ABNORMAL PATTERNING OF THE AORTIC-ARCH ARTERIES DOES NOT EVOKE CARDIAC-MALFORMATIONS

Ablation of the cardiac neural crest results in abnormal development o f the aortic arch arteries leading to altered patterning of the great arteries. The cardiac outflow tract is also affected after neural cres t ablation because normally a subset of neural crest cells migrates fr om the pharyngeal region to form the outflow septum, Using neural cres t ablation, it has not been possible to separate the occurrence of aor tic arch maldevelopment from cardiac outflow tract dysmorphogenesis. I n order to determine whether normal aortic arch artery development is a prerequisite for normal outflow tract development, we have used a co mbination of antisense treatment with back transplantation of cardiac neural folds to produce abnormal patterning of the aortic arch arterie s. Paralogous groups of Hox messages with their anterior expression do mains in pharyngeal arches 3, 4 and 6 were targeted. Antisense targete d to paralogous group 3 Hox message caused aortic arch 3 located withi n the pharyngeal arch to regress in a manner similar to aortic arch 2, while antisense targeted to paralogous group 5 Hox message caused the appearance of an additional pharyngeal arch containing a novel and co mpletely independent aortic arch artery. Antisense treatment targeting paralogous group 4 Box message led to no detectable cardiovascular ph enotype in the first 6 days of development. While regression of arch a rtery 3 was associated with abnormal branching patterns of the aorta a nd pulmonary trunk, this did not involve abnormal separation of the ao rta and pulmonary trunks, the semilunar valves or the subvalvular regi on of the outflow tract. Because none of these changes in pharyngeal o r aortic arch artery development was accompanied by abnormal developme nt of the cardiac outflow tract, it appears that normal patterning of the aortic arch arteries is not a prerequisite for normal heart develo pment. Using reverse transcription polymerase chain reaction (BT-PCR) we were unable to detect changes in any of the Hox messages except gro up 4, thus, using this particular experimental strategy, we are unable to demonstrate or refute that expression of hox genes by cardiac neur al crest cells controls aortic arch patterning. Development of the car diac outflow tract was normal in each instance. This suggests that abn ormal aortic arch patterning does not necessarily lead to cardiac malf ormations. (C) 1997 Wiley-Liss, Inc.