SUMMARY:
The demyelinating phenotype of CMT4D disease is at least in part a consequence of molecular defects in neuregulin 1/ErbB signaling.
TITLE:
Aberrant Neuregulin 1/ErbB Signaling in Charcot-Marie-Tooth Type 4D Disease
DESCRIPTION:
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…
CONTENT:
Mol Cell Biol. 2022 Jun 16:e0055921. doi: 10.1128/mcb.00559-21. Online ahead of print.
ABSTRACT
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 β4 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.
PMID:35708320 | DOI:10.1128/mcb.00559-21
SOURCE:
Molecular and cellular biology
TAGS:
CMT4D
CATEGORY:
Research
SUBCATEGORY:
n/a
DATE – PUBLISHED:
2022-06-16T13:00:33Z
DATE – DOI: 2022-06-16T13:00:33Z
DATE – PUBMED: 2022 Jun 16
DATE OUTPUT MATCHED: True
DATE – ADDED:
Thu, 16 Jun 2022 06:00:00 -0400
DATE – RETRIEVED:
06/16/22 01:32PM
2022-06-16T13:32:35-04:00
FEATURED IMAGE:
Media Uploaded (image/png)
IDENTIFIER:
pmid:35708320,doi:10.1128/mcb.00559-21
PUBMED ID:
pubmed:35708320
DOI:
10.1128/mcb.00559-21
LINK – PUBMED:
https://pubmed.ncbi.nlm.nih.gov/35708320/
LINK – DOI:
https://doi.org/10.1128/mcb.00559-21
LINK – PUBLISHER:
https://journals.asm.org/doi/10.1128/mcb.00559-21
REFERENCES:
CMT Treatment Report, Urgent Research, 2022-06-16T13:32:35-04:00, https://www.cmttreatmentreport.com.
