Prediction and characterisation of a highly conserved, remote and cAMP responsive enhancer that regulates Msx1 gene expression in cardiac neural crest and outflow tract

Kerry Ann Miller, Scott Davidson, Angela Liaros, John Barrow, Marissa Lear, Danielle Heine, Stefan Hoppler, Alasdair MacKenzie

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

Double knockouts of the Msx1 and Msx2 genes in the mouse result in severe cardiac outflow tract malformations similar to those frequently found in newborn infants. Despite the known role of the Msx genes in cardiac formation little is known of the regulatory systems (ligand receptor, signal transduction and protein-DNA interactions) that regulate the tissue-specific expression of the Msx genes in mammals during the formation of the outflow tract. In the present study we have used a combination of multi-species comparative genomics, mouse transgenic analysis and in-situ hybridisation to predict and validate the existence of a remote ultra-conserved enhancer that supports the expression of the Msx1 gene in migrating mouse cardiac neural crest and the outflow tract primordia. Furthermore, culturing of embryonic explants derived from transgenic lines with agonists of the PKC and PKA signal transduction systems demonstrates that this remote enhancer is influenced by PKA but not PKC dependent gene regulatory systems. These studies demonstrate the efficacy of combining comparative genomics and transgenic analyses and provide a platform for the study of the possible roles of Msx gene mis-regulation in the aetiology of congenital heart malformation. (C) 2008 Elsevier Inc. All rights reserved.

Original languageEnglish
Pages (from-to)686-694
Number of pages9
JournalDevelopmental Biology
Volume317
Issue number2
Early online date21 Feb 2008
DOIs
Publication statusPublished - 15 May 2008

Keywords

  • Msx1 gene
  • comparative genomics
  • Transfac
  • enhancer element
  • transgenic mouse
  • embryo
  • cardiac neural crest
  • outflow tract
  • transcription
  • PKA
  • comparative genomic tools
  • transcription factor
  • embryonic-development
  • binding sites
  • mouse
  • cells
  • heart
  • induction
  • roles
  • homeoproteins

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