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Molecular genetics of chamber specification in the developing heart: implications for congenital heart disease

Objective

Objectives:
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ù To provide refined maps of transcriptional compartments in the developing heart.
ù To identify factors and mechanisms responsible for cardiac chamber formation and specification.
ù To map transcriptional domains in experimental models of congenital heart disease.

Brief description:

This project aims at identifying inducing signals and transcription factors implicated in the specification of cardiac chambers during embryonic development. Multiple approaches will be used to dissect the molecular mechanisms responsible for generating patterning and diversity in the developing normal and malformed heart. "Cardiosensor" transgenic mice containing promoter/enhancer elements of cardiac genes linked to reporter genes will be used to reveal positional signals present in specific cardiac chambers. "Transcriptional domains", corresponding to cardiac compartments showing regional patterns of transgene expression, will be followed during cardiac morphogenesis. The boundaries between such compartments will be further refined by crossing mice from different transgenic lines, and cisacting sequences mediating regionalised transgene expression will be delimited. These sequences will be further characterized by transfection experiments, both in vitro in cultured cardiomyocytes and in vivo by direct DNA injection in adult rat heart. Differential screening techniques will be used to screen known transcription factors which may be differentially expressed in the heart and to search for novel structural and regulatory genes showing regionalized patterns of expression. Transcriptional domains will be mapped in different experimental models of cardiac malformations by crossing mice expressing chamber-specific transgenes with mutant mice with congenital cardiac malformations, such as iv/iv mice and connexin 43 knock-out mice. This study will clarify the contribution of embryonic cardiac segments to the development of various malformations. 'Cardiosensor' transgenic mice will also be exposed to retinoic acid during early gestation to define the role of retinoid signaling in patterning the anterior-posterior axis of the heart tube. The information obtained from the animal studies will be used to make a map of transcriptional domains of the developing human heart, using in situ hybridization on sections of human embryos at different developmental stages.

Keywords:
Heart development. Congenital heart disease. Embryology. Transcription factors. Gene expression. Cardiac chamber specification. Transgenic mice.

Coordinator

UNIVERSITA DEGLI STUDI DI PADOVA
Address
3,Via G. Colombo 3
35121 Padova
Italy

Participants (3)

Academisch Ziekenhuis bij de Universiteit van Amsterdam
Netherlands
Address
9,Meibergdreef
1105 AZ Amsterdam
Institut Pasteur
France
Address
25 Rue Du Docteur Roux
75724 Paris
St George's Hospital Medical School
United Kingdom
Address
Cranmer Terrace
SW17 ORE London