FMRP activity and control of Csw/SHP2 translation regulate MAPK-dependent synaptic transmission

Abstract

Noonan syndrome (NS) and NS with multiple lentigines (NSML) cognitive dysfunction are linked to SH2 domain-containing protein tyrosine phosphatase-2 (SHP2) gain-of-function (GoF) and loss-of-function (LoF), respectively. In Drosophila disease models, we find both SHP2 mutations from human patients and corkscrew (csw) homolog LoF/GoF elevate glutamatergic transmission. Cell-targeted RNAi and neurotransmitter release analyses reveal a presynaptic requirement. Consistently, all mutants exhibit reduced synaptic depression during high-frequency stimulation. Both LoF and GoF mutants also show impaired synaptic plasticity, including reduced facilitation, augmentation, and post-tetanic potentiation. NS/NSML diseases are characterized by elevated MAPK/ERK signaling, and drugs suppressing this signaling restore normal neurotransmission in mutants. Fragile X syndrome (FXS) is likewise characterized by elevated MAPK/ERK signaling. Fragile X Mental Retardation Protein (FMRP) binds csw mRNA and neuronal Csw protein is elevated in Drosophila fragile X mental retardation 1 (dfmr1) nulls. Moreover, phosphorylated ERK (pERK) is increased in dfmr1 and csw null presynaptic boutons. We find presynaptic pERK activation in response to stimulation is reduced in dfmr1 and csw nulls. Trans-heterozygous csw/+; dfmr1/+ recapitulate elevated presynaptic pERK activation and function, showing FMRP and Csw/SHP2 act within the same signaling pathway. Thus, a FMRP and SHP2 MAPK/ERK regulative mechanism controls basal and activity-dependent neurotransmission strength.

An incomplete LEOPARD syndrome presented with generalized lentigines

“…1 This variant of LS is associated with loss of function of SHP-2 but ultimately leads to activation of the RAS-MAPK pathway. 3 Although our patients barely met the minimum criteria for LS suggested by Voron et al 2 (multiple lentigines plus two other cardinal features, or three other features and an affected immediate relative), the final diagnosis of LS was confirmed through genetic testing.…”

Muscle cofilin alters neuromuscular junction postsynaptic development to strengthen functional neurotransmission

“…GluRIIA-containing receptors mediate the strength of the muscle postsynaptic response, with reduced GluRIIA selectively impairing NMJ neurotransmission strength (DiAntonio et al, 1999; Petersen et al, 1997). To examine neurotransmission in DmCFL KD muscle, we used two-electrode voltage-clamp (TEVC) recordings to measure glutamate release and GluR activation (Leahy et al, 2023). The motor neuron was stimulated at suprathreshold voltages with a glass suction electrode at 0.2 Hz, and 10 consecutive evoked excitatory junction (EJC) traces were recorded (Fig.…”

“…TEVC recordings were done on dissected wandering third instars as previously reported (Leahy et al, 2023). Briefly, all recording were done at 18°C in physiological saline (in mM): 128 NaCl, 2 KCl, 4 MgCl2, 1.0 CaCl2, 70 sucrose, and 5 HEPES (pH 7.2).…”