Biochemical evidence for the association of fragile X mental retardation protein with brain polyribosomal ribonucleoparticles

Khandjian, Édouard W.; Huot, Marc‐Étienne; Tremblay, Sarah; Davidovic, Laetitia; Mazrouï, Rachid; Bardoni, Barbara

doi:10.1073/pnas.0405398101

Cited by 157 publications

(154 citation statements)

References 62 publications

Supporting

Mentioning

138

Contrasting

Unclassified

Order By: Relevance

“…Consensus has developed over recent years that FMRP is, like BC1 RNA, a translational repressor that is active in postsynaptic microdomains (7,9,10). However, in contrast to BC1 RNA, FMRP is associated with polysomes (11)(12)(13)(14)(15), indicating that BC1 RNA and FMRP operate at different levels in the translation pathway.…”

mentioning

confidence: 99%

On BC1 RNA and the fragile X mental retardation protein

Iacoangeli¹,

Rozhdestvensky

Dolzhanskaya

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

The fragile X mental retardation protein (FMRP), the functional absence of which causes fragile X syndrome, is an RNA-binding protein that has been implicated in the regulation of local protein synthesis at the synapse. The mechanism of FMRP's interaction with its target mRNAs, however, has remained controversial. In one model, it has been proposed that BC1 RNA, a small nonprotein-coding RNA that localizes to synaptodendritic domains, operates as a requisite adaptor by specifically binding to both FMRP and, via direct base-pairing, to FMRP target mRNAs. Other models posit that FMRP interacts with its target mRNAs directly, i.e., in a BC1-independent manner. Here five laboratories independently set out to test the BC1-FMRP model. We report that specific BC1-FMRP interactions could be documented neither in vitro nor in vivo. Interactions between BC1 RNA and FMRP target mRNAs were determined to be of a nonspecific nature. Significantly, the association of FMRP with bona fide target mRNAs was independent of the presence of BC1 RNA in vivo. The combined experimental evidence is discordant with a proposed scenario in which BC1 RNA acts as a bridge between FMRP and its target mRNAs and rather supports a model in which BC1 RNA and FMRP are translational repressors that operate independently.fragile X syndrome ͉ non-protein-coding RNAs ͉ translational control S mall non-protein-coding RNAs perform important functions in the regulation of eukaryotic gene expression (1). In the mammalian central nervous system, they have been implicated in promoting organism-environment interactions (2). Small untranslated BC1 RNA is a translational repressor that is thought to participate in the regulation of local protein synthesis at the synapse (2, 3). BC1 RNA represses translation by targeting assembly of 48S initiation complexes (4). Interacting with eukaryotic initiation factor 4A (eIF4A) and poly(A) binding protein (PABP) (4-6), BC1 RNA prevents recruitment of the 43S preinitiation complex to the mRNA. Targets of BC1-mediated repression are those mRNAs that depend on the eIF4 family of factors for efficient initiation (4).Fragile X syndrome is caused by the functional absence of fragile X mental retardation protein (FMRP) (7,8). Consensus has developed over recent years that FMRP is, like BC1 RNA, a translational repressor that is active in postsynaptic microdomains (7, 9, 10). However, in contrast to BC1 RNA, FMRP is associated with polysomes (11-15), indicating that BC1 RNA and FMRP operate at different levels in the translation pathway.In an alternative model, it has been proposed that BC1 RNA and FMRP interact directly with each other (16,17). In this scenario, BC1 RNA (i) physically binds to FMRP, (ii) directly interacts, by base-pairing of its 5Ј domain, with select mRNAs that are FMRP targets, and (iii) acts as a bridge between FMRP and such target mRNAs, thus serving as a requisite adaptor (16, 17).The above two models cannot be reconciled. We, five independent groups with a longstanding interest in the molecular biology of...

