The candidate neuroprotective agent artemin induces autonomic neural dysplasia without preventing peripheral nerve dysfunction

Toxicol Pathol. May-Jun 2004;32(3):275-94. doi: 10.1080/01926230490431475.


Artemin (ART) signals through the GFR alpha-3/RET receptor complex to support sympathetic neuron development. Here we show that ART also influences autonomic elements in adrenal medulla and enteric and pelvic ganglia. Transgenic mice over-expressing Art throughout development exhibited systemic autonomic neural lesions including fusion of adrenal medullae with adjacent paraganglia, adrenal medullary dysplasia, and marked enlargement of sympathetic (superior cervical and sympathetic chain ganglia) and parasympathetic (enteric, pelvic) ganglia. Changes began by gestational day 12.5 and formed progressively larger masses during adulthood. Art supplementation in wild type adult mice by administering recombinant protein or an Art-bearing retroviral vector resulted in hyperplasia or neuronal metaplasia at the adrenal corticomedullary junction. Expression data revealed that Gfr alpha-3 is expressed during development in the adrenal medulla, sensory and autonomic ganglia and their projections, while Art is found in contiguous mesenchymal domains (especially skeleton) and in certain nerves. Intrathecal Art therapy did not reduce hypalgesia in rats following nerve ligation. These data (1) confirm that ART acts as a differentiation factor for autonomic (chiefly sympathoadrenal but also parasympathetic) neurons, (2) suggest a role for ART overexpression in the genesis of pheochromocytomas and paragangliomas, and (3) indicate that ART is not a suitable therapy for peripheral neuropathy.

MeSH terms

  • Adult
  • Animals
  • Autonomic Nervous System / drug effects
  • Autonomic Nervous System / embryology*
  • Autonomic Nervous System / physiology
  • Autonomic Nervous System Diseases / pathology
  • Blotting, Southern
  • Cells, Cultured
  • Female
  • Glial Cell Line-Derived Neurotrophic Factor Receptors
  • Humans
  • Male
  • Mice
  • Mice, Transgenic
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Nerve Tissue Proteins / pharmacology
  • Neurons / drug effects
  • Neurons / metabolism*
  • Neuroprotective Agents / metabolism*
  • Neuroprotective Agents / pharmacology
  • Peripheral Nerves / drug effects
  • Peripheral Nerves / embryology*
  • Peripheral Nerves / physiology
  • Peripheral Nervous System Diseases / pathology
  • Polymerase Chain Reaction
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-ret
  • Rats
  • Receptor Protein-Tyrosine Kinases
  • Signal Transduction / physiology


  • ARTN protein, human
  • GFRA3 protein, human
  • Gfra3 protein, mouse
  • Gfra3 protein, rat
  • Glial Cell Line-Derived Neurotrophic Factor Receptors
  • Nerve Tissue Proteins
  • Neuroprotective Agents
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-ret
  • Receptor Protein-Tyrosine Kinases
  • Ret protein, mouse
  • Ret protein, rat