MYOGENIC AND MORPHOGENETIC DEFECTS IN THE HEART TUBES OF MURINE EMBRYOS LACKING THE HOMEO BOX GENE NKX2-5

The murine homeo box gene Nkx2-5 is expressed in precardiac mesoderm a nd in the myocardium of embryonic and fetal hearts. Targeted interrupt ion of Nkx2-5 resulted in abnormal heart morphogenesis, growth retarda tion and embryonic lethality at similar to 9-10 days postcoitum (p.c.) . Heart tube formation occurred normally in mutant embryos, but loopin g morphogenesis, a critical determinant of heart form, was not initiat ed at the linear heart tube stage (8.25-8.5 days p.c.). Commitment to the cardiac muscle lineage, expression of most myofilament genes and m yofibrillogenesis were not compromised. However, the myosin light-chai n 2V gene (MLC2V) was not expressed in mutant hearts nor in mutant ES cell-derived cardiocytes. MLC2V expression normally occurs only in ven tricular cells and is the earliest known molecular marker of ventricul ar differentiation. The regional expression in mutant hearts of two ot her ventricular markers, myosin heavy-chain beta and cyclin D2, indica ted that not all ventricle-specific gene expression is dependent on Nk x2-5. The data demonstrate that Nkx2-5 is essential for normal heart m orphogenesis, myogenesis, and function. furthermore, this gene is a co mponent of a genetic pathway required for myogenic specialization of t he ventricles.