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Title: Two alleles of Med31 provide a model to study delayed fetal growth, proliferation and placental development
Author: Wolton, Kathryn
ISNI:       0000 0004 5990 6739
Awarding Body: University of Manchester
Current Institution: University of Manchester
Date of Award: 2016
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Fetal growth restriction (FGR) is the failure of a fetus to reach its pre-determined genetic growth potential during development. FGR is associated both with poor outcome in the neonatal period, and the onset of major adult diseases such as diabetes, hypertension and obesity. Therefore understanding what causes restricted fetal growth is important both for improving neonatal health, and for the minimization of major worldwide healthcare burdens. Described here are two mutant mouse lines, each with a distinct mutation in the Mediator complex gene Med31. These mutations result in reduced fetal growth, allowing for the investigation of the role of Med31 in the proper control of growth during development. The first mutant mouse line (Med31 Null) carries a C/T point mutation in exon 4 of Med31. Homozygous mutant embryos display reduced growth during development, characterized by their reduced size and smaller forelimbs compared to their heterozygous littermate controls. The second mutant mouse line (Med31 Y57C) carries a T/C point mutation in exon 3 of Med31. Similarly, homozygous mutant embryos display reduced fetal growth with reductions in forelimb length compared to their heterozygous littermate controls. In both mutant lines whole embryo growth and endochondral ossification within the limbs is perturbed. This is due to defects in cellular proliferation and the misexpression of the cell cycle genes Ccnb1 and Mtor within the mutant embryos. Additionally, the Med31 Null line is embryonic lethal by E18.5 and displays morphological defects of the placenta compared to heterozygous littermate controls. These morphological differences are suggestive of defects in the function of the placenta, and are proposed as the cause of embryonic lethality. In support of this the Med31 Y57C line is viable with no defects in placental development. New roles for Med31 in embryonic growth, cellular proliferation and placental development are identified. Moreover the two mutant lines constitue an allelic series of Med31, and the two mutations provide insights into the various ways Med31 is able to regulate transcription during development.
Supervisor: Boot-Handford, Raymond ; Hentges, Kathryn Sponsor: Syngenta
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: FGR ; Mediator Complex ; Med31 ; Embryonic Development