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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 beta-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.

SUBMITTER: Cox LJ

PROVIDER: S-EPMC3153364 | biostudies-literature | 2008 Feb

REPOSITORIES: biostudies-literature

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

Cox Llewellyn J LJ Hengst Ulrich U Gurskaya Nadya G NG Lukyanov Konstantin A KA Jaffrey Samie R SR

Nature cell biology 20080113 2

During development of the nervous system, axons and growth cones contain mRNAs such as beta-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 ...[more]

PMID: 18193038

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Project description:BackgroundDue to limited access to brain tissue, the precise mechanisms underlying neuro-axonal dysfunction in neurological disorders such as multiple sclerosis (MS) are largely unknown. In that context, profiling DNA methylation, which is a stable and cell type-specific regulatory epigenetic mark of genome activity, offers a unique opportunity to characterize the molecular mechanisms underpinning brain pathology in situ. We examined DNA methylation patterns of neuronal nuclei isolated from post-mortem brain tissue to infer processes that occur in neurons of MS patients.ResultsWe isolated subcortical neuronal nuclei from post-mortem white matter tissue of MS patients and non-neurological controls using flow cytometry. We examined bulk DNA methylation changes (total n = 29) and further disentangled true DNA methylation (5mC) from neuron-specific DNA hydroxymethylation (5hmC) (n = 17), using Illumina Infinium 450K arrays. We performed neuronal sub-type deconvolution using glutamate and GABA methylation profiles to further reduce neuronal sample heterogeneity. In total, we identified 2811 and 1534 significant (genome-wide adjusted P value < 0.05) differentially methylated and hydroxymethylated positions between MS patients and controls. We found striking hypo-5mC and hyper-5hmC changes occurring mainly within gene bodies, which correlated with reduced transcriptional activity, assessed using published RNAseq data from bulk brain tissue of MS patients and controls. Pathway analyses of the two cohorts implicated dysregulation of genes involved in axonal guidance and synaptic plasticity, with meta-analysis confirming CREB signalling as the most highly enriched pathway underlying these processes. We functionally investigated DNA methylation changes of CREB signalling-related genes by immunohistofluoresence of phosphorylated CREB in neurons from brain sections of a subcohort of MS patients and controls (n = 15). Notably, DNA methylation changes associated with a reduction of CREB activity in white matter neurons of MS patients compared to controls.ConclusionsOur data demonstrate that investigating 5mC and 5hmC modifications separately allows the discovery of a substantial fraction of changes occurring in neurons, which can escape traditional bisulfite-based DNA methylation analysis. Collectively, our findings indicate that neurons of MS patients acquire sustained hypo-5mC and hyper-5hmC, which may impair CREB-mediated neuro-axonal integrity, in turn relating to clinical symptoms.

Dataset Information

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

Publications

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

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