MALFORMATIONS OF THE HEART, KIDNEY, PALATE, AND SKELETON IN ALPHA-MHC-HOXB-7 TRANSGENIC MICE

To begin to define the genetic network involved in cardiogenesis, we g enerated mice bearing the alpha-myosin heavy chain (MHC)Hoxb-7 transge ne. We hypothesized that using the cardiac-specific alpha-MHC promoter , we can direct ectopic expression of Hoxb-7 in the heart and perturb its normal development. Both whole mount in situ hybridization and nor thern analyses showed that this alpha-MHC promoter resulted in transge ne expression in the developing heart. Severe ventricular septal defec ts (VSD) were found in several mutant mice. Interestingly, transgenic mice were observed to have other malformations as well, including clef t palate, renal anomalies, and skeletal abnormalities in the craniocer vical and costosternal regions. The kidney defect consisted of double ureter and pelvis. In summary, we have shown that a dominant gain-of-f unction mutation of Hoxb-7 using the murine alpha-MHC promoter results in perturbation of the genetic circuitry underlying multiple developm ental processes, including cardiogenesis. Misexpression of Hoxb-7 duri ng heart development may be involved in the pathogenesis of VSD.