Exencephaly and hydrocephaly in mice with targeted modification of the apolipoprotein B (Apob) gene

Apolipoprotein B (apoB) is a key structural component of several lipoproteins. These lipoproteins transport cholesterol, lipids, and vitamin E in the circulation. Humans that produce truncated forms of apoB have low plasma concentrations of apoB, beta-lipoproteins, cholesterol, and often vitamin E. This condition has been modeled in mice by targeted modification of the apoB gene. Homozygous transgenic mice display all of the hallmarks of the human disorder. Unexpectedly, approximately 30% of the perinatal homozygotes are exencephalic and of those that have closed neural tubes, approximately 30% are hydrocephalic. The latter condition has also been noted in a relatively small proportion of the heterozygous mice. Vital staining of gestational day 9 (GD9) homozygous offspring has illustrated a striking pattern of excessive cell death involving the alar plate of the hindbrain. Histological and scanning electron microscopic analyses have confirmed this finding. We speculate that varying degrees of affect, as noted among GD 9 and 10 embryos, lead to the spectrum of malformations, including hydrocephaly, present in term fetuses. Analysis of vitamin E deficiency as a possible causative factor has illustrated that homozygous fetuses, indeed, show this deficiency. Amelioration of the defects through alpha-tocopherol supplementation of the maternal diet has been explored. Further analyses of this transgenic mutant promise to provide significant information relative to the role of deficiency of vitamin E and other apoB dependent compounds in dysmorphogenesis.