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Intra-axonal translation and retrograde trafficking of CREB promotes neuronal survival

Abstract

During development of the nervous system, axons and growth cones contain mRNAs such as β-actin, cofilin and RhoA, which are locally translated in response to guidance cues. Intra-axonal translation of these mRNAs results in local morphological responses; however, other functions of intra-axonal mRNA translation remain unknown. Here, we show that axons of developing mammalian neurons contain mRNA encoding the cAMP-responsive element (CRE)-binding protein (CREB). CREB is translated within axons in response to nerve growth factor (NGF) and is retrogradely trafficked to the cell body. In neurons that are selectively deficient in axonal CREB transcripts, increases in nuclear pCREB, CRE-mediated transcription and neuronal survival elicited by axonal application of NGF are abolished, indicating a signalling function for axonally synthesized CREB. These studies identify a signalling role for axonally derived CREB, and indicate that signal-dependent synthesis and retrograde trafficking of transcription factors enables specific transcriptional responses to signalling events at distal axons.

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Figure 1: Local protein synthesis in axons is required for NGF-dependent survival.
Figure 2: CREB mRNA and protein are localized to developing axons of DRG neurons.
Figure 3: CREB is specifically translated in axons.
Figure 4: NGF-dependent translation of a CREB reporter mRNA in axons.
Figure 5: Axonal translation and retrograde transport of endogenous CREB.
Figure 6: Retrograde transport of a photoactivatable fluorescent CREB reporter protein.
Figure 7: Axonal CREB is required for CRE-dependent transcription and NGF-mediated DRG survival.
Figure 8: Local translation and retrograde transport of CREB mediates neuronal survival.

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Acknowledgements

We thank: D. Fischman for suggesting the use of Boyden chambers; K. Wu for advice and assistance; S. Schlesinger and A. Jeromin for Sindbis plasmids; R. Ratan for CRE plasmids; and A. North for advice and assistance with Dendra photoactivation. Supported by the Paralyzed Veterans of America (L.J.C), the National Institute of Mental Health, the National Alliance for Autism Research, the Klingenstein Foundation, and a Charles A. Dana foundation grant to Weill-Cornell (S.R.J), and the European Commission FP-6 Integrated Project LSHG-CT-2003-503259 (K.A.L).

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L.J.C and S.R.J. designed the experiments, analysed the data and wrote the manuscript. L.J.C. carried out the experiments, collected data and prepared the figures. N.G.G. and K.A.L. provided reagents and input for the experimental design of photoactivation experiments. U.H. designed, carried out and analysed experiments using the translational reporter and prepared figures. S.R.J. directed and planned the project.

Note: An error in the original AOP version of the article has now been corrected in both the HTML and PDF versions; the article will appear correctly in the February print issue of Nature Cell Biology.

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Correspondence to Samie R. Jaffrey.

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Supplementary Figures S1, S2 and S3, Supplementary Tables S1, S2, S3 and S4 and Supplementary Methods (PDF 722 kb)

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Cox, L., Hengst, U., Gurskaya, N. et al. Intra-axonal translation and retrograde trafficking of CREB promotes neuronal survival. Nat Cell Biol 10, 149–159 (2008). https://doi.org/10.1038/ncb1677

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