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Title: Biochemical evidence that the Dlk1 and Grb10 signalling proteins interact through a common growth regulatory pathway
Author: Hu, Xiao
Awarding Body: University of Bath
Current Institution: University of Bath
Date of Award: 2018
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Paternally-expressed Dlk1 promotes fetal growth, while maternally-expressed Grb10 inhibits fetal growth. The respective growth-regulatory roles are consistent with the predominant theory for the evolution of imprinted gene expression, the parent-offspring conflict hypothesis. This predicts that in mammals imprinting has evolved because of differing parental interests in the distribution of maternal resources to her offspring, at least in species where females tend to reproduce with more than one mate during their reproductive lifespan. Genetic evidence indicates that Dlk1 and Grb10 control embryo size and adult body composition, potentially through a common pathway. However, the biochemical links between them are still lacking. Here, I combined biochemical methods, including two sets of TMT quantitative proteomics using pMEFs and liver derived from E14.5 WT, Dlk1+/p, Grb10m/+ and Grb10m/+/Dlk1+/p mouse embryos. I found that Dlk1 and Grb10 proteins oppositely affected the expression of each other in vitro and in vivo. Proteomics analyses uncovered that Dlk1+/p embryos were divergent from Grb10m/+and Grb10m/+/Dlk1+/p which were similar at a proteomics level, supporting the genetic findings from previous studies. Furthermore, GO-term enrichment analysis revealed that RTK related biological processes were significantly enriched in Dlk1+/p , Grb10m/+ and Grb10m/+/Dlk1+/p embryos. Several RTKs and their signal partners displayed reduced expression in the knockout pMEF and liver proteomes. In particular, cell signalling studies in E14.5 pMEFs of the four genotypes suggested that PDGFR signalling may play essential roles in fetal growth regulation through a Dlk1/Grb10 growth-regulatory axis.
Supervisor: Ward, Andrew Sponsor: China Scholarship Council
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available