Dendritic trafficking of BDNF mRNA is mediated by translin and blocked by the G196A (Val66Met) mutation.
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.
Chiaruttini
C
C
BRAIN Centre for Neuroscience, Department of Life Sciences, and Dipartimento di Scienze Farmaceutiche, University of Trieste, 34127 Trieste, Italy.
Vicario
A
A
Li
Z
Z
Baj
G
G
Braiuca
P
P
Wu
Y
Y
Lee
F S
FS
Gardossi
L
L
Baraban
J M
JM
Tongiorgi
E
E
D017398:Alternative Splicing; D000818:Animals; D015153:Blotting, Western; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics* / Q000378:metabolism; D002451:Cell Compartmentation; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D003712:Dendrites / Q000378:metabolism*; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D017403:In Situ Hybridization; D051379:Mice; D008958:Models, Molecular; D020125:Mutation, Missense; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D011485:Protein Binding; D034622:RNA Interference; D034443:RNA Transport; D012333:RNA, Messenger / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction
D019208:Brain-Derived Neurotrophic Factor; D004268:DNA-Binding Proteins; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; C095563:TSN protein, human; C498303:Tsn protein, mouse; C498304:Tsn protein, rat; D049452:Green Fluorescent Proteins