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Toxicologic Pathology
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The Candidate Neuroprotective Agent Artemin Induces Autonomic Neural Dysplasia without Preventing Peripheral Nerve Dysfunction

Brad Bolon

Departments of Pathology, Amgen Imc.

Shuqian Jing

Department of Exploratory Biology, Amgen Imc.

Frank Asuncion

Department of Inflammation, Amgen Imc.

Sheila Scully

Departments of Pathology, Amgen Imc.

Marlese Pisegna

Department of Inflammation, Amgen Imc.

Gwyneth Y. Van

Departments of Pathology, Amgen Imc.

Zheng Hu

Department of Exploratory Biology, Amgen Imc.

Yan Bin Yu

Department of Exploratory Biology, Amgen Imc.

Hosung Min

Department of Functional Genomics, Amgen Imc.

Ken Wild

Department of Neurobiology, Amgen Imc.

Robert D. Rosenfeld

Department of Protein Chemistry, Amgen Inc., Thousand Oaks, California 91320-1799, USA

John Tarpley

Departments of Pathology, Amgen Imc.

Josette Carnahan

Department of Neurobiology, Amgen Imc.

Diane Duryea

Departments of Pathology, Amgen Imc.

Dave Hill

Departments of Pathology, Amgen Imc.

Steve Kaufman

Departments of Pathology, Amgen Imc.

Xiao-Qiang Yan

Departments of Pathology, Amgen Imc.

Todd Juan

Departments of Pathology, Amgen Imc.

Kathy Christensen

Departments of Pathology, Amgen Imc.

James Mccabe

Departments of Pathology, Amgen Imc.

W. Scott Simonet

Department of Exploratory Biology, Amgen Imc., ssimonet{at}amgen.com

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.

Key Words: Artemin • GFR{alpha}3 • adrenal medulla • neuropathy • paraganglioma • pheochromocytoma • sympathetic chain.

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Toxicologic Pathology, Vol. 32, No. 3, 275-294 (2004)
DOI: 10.1080/01926230490431475
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