The role of Unc45a in the production of aortic arch malformations in the zebrafish kus mutant

Human congenital aortic arch malformations occur with a high frequency, and for the most part, the etiology of these lesions is not understood. To gain insight into the mechanisms that guide aortic arch formation, we are studying the embryonic lethal zebrafish mutant, kurzschluss (kus). In kus mutants, lumenization of aortic arches (AA) 5 and 6 is delayed, and these vessels make an aberrant dorsal connection to a vein, creating an arteriovenous malformation that returns blood directly to the heart. Ventrally, while AA5 normally meets its lateral counterpart at the ventral aorta, in kus mutants, these vessels instead connect to AA4. Positional cloning of kus revealed a nonsense mutation within unc45a, which encodes a putative myosin chaperone. In situ hybridization revealed unc45a expression in brain, gut, and pharynx, but not blood vessels, suggesting that the vascular phenotype in kus is non‐cell autonomous. The aortic arches form within the context of the pharyngeal arches and encircle the pharynx. We are therefore exploring the idea that loss of unc45a is disrupting pharyngeal arch or pharynx development, which is causing a secondary disruption of the posterior aortic arches. AHA 0335202N