| First Author | Jiang LT | Year | 2022 |
| Journal | Mol Cell Biol | Volume | 42 |
| Issue | 7 | Pages | e0055921 |
| PubMed ID | 35708320 | Mgi Jnum | J:330126 |
| Mgi Id | MGI:7365302 | Doi | 10.1128/mcb.00559-21 |
| Citation | Jiang LT, et al. (2022) Aberrant Neuregulin 1/ErbB Signaling in Charcot-Marie-Tooth Type 4D Disease. Mol Cell Biol 42(7):e0055921 |
| abstractText | Charcot-Marie-Tooth type 4D (CMT4D) is an autosomal recessive demyelinating form of CMT characterized by progressive motor and sensory neuropathy. N-myc downstream regulated gene 1 (NDRG1) is the causative gene for CMT4D. Although more CMT4D cases have been reported, the comprehensive molecular mechanism underlying CMT4D remains elusive. Here, we generated a novel knockout mouse model in which the fourth and fifth exons of the Ndrg1 gene were removed. Ndrg1-deficient mice develop early progressive demyelinating neuropathy and limb muscle weakness. The expression pattern of myelination-related transcriptional factors, including SOX10, OCT6, and EGR2, was abnormal in Ndrg1-deficient mice. We further investigated the activation of the ErbB2/3 receptor tyrosine kinases in Ndrg1-deficient sciatic nerves, as these proteins play essential roles in Schwann cell myelination. In the absence of NDRG1, although the total ErbB2/3 receptors expressed by Schwann cells were significantly increased, levels of the phosphorylated forms of ErbB2/3 and their downstream signaling cascades were decreased. This change was not associated with the level of the neuregulin 1 ligand, which was increased in Ndrg1-deficient mice. In addition, the integrin beta4 receptor, which interacts with ErbB2/3 and positively regulates neuregulin 1/ErbB signaling, was significantly reduced in the Ndrg1-deficient nerve. In conclusion, our data suggest that the demyelinating phenotype of CMT4D disease is at least in part a consequence of molecular defects in neuregulin 1/ErbB signaling. |
