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Braf-mutant Schwann cells divert to a repair phenotype to induce congenital demyelinating neuropathy [ScN]

ABSTRACT: RASopathies are a diverse group of developmental disorders associated with germline or somatic mutations in genes of the Mitogen Activated Protein Kinase (MAPK) signaling pathway. We characterized in this dataset a mosaic mouse model, in which a constitutively active form of the MAPK effector Braf (V600E) is expressed in the embryonic progenitors of myelin-forming Schwann cells of peripheral nerves under the control of the MpZ(P0)-Cre recombinase. These mice develop an early, fully penetrant degenerative peripheral neuropathy. The RNAseq experiment compares total RNA extracted from whole sciatic nerves between spinal cord and knee between mutant and control pairs of littermates from six distinct outbred litters at postnatal day 21.

ORGANISM(S): Mus musculus

PROVIDER: GSE262047 | GEO | 2024/12/31

REPOSITORIES: GEO

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Project description:Hereditary Motor and Sensory Neuropathies (HMSN) are the most common inherited peripheral neuropathies and comprise a group of genetically heterogeneous diseases. We study the genetic defects causing three demyelinating disorders: HMSN1A, HMSN-LOM and congenital cateracts facial dysmophism neuropathy (CCFDN) syndrome, which are caused by mutations in PMP22, NDRG1 and CTDP1, respectively. The function and patho-mechanisms of these genes is still unknown. To identify effects downstream of the mutations, thereby possibly involved in the disease process, we used Serial expression of gene expression (SAGE) and microarray analysis. We analyzed human Schwann cell lines from three normal subjects, one HMSN-LOM patient, two HMSN-1A patients and two CCFDN patients and compared our data to a recent dataset of human Schwann cells (4 normal subjects passage 1 vs. 3, GDS1869/GSE4030 M.B. Bunge, 2006). We excluded genes that were not consistently regulated between biological and technical replicates and genes that were found to be influenced by passage number (p<0.05). Comparing expression profiles of demyelinating neuropathies with different mutations we identified: 1. expression signatures specific for each genotype. 2. Genes commonly (dys)regulated in all screened neuropathies. Interestingly, these include genes that play a role in reorganization of sodium channels in central and peripheral nerves (S100A10, CD90), or extracellular matrix remodeling (e.g. TGFBI, SERPINE1, THBS1). We also found high up-regulation of genes involved in Schwann cell lineage and in particular, genes that are associated with an immature or pre-myelinating Schwann cell phenotype (i.e. Sox2, Sox10, COL18A1, TFAP2A, Pax3, CDH19). Our study shows that many genes, possibly contributing to nerve pathology can be identified by this approach. Experiment Overall Design: Experimental design: in total 12 (two-color) arrays were run. All neuropathy samples were in duplicate (technical replicates). Two CCFDN and two HMSN1A patients were also analyzed as biological replicates. Three healthy subjects were included from which one was in duplicate. All samples (Cy3) were compared to a common reference pool (Cy5) which consisted of a mix of all samples.

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Braf-mutant Schwann cells divert to a repair phenotype to induce congenital demyelinating neuropathy [ScN]

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