingly, expressing a dominant-negative mutant of GAB1, which reduced its interaction with SHP2(D61G), selectively in excitatory neurons, reversed SHP2(D61G)-mediated deficits. Moreover, ectopic expression of GAB1 and GRB2 together with SHP2(D61G) in inhibitory neurons resulted in ERK activation. These results demonstrate that RAS-ERK signaling networks are notably different between excitatory and inhibitory neurons, accounting for the cell type-specific pathophysiology of NS and perhaps other RASopathies.
- Files in This Item
- There are no files associated with this item.
- Appears in
Collections - College of Natural Sciences > Department of Life Science > 1. Journal Articles
![qrcode](https://api.qrserver.com/v1/create-qr-code/?size=55x55&data=https://scholarworks.bwise.kr/cau/handle/2019.sw.cau/18123)
Items in ScholarWorks are protected by copyright, with all rights reserved, unless otherwise indicated.