AWARD 2010:
Delivered during the Weinstein Conference 2010, endorsed by the Working Group in Amsterdam (the Netherlans) - 20 May 2010
CORRESPONDING AUTHOR: Karim Mesbah
Karim obtained his PhD in the laboratory of Professor Charles Babinet, at the Pasteur Institute, Paris, France. During his PhD, he characterised mutant mice obtained by gene trap insertion and in particular a mutant in a component of the secretory pathway with defects in development of the outflow tract of the heart. He currently is a post-doctoral fellow in the laboratory of Dr Robert Kelly in the Developmental Biology Institute of Marseille-Luminy, France. he is particularly interested in the cellular and molecular mechanisms that control the behaviour of the progenitor cells of the outflow tract. His work is supported by the EU FP6 project Heart Repair and FP7 project CardioGeNet.
ABSTRACT: Cooperative roles of Tbx1 and Tbx3 during early outflow tract development
Karim Mesbah* (1), M. Sameer Rana (2), Laure Lo Ré (1), Virginia Papaioannou (3), Vincent M. Christoffels (2), Robert G. Kelly (1).
(1) Developmental Biology Institute of Marseilles - Luminy, UMR 6216 CNRS-Université de la Méditerranée, Campus de Luminy, Case 907, 13288 Marseille Cedex 9, France
(2) Department of Anatomy, Embryology & Physiology, Academic Medical Center, University of Amsterdam, Meibergdreef 15 L2-108, 1105 AZ Amsterdam, The Netherlands
(3) Department of Genetics and Development, Columbia University, 701 W 168th St., New York, USA
In the early embryo progenitor cells of the second heart field (SHF) contribute to rapid growth of the heart tube. SHF cells in pharyngeal mesoderm are adjacent to pharyngeal ectoderm and endoderm and SHF deployment is concomitant with neural crest cell migration. Tbx1, the major DiGeorge syndrome candidate gene and Tbx3, encoding a transcriptional repressor, are required for outflow tract development. These two genes have complementary expression profiles in the pharyngeal region; Tbx1 is expressed in the lateral pharyngeal endoderm, ectoderm and mesoderm (including the SHF) while Tbx3 is expressed in ventral pharyngeal endoderm and neural crest cells. Tbx3 transcript levels are decreased in neural crest cells in the caudal pharynx of Tbx1 null embryos suggesting that Tbx3 expression may be regulated by Tbx1 dependent signals originating from pharyngeal epithelia or mesoderm. We are investigating potential interaction between these genes by a genetic cross. Pharyngeal arch artery defects in double heterozygous Tbx1;Tbx3 mutant embryos are similar in severity and frequency to those in Tbx1 heterozygous embryos. However, double homozygous Tbx1;Tbx3 mutant embryos have impaired development and display lethality at midgestation. These embryos are characterized by pericardial edema associated with a failure of heart tube elongation and looping. This phenotype is more severe than that of Tbx1 or Tbx3 homozygous mutant embryos suggesting a cooperative role of these two factors during early heart morphogenesis. Altered expression of Tbx2 is also observed in Tbx1 mutant embryos. We are currently analyzing the molecular phenotype of double homozygous Tbx1;Tbx3 embryos.
AWARD 2009:
Delivered during the Working Group Annual Meeting 09 in Málaga (Spain) - 16th-18th March 2009
CORRESPONDING AUTHOR: Ross Breckenridge
Ross obtained his medical degree from Oxford University, then went on to do his PhD in the laboratory of Enrique Amaya at the Wellcome/CRUK Institute, University of Cambridge.
He then completed his training in Clinical Pharmacology at University College London. He is currently in Tim Mohun's lab at the MRC-NIMR, Mill Hill. He is interested in the developmental biology of the cardiovascular system, and adult heart failure/cardiomyopathy.
ABSTRACT: A role for Hand1 in heart failure?
By Breckenridge, R. A., Dupays, L., Zuberi, Z., Tinker, A., Mohun, T. J.
Institution: National Institute for Medical Research, Mill Hill, London, UK
e-mail (corresponding author): rbrecke@nimr.mrc.ac.uk
Heart failure is a complex, poorly understood syndrome with a poor prognosis. Many changes in gene expression in the failing heart have been described, including the re-expression of “fetal” genes. The significance of these changes is not clear. However, the fetal myocardium has striking similarities with adult failing myocardium in terms of electrophysiology, energy production and gene expression.
The transcription factor Hand1 is implicated in embryonic development of the left ventricle, and expression is maintained at a low level in the adult heart. We, and others, have shown that elevations in Hand1 RNA expression are associated with heart failure and cardiomyopathy. At birth, myocardial Hand1 expression decreases rapidly, coincident with cardiac maturation.
We have developed an inducible transgenic system allowing heart-specific overexpression of Hand1. We have used this to investigate the effect of upregulating cardiac Hand1 expression in the adult and neonatal mouse.
Hand1 upregulation leads to a heart-failure like phenotype in the adult. Hand1 upregulating hearts show remodelling of the cardiac end-plate, altered ECG morphology, decreased energy production and a greatly reduced threshold for ventricular tachycardia. These changes closely resemble the fetal heart. Furthermore, abolition of neonatal cardiac Hand1 downregulation prevents cardiac maturation, and leads to ventricular rupture.
We hypothesise that Hand1 is a key regulator of the adult cardiac phenotype in maturation and disease.