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Title: Gene regulatory systems responsible for MSX1 expression in developing limb muscle and heart
Author: Miller, Kerry
ISNI:       0000 0001 3402 7314
Awarding Body: University of Aberdeen
Current Institution: University of Aberdeen
Date of Award: 2006
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Msx1 and Msx2 double mutants exhibit severe limb and heart phenotypes.  Msx1 has been shown to inhibit terminal differentiation by acting as a potent repressor of transcriptional regulation.  This study outlines the identification of two  highly conserved enhancer elements of the Msx1 gene that drive transgene expression in two distinct migrating cell populations. The proximal enhancer, PE, drives transgene expression in Pax3 expressing pre-muscle masses, which in the context of the known function of Msx1 in muscle de-differentiation, supports a role for Msx1 in delaying the differentiation of myogenic limb precursor cells and aiding in their migration.  Furthermore, using a combination of bioinformatics, reporter gene assays in tissue culture, transgenics and ChIP assays, an interaction of the TCF4 transcription factor and PE was identified that is critical for its expression.  Consistent with this, transgenic explant culture data demonstrates a role of Wnt signalling in supporting the activity of the PE enhancer immigrating limb pre-muscle mass cells where Msx1 may play a role in allowing migration of these cells by hindering myogenesis. Msx1 is expressed in cardiac neural crest (CNC) cells migrating from rhombomere 6 and has been shown to be essential in outflow tract development.  An additional enhancer of Msx1 was identified, KE, that has been exceptionally highly conserved in cis with the Msx1 gene in all vertebrate species.  Transgene expression in CNC and the presence of heart-specific transcription binding sites within KE suggest a role for this element during cardiogenesis. The identification of these enhancers, which have been better conserved than the coding sequence of the gene they regulate, argues a shift in focus from gene coding regions to gene regulatory regions when attempting to identify the genetic causes of congenital limb and heart malformations.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available