The mammalian Tolloid-like 1 gene, Tll1, is necessary for normal septationand positioning of the heart

Mammalian Tolloid-like 1 (mTLL-1) is an astacin-like metalIoprotease, highl y similar in domain structure to the morphogenetically important proteases bone morphogenetic protein-1 (BMP-1) and Drosophila Tolloid, To investigate possible roles for mTLL-1 in mammalian development, we have used gene targ eting in ES cells to produce mice with a disrupted allele for the correspon ding gene, TU1, Homozygous mutants were embryonic lethal, with death at mid -gestation from cardiac failure and a unique constellation of developmental defects that were apparently confined solely to the heart. Constant featur es were incomplete formation of the muscular interventricular septum and an abnormal and novel positioning of the heart and aorta. Consistent with rol es in cardiac development, Till expression was specific to precardiac tissu e and endocardium in 7.5 and 8.5 days p.c. embryos, respectively. Tll1 expr ession was also high in the developing interventricular septum, where expre ssion of the BMP-1 gene, Bmp1, was not observed. Cardiac structures that we re not affected in Tll1(-/-) embryos either showed no TRI expression (atrio -ventricular cushions) or showed overlapping expression of Tll1 and Bmp1 (a orticopulmonary septum), suggesting that products of the Bmpl gene may be c apable of functionally substituting for mTLL-1 at sites in which they are c o-expressed, Together, the various data show that mTLL-1 plays multiple rol es in formation of the mammalian heart and is essential for formation of th e interventricular septum, embryos, respectively. Tll1 expression was also high in the developing interventricular septum, where expression of the BMP -1 gene, Bmp1, was not observed. Cardiac structures that were not affected in Tll1-/- embryos either showed no TRI expression (atrio-ventricular cushi ons) or showed overlapping expression of Tll1 and Bmp1 (aorticopulmonary se ptum), suggesting that products of the Bmpl gene may be capable of function ally substituting for mTLL-1 at sites in which they are co-expressed, Toget her, the various data show that mTLL-1 plays multiple roles in formation of the mammalian heart and is essential for formation of the interventricular septum.