Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA169139 | ENA |
REPOSITORIES: ENA
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Project description:RET/GDNF and ET3/EDNRB regulate cell survival, differentiation and migration of neural crest-derived cells. Many signalling mediators of RET have been characterized but the target genes at the end of the signalling cascade are largely unknown. Since the RET/EDNRB crosstalk has been previously shown, we used a Caenorhabditis elegans knockout strain of Nep-1, a homologue of human ECE1 (endothelin-converting enzyme-1), to identify new target genes. Transcriptome comparison between wild-type and Nep-1 strains at different stages identified vit-3 as a differentially expressed gene. Molecular studies of the vit3 mammalian homologue, Apoliporotein B (APOB), were performed in the murine Neuro2a cell line, a model of ENS development. Apob expression in Neuro2a is specifically activated by the RET/GDNF signalling pathway, since Ret silencing abolished Apob increase, and this effect is induced by MAPK P38 kinase activation. Mouse Apob promoter study revealed that there is a p53-dependent repressor element in the promoter region which blocks Apob expression and we show that actually p53 binds to this region. We demonstrated that RET/GDNF and EDNRB/endothelin 3 (ET-3) cooperate in inducing neuronal differentiation resulting in Apob activation. We also show that Apob expression is downregulated in mouse embryos homozygous for the mutation RetC620R and presenting a severe HSCR phenotype, whereas heterozygous mice, phenotypically normal, present a significant increase in Apob expression. These data suggest that Apob has an important role in RET-mediated neuronal development and APOB decrease may have an impact in human disorders where RET absence has been already identified, such as HSCR and Parkinson disease. Gene expression analysis using Affymetrix GeneChip C. elegans arrays in order to identify genes up- or down-regulated in nep-1 strains, homologue of human ECE1 (endothelin-converting enzyme 1).
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