Development of a lethal congenital heart defect in the splotch (Pax3) mutant mouse

The splotch (Sp2h) mutation disrupts the Pax3 gene and is lethal in homozygotes. The aim of the present study was to investigate the cause of lethality.

Using the splotch (Sp2H) mouse mutant, we demonstrated that approximately 60% of Sp2H homozygotes die in utero at 13.5-14.5 days of gestation. All these embryos have cardiac malformations involving partial or complete failure of septation of the outflow tract. Although the cause of death in utero is 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 Sp2H homozygotes die around the time of birth, and these embryos have grossly normal hearts. All Sp2H homozygotes have neural tube defects, either spina bifida, exencephaly, or both. Although these defects clearly do not cause death in utero, they are very likely responsible for the perinatal death of homozygotes that survive to late gestation. There is no correlation between the presence or absence of a cardiac defect and the type of neural tube defect. On the other hand, there is a striking correlation between presence of a cardiac defect and reduction or absence of dorsal root ganglia, which are derivatives of the neural crest.

In this paper, we show that the lethality has a biphasic pattern, and the data strongly suggests that mid-gestation lethality is due to cardiac defects and not the associated neural tube defects. This finding supports the idea that 'conotruncal' cardiac defects involving the ventricular outflow tracts develop as a result of failure of the 'cardiac' neural crest to colonise the developing heart in the mid-gestation embryo, and that the resulting heart defects are solely responsible for the observed mortality.