Abstract
Survival and maturation of dorsal root ganglia sensory neurons during development depend on target-derived neurotrophins. These target-derived signals must be transmitted across long distances to alter gene expression. Here, we address the possibility that long-range retrograde signals initiated by target-derived neurotrophins activate a specialized transcriptional program. The transcription factor MEF2D is expressed in sensory neurons; we show that expression of this factor is induced in response to target-derived neurotrophins that stimulate the distal axons. We demonstrate that MEF2D regulates expression of an anti-apoptotic bcl-2 family member, bcl-w. Expression of mef2d and bcl-w is stimulated in response to activation of a Trk-dependent ERK5/MEF2 pathway, and our data indicate that this pathway promotes sensory neuron survival. We find that mef2d and bcl-w are members of a larger set of retrograde response genes, which are preferentially induced by neurotrophin stimulation of distal axons. Thus, activation of an ERK5/MEF2D transcriptional program establishes and maintains the cellular constituents of functional sensory circuits.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Cell Survival / drug effects
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Cell Survival / physiology
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Cells, Cultured
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Chlorocebus aethiops
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Embryo, Mammalian
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Enzyme Inhibitors / pharmacology
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Ganglia, Spinal / cytology
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Gene Expression Regulation / drug effects*
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Gene Expression Regulation / physiology
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Green Fluorescent Proteins / genetics
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In Situ Nick-End Labeling / methods
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Mitogen-Activated Protein Kinase 7 / metabolism
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Nerve Growth Factors / pharmacology*
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Nerve Tissue Proteins / genetics
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Nerve Tissue Proteins / metabolism
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Protein Tyrosine Phosphatases, Non-Receptor / genetics
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Protein Tyrosine Phosphatases, Non-Receptor / metabolism*
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Proto-Oncogene Proteins c-bcl-2 / genetics
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Proto-Oncogene Proteins c-bcl-2 / metabolism*
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RNA Interference / physiology
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RNA, Messenger / metabolism
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Rats
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Sensory Receptor Cells / drug effects
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Sensory Receptor Cells / physiology*
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Signal Transduction / drug effects
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Signal Transduction / genetics
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Transfection / methods
Substances
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Enzyme Inhibitors
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Nerve Growth Factors
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Nerve Tissue Proteins
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Proto-Oncogene Proteins c-bcl-2
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RNA, Messenger
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Green Fluorescent Proteins
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Mitogen-Activated Protein Kinase 7
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PTPN9 protein, human
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Protein Tyrosine Phosphatases, Non-Receptor