J. Neurosci. -- eLetters for Poon et al., 26 (51) 13390-13399

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DevelopmentPlasticityRepair:
Michael M. Poon, Sang-Hyun Choi, Christina A. M. Jamieson, Daniel H. Geschwind, and Kelsey C. Martin
Identification of Process-Localized mRNAs from Cultured Rodent Hippocampal Neurons
J. Neurosci. 2006; 26: 13390-13399 [Abstract] [Full text] [PDF]

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Concerning the Mechanism of Elongation Factor 1A Local Synthesis in Dendrites
Robert B. Denman (11 January 2007)

Concerning the Mechanism of Elongation Factor 1A Local Synthesis in Dendrites 11 January 2007

Robert B. Denman,
Head Biochemical Molecular Neurobiology Laboratory
New York State Institute for Basic Research in Developmental Disabilities, 10314
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Re: Concerning the Mechanism of Elongation Factor 1A Local Synthesis in Dendrites

rbdenman{at}yahoo.com Robert B. Denman

In Poon et al’s recent paper entitled “Identification of Process Localized mRNAs from Cultured Hippocampal Neurons” they note that several of the messages, which they identified as components of dendritically localized staufen-containing RNA granules i.e. G-protein alpha-inhibiting 2 (Gnalphai2), neuronatin (NNAT), eukaryotic initiation factor 5 (eIF5), Rho-interacting protein 3 (RIP3) and cytoplasmic dynein light chain have also been identified as FMRP target mRNAs (Brown et al., 2001; Miyashiro et al., 2003). However, they failed to mention that we showed that eEF-1A mRNA (one of the prototypical messages in their paper) binds to FMRP in vitro and that heterologous expression of FMRP in cultured cells results in a concentration-dependent decrease in eEF-1A protein, but has no effect on the levels of its mRNA (Sung et al., 2003). This effect is not observed when FXR1P is heterologously expressed. Furthermore, lymphoblastoid cells from fragile X patients have 3-fold more eEF-1A protein than lymphoblastoid cells from normal controls, despite the fact that eEF-1A mRNA levels in these two cell types are the same. Thus, eEF- 1A mRNA has the hallmarks of a message whose translation is negatively regulated by FMRP.
These data coupled with recently published studies on eEF-1A translation in the brain have potential implications for understanding the function of FMRP in dendrites. Both eEF-1A and FMRP are transiently increased following treatment with the group I mGluR agonist DHPG (Huang et al., 2005; Hou et al., 2006). This suggests that newly synthesized FMRP is not able to negatively regulate eEF-1A mRNA in dendrites. This might occur if FMRP were either not phosphorylated and thus unable to stall the translation of eEF-1A mRNA (Ceman et al., 2003), or if the FMRP isoform that was locally synthesized lacked the phosphorylation site via alternative splicing. Alternatively, perhaps in dendrites FMRP is bound to a protein that modifies its translational regulatory activity, turning it from a negative to a positive translational regulator. Further experiments will be necessary to differentiate these possibilities and characterize the underlying mechanism of eEF-1A local translation.
Robert B. Denman, Ph.D. Head Biochemical Molecular Neurobiology Laboratory New York State Institute for Basic Research In Developmental Disabilities 1050 Forest Hill Road Staten Island, NY 10314 Tel: 718-494-5199 Fax: 718-494-5905 e-mail: rbdenman@yahoo.com
References
Brown V, Jin P, Ceman S, Darnell JC, O'Donnell WT, Tenenbaum SA, Jin X, Feng Y, Wilkinson KD, Keene JD (2001) Microarray identification of FMRP -associated brain mRNAs and altered mRNA translational profiles in fragile X syndrome. Cell 107:477-487.
Ceman S, O'Donnell WT, Reed M, Patton S, Pohl J, Warren ST (2003) Phosphorylation influences the translation state of FMRP-associated polyribosomes. Hum Mol Genet 12:3295-3305.
Hou L, Antion MD, Hu D, Spencer CM, Paylor R, Klann E (2006) Dynamic translational and proteasomal regulation of fragile X mental retardation protein controls mGluR-dependent Long-Term Depression. Neuron 51:441-454.
Huang F, Chotiner JK, Steward O (2005) The mRNA for elongation factor 1{alpha} is localized in dendrites and translated in response to treatments that induce long-term depression. J Neurosci 25:7199-7209.
Miyashiro KY, Beckel-Mitchener A, Purk TP, Becker KG, Barret T, Liu L, Carbonetto S, Weiler IJ, Greenough WT, Eberwine J (2003) RNA cargoes associating with FMRP reveal deficits in cellular functioning in Fmr1 null mice. Neuron 37:417-431.
Sung Y-J, Dolzhanskaya N, Nolin SL, Brown WT, Currie JR, Denman RB (2003) The fragile X mental retardation protein FMRP binds elongation factor 1A mRNA and negatively regulates its translation in vivo. J Biol Chem 278:15669-15678.