title: Increased activation of the epidermal growth factor receptor in transgenic mice overexpressing epigen causes peripheral neuropathy.
abstract: In the mammalian nervous system, axons are commonly surrounded by myelin, a lipid-rich sheath that is essential for precise and rapid conduction of nerve impulses. In the peripheral nervous system (PNS), myelin sheaths are formed by Schwann cells which wrap around individual axons. While the tyrosine kinase receptors ERBB2 and ERBB3 are established mediators of peripheral myelination, less is known about the functions of the related epidermal growth factor receptor (EGFR) in the regulation of PNS myelination. Here, we report a peripheral neurodegenerative disease caused by increased EGFR activation. Specifically, we characterize a symmetric and distally pronounced, late-onset muscular atrophy in transgenic mice overexpressing the EGFR ligand epigen. Histological examination revealed a demyelinating neuropathy and axon degeneration, and molecular analysis of signaling pathways showed reduced protein kinase B (PKB, AKT) activation in the nerves of Epigen-tg mice, indicating that the muscular phenotype is secondary to PNS demyelination and axon degeneration. Crossing of Epigen-tg mice into an EGFR-deficient background revealed the pathology to be completely EGFR-dependent. This mouse line provides a new model for studying molecular events associated with early stages of peripheral neuropathies, an essential prerequisite for the development of successful therapeutic interventions.
authors.affiliation: Institute of Molecular Animal Breeding and Biotechnology, Laboratory for Functional Genome Analysis (LAFUGA), Gene Center, LMU Munich, 81377 Munich, Germany. Electronic address: dahlhoff@lmb.uni-muenchen.de.
authors.forename: Maik
authors.initials: M
authors.lastname: Dahlhoff
authors.forename: Daniela
authors.initials: D
authors.lastname: Emrich
authors.forename: Eckhard
authors.initials: E
authors.lastname: Wolf
authors.forename: Marlon R
authors.initials: MR
authors.lastname: Schneider
mesh_terms: D000818:Animals; D015153:Blotting, Western; D003711:Demyelinating Diseases; D004815:Epidermal Growth Factor / Q000502:physiology*; D066261:Epigen; D066246:ErbB Receptors / Q000502:physiology*; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009133:Muscular Atrophy / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D009186:Myelin Sheath / Q000378:metabolism; D010523:Peripheral Nervous System Diseases / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction
chemical_list: C587854:EPGN protein, human; C587855:Epgn protein, mouse; D066261:Epigen; D012333:RNA, Messenger; D004815:Epidermal Growth Factor; C541485:EGFR protein, mouse; D066246:ErbB Receptors
keywords: Axon degeneration; Demyelination; EGFR; Epigen; Mouse model