show abstract

mentioning

confidence: 99%

On BC1 RNA and the fragile X mental retardation protein

Iacoangeli¹,

Rozhdestvensky

Dolzhanskaya

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

show abstract

“…The lack of FMRP results in delayed dendritic spine maturation in fragile X patients as well as in Fmr1 knockout (KO) mice (4)(5)(6)(7)(8), indicating the essential role of FMRP in synapse development. Furthermore, the association of FMRP with translating polyribosomes (9)(10)(11)(12) and micro-RNA machinery (13) suggests that FMRP governs translation efficiency of its mRNA targets, which in turn modulates synaptic development and plasticity.…”

mentioning

confidence: 99%

The fragile X protein controls microtubule-associated protein 1B translation and microtubule stability in brain neuron development

Wang

Liang

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

284

266

View full text Add to dashboard Cite

The fragile X mental retardation protein (FMRP) is a selective RNA-binding protein implicated in regulating translation of its mRNA ligands. The absence of FMRP results in fragile X syndrome, one of the leading causes of inherited mental retardation. Delayed dendritic spine maturation was found in fragile X mental retardation patients as well as in Fmr1 knockout (KO) mice, indicating the functional requirement of FMRP in synaptic development. However, the biochemical link between FMRP deficiency and the neuronal impairment during brain development has not been defined. How FMRP governs normal synapse development in the brain remains elusive. We report here that the developmentally programmed FMRP expression represses the translation of microtubule associated protein 1B (MAP1B) and is required for the accelerated decline of MAP1B during active synaptogenesis in neonatal brain development. The lack of FMRP results in misregulated MAP1B translation and delayed MAP1B decline in the Fmr1 KO brain. Furthermore, the aberrantly elevated MAP1B protein expression leads to abnormally increased microtubule stability in Fmr1 KO neurons. Together, these results indicate that FMRP plays critical roles in controlling cytoskeleton organization during neuronal development, and the abnormal microtubule dynamics is a conceivable underlying factor for the pathogenesis of fragile X mental retardation.T he absence of fragile X mental retardation protein (FMRP), a messenger ribonucleoprotein (mRNP) associated with a subclass of brain mRNAs, results in fragile X mental retardation, affecting 1 in 4,000 males and 1 in 8,000 females (1-3). The lack of FMRP results in delayed dendritic spine maturation in fragile X patients as well as in Fmr1 knockout (KO) mice (4-8), indicating the essential role of FMRP in synapse development. Furthermore, the association of FMRP with translating polyribosomes (9-12) and micro-RNA machinery (13) suggests that FMRP governs translation efficiency of its mRNA targets, which in turn modulates synaptic development and plasticity.FMRP has been shown to act as a translation repressor for its associated mRNAs in vitro as well as in cultured cell lines (14-17). To date, Ͼ400 mRNAs have been identified to associate with FMRP in vivo (18-21). In fragile X patient cells and synaptoneurosomes isolated from the Fmr1 KO brain, the lack of FMRP causes abnormal polyribosome-association of several mRNAs that normally bind to FMRP (18,21). Consistent with the proposed function of FMRP in regulating translation in synaptic plasticity, activity-dependent production of the synaptic protein PSD95 is abrogated in the Fmr1 KO primary neuronal cultures (22). In addition, the mRNA of the microtubuleassociated protein 1B (MAP1B), a neuronal MAP playing principle roles in neurite and synapse development (23), is a predicted target of FMRP (18,19,21). Interestingly, deficiency of Drosophila Fmr1 (dFmr1) results in abnormally elevated expression of the microtubule associated protein Futsch and synaptic over growth at the neuromuscular...

show abstract

“…Cette association n'a été validée expérimentalement que récemment [17,18]. Chez les souris Fmr1 -/-, l'absence de FMRP conduit à une répartition anormale de certains ARNm le long des polyribosomes du cerveau [14].…”

Section: Fmrp Et La Régulation De La Traduction Dans Les Cellules « Nunclassified