| First Author | Ryu HH | Year | 2019 |
| Journal | Sci Signal | Volume | 12 |
| Issue | 571 | PubMed ID | 30837304 |
| Mgi Jnum | J:284319 | Mgi Id | MGI:6380798 |
| Doi | 10.1126/scisignal.aau5755 | Citation | Ryu HH, et al. (2019) Excitatory neuron-specific SHP2-ERK signaling network regulates synaptic plasticity and memory. Sci Signal 12(571) |
| abstractText | 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. |
