Neurotrophin-3 promotes the cholinergic differentiation of sympathetic neurons.
Neurotrophins influence the epigenetic shaping of the vertebrate nervous system by regulating neuronal numbers during development and synaptic plasticity. Here we attempt to determine whether these growth factors can also regulate neurotransmitter plasticity. As a model system we used the selection between noradrenergic and cholinergic neurotransmission by paravertebral sympathetic neurons. Developing sympathetic neurons express the neurotrophin receptors TrkA and TrkC, two highly related receptor tyrosine kinases. Whereas the TrkA ligand nerve growth factor (NGF) has long been known to regulate both the survival and the expression of noradrenergic traits in sympathetic neurons, the role of TrkC and of its ligand neurotrophin-3 (NT3) has remained unclear. We found that TrkC expression in the avian sympathetic chain overlaps substantially with that of choline acetyltransferase. In sympathetic chain explants, transcripts of the cholinergic marker genes choline acetyltransferase and vasoactive intestinal polypeptide were strongly enriched in the presence of NT3 compared with NGF, whereas the noradrenergic markers tyrosine hydroxylase and norepinephrine transporter were reduced. The transcription factor chicken achaete scute homolog 1 was coexpressed with cholinergic markers. The effects of NT3 are reversed and antagonized by NGF. They are independent of neuronal survival and developmentally regulated. These results suggest a role for NT3 as a differentiation factor for cholinergic neurons and establish a link between neurotrophins and neurotransmitter plasticity.
Department of Neurobiochemistry, Max Planck Institute of Neurobiology, Martinsried, Germany.
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Brodski
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Schnürch
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Dechant
D000818:Animals; D030161:Avian Proteins; D051792:Basic Helix-Loop-Helix Proteins; D015153:Blotting, Western; D002352:Carrier Proteins / Q000235:genetics; D016923:Cell Death / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002642:Chick Embryo; D002795:Choline O-Acetyltransferase / Q000235:genetics / Q000378:metabolism; D020934:Ciliary Neurotrophic Factor / Q000494:pharmacology; D046508:Culture Techniques; D004268:DNA-Binding Proteins / Q000235:genetics; D005728:Ganglia, Sympathetic / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D018398:Homeodomain Proteins / Q000235:genetics; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D020932:Nerve Growth Factor / Q000494:pharmacology; D009419:Nerve Tissue Proteins; D016501:Neurites / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D020933:Neurotrophin 3 / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology*; D050484:Norepinephrine Plasma Membrane Transport Proteins; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020917:Receptor, trkA / Q000235:genetics; D020812:Receptor, trkC / Q000235:genetics / Q000378:metabolism*; D027981:Symporters; D014157:Transcription Factors / Q000235:genetics; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics; D014660:Vasoactive Intestinal Peptide / Q000235:genetics
D030161:Avian Proteins; D051792:Basic Helix-Loop-Helix Proteins; D002352:Carrier Proteins; D002795:Choline O-Acetyltransferase; D020934:Ciliary Neurotrophic Factor; D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D020932:Nerve Growth Factor; D009419:Nerve Tissue Proteins; D020933:Neurotrophin 3; D050484:Norepinephrine Plasma Membrane Transport Proteins; D012333:RNA, Messenger; D020917:Receptor, trkA; D020812:Receptor, trkC; D027981:Symporters; D014157:Transcription Factors; D014446:Tyrosine 3-Monooxygenase; D014660:Vasoactive Intestinal Peptide; C099107:CASH-1 protein, Gallus gallus