Format

Send to

Choose Destination
Sci Signal. 2019 Mar 5;12(571). pii: eaau5755. doi: 10.1126/scisignal.aau5755.

Excitatory neuron-specific SHP2-ERK signaling network regulates synaptic plasticity and memory.

Author information

1
Department of Physiology, Seoul National University College of Medicine, Seoul 03080, Korea.
2
Department of Life Science, Chung-Ang University, Seoul 06974, Korea.
3
School of Biological Sciences, College of Natural Sciences, Seoul National University, Seoul 08826, Korea.
4
Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, Korea.
5
Department of Pharmacology, Wonkwang University School of Medicine, Iksan 54538, Korea.
6
Neuroscience Research Institute, Seoul National University College of Medicine, Seoul 03080, Korea.
7
Department of Neurobiology, Integrative Center for Learning and Memory, Brain Research Institute, University of California Los Angeles, California, CA 90095, USA.
8
Department of Physiology, Seoul National University College of Medicine, Seoul 03080, Korea. yongseok7@snu.ac.kr.

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 SHP2D61G 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 SHP2D61G, selectively in excitatory neurons, reversed SHP2D61G-mediated deficits. Moreover, ectopic expression of GAB1 and GRB2 together with SHP2D61G 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.

PMID:
30837304
DOI:
10.1126/scisignal.aau5755

Supplemental Content

Full text links

Icon for HighWire
Loading ...
Support Center