The candidate neuroprotective agent artemin induces autonomic neural dysplasia without preventing peripheral nerve dysfunction.
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.
Bolon
Brad
B
Department of Pathology, Amgen Inc., Thousand Oaks, California 91320-1799, USA.
Jing
Shuqian
S
Asuncion
Frank
F
Scully
Sheila
S
Pisegna
Marlese
M
Van
Gwyneth Y
GY
Hu
Zheng
Z
Yu
Yan Bin
YB
Min
Hosung
H
Wild
Ken
K
Rosenfeld
Robert D
RD
Tarpley
John
J
Carnahan
Josette
J
Duryea
Diane
D
Hill
Dave
D
Kaufman
Steve
S
Yan
Xiao-Qiang
XQ
Juan
Todd
T
Christensen
Kathy
K
McCabe
James
J
Simonet
W Scott
WS
D000328:Adult; D000818:Animals; D001341:Autonomic Nervous System / Q000187:drug effects / Q000196:embryology* / Q000502:physiology; D001342:Autonomic Nervous System Diseases / Q000473:pathology; D015139:Blotting, Southern; D002478:Cells, Cultured; D005260:Female; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000378:metabolism* / Q000494:pharmacology; D010525:Peripheral Nerves / Q000187:drug effects / Q000196:embryology* / Q000502:physiology; D010523:Peripheral Nervous System Diseases / Q000473:pathology; D016133:Polymerase Chain Reaction; D011518:Proto-Oncogene Proteins; D051096:Proto-Oncogene Proteins c-ret; D051381:Rats; D020794:Receptor Protein-Tyrosine Kinases; D015398:Signal Transduction / Q000502:physiology
C490886:ARTN protein, human; C494993:GFRA3 protein, human; C494994:Gfra3 protein, mouse; C494995:Gfra3 protein, rat; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D011518:Proto-Oncogene Proteins; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases; C494999:Ret protein, mouse; C495001:Ret protein, rat