Cardiac morphogenesis has received scant attention from the molecular and cell biologist, despite compelling clinical needs such as understanding the mechanistic basis for congenital malformations of valves septa, and cardiac muscle itself. The proposed Program Project in Cardiac Development draws on the established expertise of investigators in transcriptional control, cardiac growth factors, and myogenic determination whose past and recent scientific collaborations provide an important impetus to the current application, highlighted by the complex interplay they have shown among three transcription factors -- serum response factor (SRF), prototype of the MADS box family; YYI, a C2H2 zinc finger protein of the GLI-Kruppel family; and MHox, a mesodermally restricted homeobox protein that is highly expressed in the developing myocardium. These investigators are joined by two outstanding developmental biologists expert in transgenic mouse technology and homologous recombination, respectively, who recently have exploited insertional mutagenesis and """"""""know-out"""""""" mutations to construct novel strains of mice in which cardiac growth and development are abnormal. The Program Project comprises five collaborative studies, each relating to the molecular biology and molecular genetics of cardiac differentiation and morphogenesis. Supported by Core facilities for homologous recombination for transgenic mice and for immunocytochemistry and in situ hybridization. These projects and the responsible investigators are site-directed mutagenesis, know-out mutations, and isolation of accessory proteins for SRF and YY1 identification of MHox cis- acting sequences, their trans-acting factors, and MHox-dependent target genes dominant-inhibitory mutants of growth factor signalling proteins, in transgenic mice, as a generic strategy of construct loss-of-function mutations in vivo analysis of a novel locus causing situs inversus, reversal of the left-right body axis, identified by insertional mutagenesis; characterization and genetic rescue of mice homozygous for disruption of the c-myc gene, which causes cardia malformations and is lethal at 10.5 days of gestation. These investigations will comprise of genetic analysis of the role played int he intact animal by candidate components of the regulatory circuitry underlying establishment of the cardiac muscle lineage, the onset and maintenance of cardiac muscle gene transcription, and the basis of cardiac organogenesis.
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