Imprinted gene function in a mouse model of developmental programming of life long health

Student thesis: Doctoral ThesisPhD


The connection between early life environment and future health of offspring has been the subject of both human epidemiological and animal model studies. An adverse prenatal environment has the potency to produce low birth weight offspring from mothers exposed to such nutritional environment and this affects health in later life as metabolic syndromes such as obesity, cardiovascular disease and type II diabetes. As such understanding the mechanism of developmental programming is very important in combating these syndromes and taking preventive measures. This project aims to identify the developmental programming genes and understand the underlying epigenetic and molecular mechanisms of developmental programming that takes place during the critical
developmental time frame in prenatal, neonatal and postnatal stages. Imprinted genes are most likely playing key roles in developmental programming due to their susceptibility to the environmental conditions and some of the imprinted genes selected in these studies have key role in growth and metabolism. Other key developmental genes either imprinted or not will also be studied along with
Grb10 gene which is proposed to be a developmental gene. We used a novel Grb10 maternal knockout combined with a low protein mouse model to study and understand better the mechanisms of developmental programming which is until now quite elusive. In order to do that, first, morphological studies that involved wet body weight analysis of embryos at E18.5(prenatal), pups at day 1 of birth
(neonatal), pups at week 3 (postnatal-weaning) and adult mice at week 15 were undertaken. Our results obtained by comparing wild types to Grb10 maternal knockout pups from mothers on low protein and control(regular) diet showed a significant genetic effect at E18.5, genetic and diet effect on the day of birth and significant genetic as well as catch up growth at week 3 and significant weight
difference between CON and HFD diet mice at week 15. Sex specific differences stated appearing by Week15. Organ weight analysis at E18.5 also showed genetic effect where some of the organs were larger in the Grb10KO. We did a thorough sex specific, diet specific and genotype specific weight analyses to understand better how mouse genetic and adverse maternal gestational environment
influence one another in effecting life long health. We suggest that one or more factors, Gr10 status in the offspring, in the mother or maternal diet influences developmental programming and we have found nice evidence for this through this study. Gene expression results using Rt-qPCR and RNA Seq revealed a set of imprinted genes, insulin responsive genes and lipid metabolism genes that are highly regulated in our model. In addition to that a set of 179 highly regulated genes were obtained from an unbiased RNA Seq screen. Quantitative enrichment analysis revealed that insulin responsive genes are downregulated more in the Grb10KOs and the lipid metabolism genes are downregulated in the LPD
groups. We also found go terms related to lipid metabolism, small molecule metabolism and many other metabolism and lipid related terms as well as gene clusters involved in PPAR signaling pathway and lipid metabolic pathway. Our developmental programming model has shown that in utero environment plays an important role in developmental programming and the programming effect is
very strong and lasts for the entirety of the offspring even though the stimulus itself like the imprinted genes or the diet effect may be very subtle.
Date of Award29 Mar 2023
Original languageEnglish
Awarding Institution
  • University of Bath
SupervisorAndrew Ward (Supervisor) & Adele Murrell (Supervisor)

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