Fragile X Mental Retardation Protein is involved in protein synthesis-dependent collapse of growth cones induced by Semaphorin-3A

Chanxia Li

doi:10.3389/neuro.04.011.2009

Abstract

Fragile X syndrome, the most frequent form of familial mental retardation, is caused by mutation of the Fmr1 gene. Fmr1 encodes the fragile X mental retardation protein (FMRP), an mRNA binding protein regulating local, postsynaptic mRNA translation along dendrites necessary for long-term synaptic plasticity. However, recent studies on FMRP localization in axons and growth cones suggest a possible function in the regulation of local protein synthesis needed for axon guidance. Here, we have demonstrated that FMRP is involved in axonal and growth cone responses induced by the axon guidance factor, Semaphorin-3A (Sema3A). In cultured hippocampal neurons from wild type mice, Sema3A-induced growth cone collapse was protein synthesis-dependent. In contrast, Sema3A-induced growth cone collapse was attenuated in Fmr1 knock-out (KO) neurons and insensitive to protein synthesis inhibitors, suggesting that FMRP is involved in protein synthesis-dependent growth cone collapse. Sema3A increased phosphorylation of eukaryotic initiation factor 4E (eIF4E), an indicator of local translation, in distal axons and growth cones of wild type, but not Fmr1 KO neurons. Furthermore, Sema3A rapidly induced a protein synthesis-dependent increase in levels of microtubule associated protein 1B (MAP1B) in distal axons of wild type neurons, but this response was attenuated in Fmr1 KO neurons. These results suggest a possible role of FMRP to regulate local translation and axonal protein localization in response to Sema3A. This study reveals a new link between FMRP and semaphorin signaling in vitro, and raises the possibility that FMRP may have a critical role in semaphorin signaling in axon guidance during brain development.

Highlights

Fragile X syndrome (FXS), the most common form of inherited mental retardation, is caused by mutation of the Fmr1 gene, encoding the fragile X mental retardation protein (FMRP) (Pieretti et al, 1991; Verkerk et al, 1991; O’Donnell and Warren, 2002; Penagarikano et al, 2007)
We have demonstrated that FMRP is involved in axonal and growth cone responses induced by the axon guidance factor, Semaphorin-3A (Sema3A)
Sema3A rapidly induced a protein synthesis-dependent increase in levels of microtubule associated protein 1B (MAP1B) in distal axons of wild type neurons, but this response was attenuated in Fmr1 KO neurons.These results suggest a possible role of FMRP to regulate local translation and axonal protein localization in response to Sema3A

Summary

Introduction

Fragile X syndrome (FXS), the most common form of inherited mental retardation, is caused by mutation of the Fmr gene, encoding the fragile X mental retardation protein (FMRP) (Pieretti et al, 1991; Verkerk et al, 1991; O’Donnell and Warren, 2002; Penagarikano et al, 2007). FMRP is a selective RNA-binding protein implicated in regulating dendritic mRNA transport and local protein synthesis at synapses (Antar and Bassell, 2003; Jin and Warren, 2003; Bassell and Kelic, 2004; Bear et al, 2004; Jin et al, 2004; Willemsen et al, 2004). More than 400 mRNAs have been reported to associate with FMRP (Brown et al, 2001; Darnell et al, 2001; Miyashiro et al, 2003; Zalfa et al, 2003) Many of these FMRP-associated mRNAs display abnormal polyribosome association in fragile X patient cells and in the brain of Fmr KO mice (Brown et al, 2001; Zalfa et al, 2003; Lu et al, 2004), supporting the hypothesis that FMRP governs translation of its mRNA ligands. Dysregulation of glutamate receptor-regulated protein synthesis at synapses is believed

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