The two closely related forkhead/winged helix transcription factors, Foxc1 (Mf1) and Foxc2 (Mfh1), are expressed in overlapping populations of cells contributing to endothelial cells of the heart and blood vessels and mesenchyme of the valves, outflow tract and aortic arches. We have shown that mice homozygous for null mutations in either Foxc1 or Foxc2 die pre- or perinatally with the same spectrum of cardiovascular defects, including interruption or coarctation of the aortic arch and ventricular septal defects. Most compound heterozygous mutant side with similar defects, leading to the central hypotheses that the two genes interact to regulate cardiovascular development, either through co-operative but non-identical functions, or strictly through dosage of the two gene products in the same. Using specific antibodies, we will determine the temporal and cellular localization of Foxc1 and Foxc2 protein in endothelial and neural crest mesenchyme during normal cardiovascular development (Aim 1), including coronary vessel development. The proposed hypothesis will be tested by analyzing the phenotype of more severe compound mutants and comparing these with single mutant phenotypes (Aim 2, 3). Finally, we will generate mutant mice in which Foxc1 is replaced with Foxc2 and vice versa to test if the two genes are interchangeable in vivo (Aim 2, 3).
This aim will also generate conditional mutant alleles for deleting both genes in neural crest and epicardially-derived cells (Aim 2, 3).
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