Translational Control of Synaptic Plasticity and Memory - Biophysical Approaches to Translational Control of Gene Expression - page 294

Additionally, activity-dependent synaptic spine maturation and dendritic BDNF
expression has been shown to depend on mGluR-mediated phosphorylation of eEF2
by eEFK (Verpelli et al. 2010 ) .

14.7 FMRP

Fragile X syndrome (FXS) is the most frequent form of single-gene inherited men-
tal retardation and many cases manifest as ASDs (Levenga et al. 2010 ) . In humans,
the FMR1 gene codes for the FMRP, a transcript-specific RNA-binding protein
whose action is generally believed to repress translation (Hinds et al. 1993 ) . Various
mutations causing loss of FMRP expression result in FXS. FMRP is highly expressed
in the mammalian brain (Hinds et al. 1993 ). Moreover, FMRP is localized to neu-
ronal dendrites and dendritic spines. The RNA binding activity of FMRP is thought
to be mediated through three domains: two hnRNP-K-homology (KH) domains and
an RGG box (arginine-glycine-glycine) domain. FMRP selectively binds approxi-
mately 4% of mammalian mRNAs and is believed to help regulate their function
(Hinds et al. 1993 ). In several studies, it has been clearly shown that FMRP associ-
ates with actively translating polyribosomes in neuronal and non-neuronal cells and
in brain synaptoneurosomes (Feng et al. 1997b ). This association is mediated by the
KH domains of FMRP. Interestingly, a missense mutation in the second KH domain
has been reported in a rare FXS patient (Feng et al. 1997a ) . Phosphorylated FMRP
associates with stalled ribosomes, whereas nonphosphorylated FMRP cosediments
with actively translating ribosomes (Ceman et al. 2003 ) . FMRP phosphorylation is
regulated by S6K1 (Narayanan et al. 2008 ) which phosphorylates FMRP on a con-
served serine residue that is required for mRNA binding.
A recent high-throughput study demonstrated that FMRP interacts with the cod-
ing region of pre- and post-synaptic transcripts, as well as ASD-associated tran-
scripts (Darnell et al. 2011 ). The mechanism proposed for FMRP's translational
repression of bound transcripts is via the stalling of ribosomal translocation on these
target mRNAs (Darnell et al. 2011 ). Another model suggests that FMRP represses
translation through its interaction with BC1 (a neuronal RNA) (Zalfa et al. 2003 ) .
BC1 binding to FMRP can lead to increased binding to its target mRNAs or to the
inhibition of eIF4A, thus favoring the repression of translation initiation on mRNAs
with structured 5¢ UTRs (Wang et al. 2002 ; Lin et al. 2008 ) . However, the FMRP-BC1
interaction is contentious since several studies have failed to recapitulate this finding
(Bagni 2008 ; Iacoangeli et al. 2008 ). Recently, it was also shown that FMRP inter-
acts with Cytoplasmic FMRP Interacting Protein 1 (CYFIP1), which is an eIF4E-
binding protein that competes for eIF4E binding with eIF4G (Napoli et al. 2008 ) .
Unlike the 4E-BPs, CYFIP1 does not bind to eIF4E through the canonical eIF4E-
binding site.
FMR1 KO animals have provided invaluable insight into the molecular pathways
associated with FMRP in the brain. A salient feature of FXS patients is the increased
occurrence of dendritic spines with a long, thin morphology (immature spines)