Fragile X Related Protein 1 Clusters with Ribosomes and Messenger RNAs at a Subset of Dendritic Spines in the Mouse Hippocampus

Abstract

The formation and storage of memories in neuronal networks relies on new protein synthesis, which can occur locally at synapses using translational machinery present in dendrites and at spines. These new proteins support long-lasting changes in synapse strength and size in response to high levels of synaptic activity. To ensure that proteins are made at the appropriate time and location to enable these synaptic changes, messenger RNA (mRNA) translation is tightly controlled by dendritic RNA-binding proteins. Fragile X Related Protein 1 (FXR1P) is an RNA-binding protein with high homology to Fragile X Mental Retardation Protein (FMRP) and is known to repress and activate mRNA translation in non-neuronal cells. However, unlike FMRP, very little is known about the role of FXR1P in the central nervous system. To understand if FXR1P is positioned to regulate local mRNA translation in dendrites and at synapses, we investigated the expression and targeting of FXR1P in developing hippocampal neurons in vivo and in vitro. We found that FXR1P was highly expressed during hippocampal development and co-localized with ribosomes and mRNAs in the dendrite and at a subset of spines in mouse hippocampal neurons. Our data indicate that FXR1P is properly positioned to control local protein synthesis in the dendrite and at synapses in the central nervous system.

FXR1P is a GSK3β substrate regulating mood and emotion processing

“…Furthermore, histological examination confirmed the presence of recombinant GFP-FXR1P in the cell body and MAP2-positive dendrites of infected cortical neurons (Fig. 5C), thus confirming that the subcellular distribution of GFP-FXR1P corresponds to that of endogenous FXR1P (41). Finally, overexpression of GFP-FXR1P in prelymbic prefrontal cortex neurons replicated the behavioral effects of GSK3β deletion and VAL 10 treatment in the DLET (Fig.…”

“…A study of hippocampal neurons has shown an association of FXR1P with neuronal polyribosomes in dendritic clusters (41). Furthermore, FXR1P has been recently identified as a negative regulator for the translation of the ionotopic-glutamate AMPA receptor subunit GluA2.…”

Modeling fragile X syndrome in the <i>Fmr1</i> knockout mouse

“…FMRP is an RNA-binding protein that is enriched in neurons, particularly in the cell body, dendrites and postsynaptic spines (14,28,53,54). Dendritic spines, small protrusions along neuronal dendrites, are sites of excitatory synaptic input, which contain receptors and signaling molecules that are essential for synaptic neurotransmission (55).…”

FXR1P Limits Long-Term Memory, Long-Lasting Synaptic Potentiation, and De Novo GluA2 Translation

“…While FXR1P can regulate protein synthesis in non-neuronal cells (Garnon et al, 2005; Vasudevan and Steitz, 2007), its role in mRNA translation and synaptic plasticity in neurons is unknown, largely related to the fact that complete loss of FXR1P in mice results in perinatal lethality (Mientjes et al, 2004). Our recent discovery that FXR1P co-localizes with translation machinery in dendrites and near a subset of dendritic spines (Cook et al, 2011) prompted us to investigate its function in brain development, plasticity and synaptic protein expression and to compare its role to FXR2P and FMRP.…”