Neuregulin 1-erbB signaling is necessary for normal myelination and sensory function.
To investigate the role of erbB signaling in the interactions between peripheral axons and myelinating Schwann cells, we generated transgenic mice expressing a dominant-negative erbB receptor in these glial cells. Mutant mice have delayed onset of myelination, thinner myelin, shorter internodal length, and smaller axonal caliber in adulthood. Consistent with the morphological defects, transgenic mice also have slower nerve conduction velocity and defects in their responses to mechanical stimulation. Molecular analysis indicates that erbB signaling may contribute to myelin formation by regulating transcription of myelin genes. Analysis of sciatic nerves showed a reduction in the levels of expression of myelin genes in mutant mice. In vitro assays revealed that neuregulin-1 (NRG1) induces expression of myelin protein zero (P0). Furthermore, we found that the effects of NRG1 on P0 expression depend on the NRG1 isoform used. When NRG1 is presented to Schwann cells in the context of cell-cell contact, type III but not type I NRG1 regulates P0 gene expression. These results suggest that disruption of the NRG1-erbB signaling pathway could contribute to the pathogenesis of peripheral neuropathies with hypomyelination and neuropathic pain.
Division of Neuroscience, Children's Hospital Boston, Harvard Medical School, Boston, Massachusetts 02115, USA.
Suzhen
S
Chen
Miguel Omar
MO
Velardez
Xavier
X
Warot
Zhao-Xue
ZX
Yu
Shyra J
SJ
Miller
Didier
D
Cros
Gabriel
G
Corfas
D000818:Animals; D001369:Axons / Q000378:metabolism / Q000473:pathology; D002450:Cell Communication / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics; D004195:Disease Models, Animal; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D018993:Myelin P0 Protein / Q000096:biosynthesis / Q000235:genetics; D009185:Myelin Proteins / Q000096:biosynthesis / Q000235:genetics; D009186:Myelin Sheath / Q000235:genetics / Q000378:metabolism; D009413:Nerve Fibers, Myelinated / Q000378:metabolism* / Q000473:pathology; D009431:Neural Conduction / Q000235:genetics; D020890:Neuregulin-1 / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D018739:Oncogene Proteins v-erbB / Q000235:genetics*; D010525:Peripheral Nerves / Q000254:growth & development* / Q000378:metabolism / Q000473:pathology; D010523:Peripheral Nervous System Diseases / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D012583:Schwann Cells / Q000378:metabolism* / Q000473:pathology; D012584:Sciatic Nerve / Q000254:growth & development / Q000378:metabolism / Q000473:pathology; D012677:Sensation / Q000235:genetics*
D018993:Myelin P0 Protein; D009185:Myelin Proteins; D020890:Neuregulin-1; D018739:Oncogene Proteins v-erbB; D020033:Protein Isoforms