title: Genetic and acute CPEB1 depletion ameliorate fragile X pathophysiology.
abstract: Fragile X syndrome (FXS), the most common cause of inherited mental retardation and autism, is caused by transcriptional silencing of FMR1, which encodes the translational repressor fragile X mental retardation protein (FMRP). FMRP and cytoplasmic polyadenylation element-binding protein (CPEB), an activator of translation, are present in neuronal dendrites, are predicted to bind many of the same mRNAs and may mediate a translational homeostasis that, when imbalanced, results in FXS. Consistent with this possibility, Fmr1(-/y); Cpeb1(-/-) double-knockout mice displayed amelioration of biochemical, morphological, electrophysiological and behavioral phenotypes associated with FXS. Acute depletion of CPEB1 in the hippocampus of adult Fmr1(-/y) mice rescued working memory deficits, demonstrating reversal of this FXS phenotype. Finally, we find that FMRP and CPEB1 balance translation at the level of polypeptide elongation. Our results suggest that disruption of translational homeostasis is causal for FXS and that the maintenance of this homeostasis by FMRP and CPEB1 is necessary for normal neurologic function.
authors.affiliation: 1] Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA. [2] [3].
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Udagawa
authors.forename: Natalie G
authors.initials: NG
authors.lastname: Farny
authors.forename: Mira
authors.initials: M
authors.lastname: Jakovcevski
authors.forename: Hanoch
authors.initials: H
authors.lastname: Kaphzan
authors.forename: Juan Marcos
authors.initials: JM
authors.lastname: Alarcon
authors.forename: Shobha
authors.initials: S
authors.lastname: Anilkumar
authors.forename: Maria
authors.initials: M
authors.lastname: Ivshina
authors.forename: Jessica A
authors.initials: JA
authors.lastname: Hurt
authors.forename: Kentaro
authors.initials: K
authors.lastname: Nagaoka
authors.forename: Vijayalaxmi C
authors.initials: VC
authors.lastname: Nalavadi
authors.forename: Lori J
authors.initials: LJ
authors.lastname: Lorenz
authors.forename: Gary J
authors.initials: GJ
authors.lastname: Bassell
authors.forename: Schahram
authors.initials: S
authors.lastname: Akbarian
authors.forename: Sumantra
authors.initials: S
authors.lastname: Chattarji
authors.forename: Eric
authors.initials: E
authors.lastname: Klann
authors.forename: Joel D
authors.initials: JD
authors.lastname: Richter
mesh_terms: D020413:3' Untranslated Regions; D000818:Animals; D004195:Disease Models, Animal; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics* / Q000502:physiology*; D005600:Fragile X Syndrome / Q000235:genetics* / Q000503:physiopathology* / Q000523:psychology; D006624:Hippocampus / Q000503:physiopathology; D006801:Humans; D008297:Male; D008570:Memory, Short-Term / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology*; D039221:mRNA Cleavage and Polyadenylation Factors / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology*
chemical_list: D020413:3' Untranslated Regions; D051860:Fragile X Messenger Ribonucleoprotein 1; D012333:RNA, Messenger; D014157:Transcription Factors; D039221:mRNA Cleavage and Polyadenylation Factors; C490386:CPEB1 protein, human; C490387:Cpeb1 protein, mouse; C497683:FMR1 protein, human; C497684:Fmr1 protein, mouse