Analysis of cardiovascular anomalies in the Hoxa3 and Pax-3 homozygous null mutant mice.

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Hoxa3 gene is expressed in the third pharyngeal arch and pouch and is required for development of the third arch artery in addition to the thymus, parathyroid land and carotid body. We statistically analyzed malformations of the carotid artery system in Hoxa3 homozygous mutant mice, in comparison with wild-type and heterozygous littermates. In the Hoxa3 homozygotes, the third arch artery was observed at E 10.5 but degenerated at E 11.5. Therefore the common carotid artery, the derivative of the third arch artery was absent or very short in the null mutants. The tunica media of great arteries derived from the arch arteries is formed by the ectomesenchymal neural crest cells. To assess the cause of the third arch artery regression, the Hoxa3 heterozygous mice were crossed with the connexin43-lacZ transgenic mice in which neural crest cells are specified by β-galactosidase expression. The neural crest cells normally migrated into the third pharyngeal arch and surrounded the arch artery in the null mutants as well as wild types. The expressions of VEGF_<165>, its receptors (tyrosine kinases Flt-1 and Flk-1), endothelin ET-1 and dHand which are responsible for development of embryonic blood vessels or arch arteries, were analyzed in the third arch artery of the E 10.5 Hoxa3 null mutants, in comparison with wild types, by the laser capture microdissection and real-time PCR methods. VEGF_<165> mRNA was almost lost and ET-1 mRNA was markedly reduced in the null mutants. Flk-1 mRNA expression was down-regulated whereas Flt-1 mRNA was up-regulated in the mutants. The Hoxa3 gene may ragulate the pathways of both VEGF and ET-1 systems for the third arch artery development.