Abstract
The FE65 adaptor proteins (FE65, FE65L1 and FE65L2) bind proteins that function in diverse cellular pathways and are essential for specific biological processes. Mice lacking both FE65 and FE65L1 exhibit ectopic neuronal positioning in the cortex and muscle weakness. p97FE65-KO mice, expressing a shorter FE65 isoform able to bind amyloid precursor protein family members (APP, APLP1, APLP2), develop defective long-term potentiation (LTP) and aged mice display spatial learning and memory deficits that are absent from young mice. Here, we examined the central and peripheral nervous systems of FE65-KO, FE65L1-KO and FE65/FE65L1-DKO mice. We find spatial learning and memory deficits in FE65-KO and FE65L1-KO mice. Severe motor impairments, anxiety, hippocampal LTP deficits and neuromuscular junction (NMJ) abnormalities, characterized by decreased size and reduced apposition of pre- and postsynaptic sites, are observed in FE65/FE65L1-DKO mice. As their NMJ deficits resemble those of mutant APP/APLP2-DKO mice lacking the FE65/FE65L1 binding site, the NMJs of APLP2/FE65-DKO and APLP2/FE65L1-DKO mice were analyzed. NMJ deficits are aggravated in these mice when compared to single FE65- and FE65L1-KO mice. Together, our data demonstrate a role for FE65 proteins at central and peripheral synapses possibly occurring downstream of cell surface-associated APP/APLPs.
Highlights
The FE65 protein family members, FE65 and FE65 like proteins (FE65L1, FE65L2) are scaffolding proteins containing two PTB domains and a WW domain that mediate complex formation with a diverse set of proteins[1]
These behavioral studies initially included 12 FE65/FE65L1-double knockout (DKO) mice, but we found that two mice had developed unilateral eye lens opacity shortly after performing the behavioral tests
To determine whether a similar genetic interaction can be found between Amyloid Precursor Protein (APP) and FE65 protein family members, we examined the NMJ morphologies in 8-month old FE65/APLP2- (Fig. 5a–d) and FE65L1/APLP2-DKO (Fig. 5e–h) mice
Summary
The FE65 protein family members, FE65 and FE65 like proteins (FE65L1, FE65L2) are scaffolding proteins containing two PTB domains and a WW domain that mediate complex formation with a diverse set of proteins[1]. The p97FE65-KO mice display early-phase long-term potentiation (LTP) deficits elicited in vivo by a single 100 Hz train[15]. These data indicate that the p97 isoform of FE65 plays only a minor role in spatial memory formation and may be involved in short-term plasticity. We report severe deficits in motor and cognitive behaviors in mice lacking FE65 protein family members. These are associated with neuromuscular junction abnormalities and altered LTP, respectively. Establishing FE65 family proteins as essential synaptic components in mice
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