Dendritic trafficking of BDNF mRNA is mediated by translin and blocked by the G196A (Val66Met) mutation

Abstract

Alternatively spliced brain-derived neurotrophic factor (BDNF) transcripts are targeted to distinct cellular compartments in neurons but the mechanisms underlying this sorting are unknown. Although only some BDNF isoforms are targeted to dendrites, we have found that the coding region common to all BDNF transcripts contains a constitutively active dendritic targeting signal and that this signal is suppressed in transcripts containing exons 1 or 4, which are restricted to the cell soma and proximal dendrites. This dendritic targeting signal is mediated by translin, an RNA-binding protein implicated in RNA trafficking, and is disrupted by the G196A mutation associated with memory deficits and psychiatric disorders. Molecular modeling and mutational studies indicate that the G196A mutation blocks dendritic targeting of BDNF mRNA by disrupting its interaction with translin. These findings implicate abnormal dendritic trafficking of BDNF mRNA in the pathophysiology of neuropsychiatric disorders linked to the G196A mutation.neuropsychiatric disorders ͉ neurotrophins S everal lines of evidence indicate that targeting of BDNF mRNA to dendrites plays a key role in mediating synaptic plasticity (1-4). However, the molecular mechanisms regulating this process and the differential subcellular localization of alternatively spliced BDNF transcripts, remain to be clarified.Multiple BDNF transcripts are generated by alternative splicing of one 5Ј exon with a shared 3Ј exon containing the entire BDNF coding region and either a short or long 3Ј UTR sequence (5, 6). In recent studies, we have demonstrated that BDNF transcripts differ in their subcellular localization (7). Exon 1 and 4 transcripts are localized in the cell soma, while exon 2 and 6 transcripts show a somato-dendritic localization. Thus, splice variants appear to encode spatial localization signals used to preferentially regulate BDNF expression in different subcellular domains (2, 3). A recent study has suggested that the long 3Ј UTR contains signals necessary for dendritic targeting of BDNF transcripts (4). However, it is unlikely that this mechanism can fully account for the differential dendritic targeting displayed by BDNF transcripts because more than one-third of exon 4 transcripts, which are retained in the soma, contain the long 3Ј UTR. Conversely, more than one-half of exon 6 transcripts, an isoform that displays targeting to dendrites, contain the short 3Ј UTR. To help define the mechanisms underlying differential localization of BDNF transcripts, we have tested the hypothesis that additional signals might be encoded by other BDNF mRNA regions.

BDNF-induced local protein synthesis and synaptic plasticity

“…The CPE-like elements are apparently required for both constitutive and activity-dependent localization of the transcript in dendrites (Oe and Yoneda, 2010). In separated studies, the destination of BDNF mRNA was, ultimately, ruled by the presence of 5 0 UTR exons (Baj et al, 2011;Chiaruttini et al, 2009). The selective localization of several 5 0 UTR splice variants in dendrites was coupled to local TrkB activation and differentially modulates dendritic complexity (Baj et al, 2011).…”

“…The cis-acting elements on the mRNAs (also called zipcodes or localization elements) can vary in length and in spatial arrangement and, with few exceptions, are contained in the 3 0 -untranslated region (UTR) (Andreassi and Riccio, 2009). Nevertheless, the presence of localization elements in the 5 0 UTR and in the coding sequence has also been reported (Chiaruttini et al, 2009;Pal et al, 2003). One of the shortest, well described, zipcodes was found in MBP mRNA and is only 11-nucleotides long (Munro et al, 1999).…”

“…This process most likely requires additional and at the moment unknown factors. Translin binds to the coding sequence of BDNF mRNA regulating both constitutive and activity-induced transport of the transcript to dendrites (Chiaruttini et al, 2009). It was further demonstrated that, depending on the stimuli, translin may be required or not for BDNF mRNA trafficking (Wu et al, 2011).…”

“…The short 3 0 UTR-carrying mRNAs apparently are restricted to the soma whereas the long 3 0 UTRcontaining mRNAs are also found in dendrites . Nevertheless, BDNF constructs carrying a short 3 0 UTR were shown to be targeted to dendrites in cultured hippocampal neurons (Baj et al, 2011;Chiaruttini et al, 2009;Oe and Yoneda, 2010). The short 3 0 UTR-mediated dendritic targeting of the transcript may rely on the presence of cytoplasmic polyadenylation element (CPE)e like motifs in its sequence (Oe and Yoneda, 2010).…”

BDNF Val66Met Impairs Fluoxetine-Induced Enhancement of Adult Hippocampus Plasticity

“…This SNP leads to a nucleotide change from G to A at position 196 and subsequent amino acid change at position 66 in the BDNF prodomain, from valine to methionine, and interferes with the trafficking of BDNF mRNA (Chiaruttini et al, 2009), as well as a selective impairment in the activitydependent release of BDNF (Egan et al, 2003;Chen et al, 2004Chen et al, , 2005Chen et al, , 2006. Human carriers of this SNP have impairments in hippocampus-dependent memories and the extinction of learned fear (Egan et al, 2003;Soliman et al, 2010).…”