DEVELOPMENT OF A LETHAL CONGENITAL HEART DEFECT IN THE SPLOTCH (PAX3)MUTANT MOUSE

Objective: The splotch (Sp(2H)) mutation disrupts the Pax3 gene and is lethal in homozygotes. The aim of the present study was to investigat e the cause of lethality, Methods and results: Using the splotch (Sp(2 H)) mouse mutant, we demonstrated that approximately 60% of Sp(2H) hom ozygotes die in utero at 13.5-14.5 days of gestation. All these embryo s have cardiac malformations involving partial or complete failure of septation of the outflow tract. Although the cause of death in utero i s unknown, the dying embryos are edematous, their superior caval veins are over-expanded, and the fetal liver is enlarged and engorged with blood, all signs of cardiac failure. The remaining Sp(2H) homozygotes die around the time of birth, and these embryos have grossly normal he arts. All Sp(2H) homozygotes have neural tube defects, either spina bi fida, exencephaly, or both. Although these defects clearly do not caus e death in utero, they are Very likely responsible for the perinatal d eath of homozygotes that survive to late gestation. There is no correl ation between the presence or absence of a cardiac defect and the type of neural tube defect. On the other hand, there is a striking correla tion between presence of a cardiac defect and reduction or absence of dorsal root ganglia, which are derivatives of the neural crest. Conclu sions: In this paper, we show that the lethality has a biphasic patter n, and the data strongly suggests that mid-gestation lethality is due to cardiac defects and not the associated neural tube defects. This fi nding supports the idea that 'conotruncal' cardiac defects involving t he ventricular outflow tracts develop as a result of failure of the 'c ardiac' neural crest to colonise the developing heart in the mid-gesta tion embryo, and that the resulting heart defects are solely responsib le for the observed mortality. (C) 1997 Elsevier Science B.V.