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The role of AP-2 alpha in the development of the outflow tract and pharyngeal arch arteries
  1. SD Bamforth1,
  2. D Venkatesh1,
  3. C Broadbent2,
  4. JE Schneider2,
  5. S Bhattacharya2
  1. 1Institute of Human Genetics, Newcastle-upon-Tyne, UK
  2. 2Department of Cardiovascular Medicine, Oxford, UK

Abstract

Congenital cardiovascular malformation (CCVM) is the most common birth defect and comprises abnormalities of the outflow tract and the great vessels that develop from the pharyngeal arch arteries. Genetic mutations are implicated in causing CCVM, and transgenic mouse models have been created that develop phenotypes reminiscent of human CCVM. One such model has a targeted inactivation of the transcription factor AP-2α (Tcfap2a). In the mouse AP-2α is expressed in the ectoderm, neural crest and mesenchyme of the pharyngeal arches around the time that the pharyngeal arch arteries are developing. Mice null for Tcfap2a present with cardiovascular defects such as ventricular septal defect (VSD), double-outlet right ventricle (DORV), interrupted aortic arch (IAA) and anomalous right subclavian artery (A-RSA). In this study we wanted to identify tissues in which Tcfap2a is crucial for the correct development of the cardiac outflow tract and pharyngeal arch arteries. To achieve this, Tcfap2a was selectively deleted from those cells in the pharyngeal arches in which it is expressed under normal conditions: the ectoderm, second heart field and neural crest. All mice were backcrossed for several generations onto a C57Bl/6 genetic background. Embryos were collected at E14.5–15.5 and analysed by magnetic resonance imaging and histology to assess cardiovascular developmental abnormalities (table). Initially, embryos homozygous null for Tcfap2a were examined to ascertain the incidence and frequency of CCVM on a C57Bl/6 genetic background. A high incidence of cardiovascular defects, including DORV, VSD, IAA and vascular ring was confirmed (fig). When Tcfap2a was selectively deleted from the pharyngeal ectoderm, A-RSA was observed in three of eight embryos. Deletion of Tcfap2a from the second heart field resulted in one embryo from six examined exhibiting IAA and a vascular ring. When Tcfap2a was deleted from the neural crest, cardiovascular defects were observed in five of nine embryos. Two embryos presented with a VSD alone, one with VSD and transposition of the great arteries and two embryos had A-RSA. Taken together, these results suggest that Tcfap2a is required in multiple tissues to control correct cardiovascular development, as deletion from one cell type or domain is not sufficient to recapitulate fully the cardiovascular phenotype seen in the global Tcfap2a null embryos.

Abstract 103 Figure

3D reconstructions of E15.5 embryo hearts. Wild-type heart showing normal anatomy from (a) ventral and (b) dorsal views. Tcfap2a null heart showing ventricular septal defect (VSD), double-outlet right ventricle (DORV), interrupted aortic arch (IAA) and vascular ring from (c) ventral and (d) dorsal views. Ao, aorta; LCC, left common carotid; LSA, left subclavian artery; LV, left ventricle; PT, pulmonary trunk; RCC, right common carotid; RSA, right subclavian artery; RV, right ventricle; Tr, tricuspid valve. Scale 500 μmol.

Abstract 103 Table

Incidence of congenital cardiovascular malformation seen in Tcfap2a null and conditionally deleted embryos

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