EXENCEPHALY AND HYDROCEPHALY IN MICE WITH TARGETED MODIFICATION OF THE APOLIPOPROTEIN-B (APO-B) GENE

Apolipoprotein B (apoB) is a key structural component of several lipop roteins. These lipoproteins transport cholesterol, lipids, and vitamin E in the circulation. Humans that produce truncated forms of apoB hav e low plasma concentrations of apoB, beta-lipoproteins, cholesterol, a nd often vitamin E. This condition has been modeled in mice by targete d modification of the apoB gene. Homozygous transgenic mice display al l of the hallmarks of the human disorder. Unexpectedly, approximately 30% of the perinatal homozygotes are exencephalic and of those that ha ve closed neural tubes, approximately 30% are hydrocephalic. The latte r condition has also been noted in a relatively small proportion of th e heterozygous mice. Vital staining of gestational day 9 (GD9) homozyg ous offspring has illustrated a striking pattern of excessive cell dea th involving the alar plate of the hindbrain. Histological and scannin g electron microscopic analyses have confirmed this finding. We specul ate that varying degrees of affect, as noted among GD 9 and 10 embryos , lead to the spectrum of malformations, including hydrocephaly, prese nt in term fetuses. Analysis of vitamin E deficiency as a possible cau sative factor has illustrated that homozygous fetuses, indeed, show th is deficiency. Amelioration of the detects through alpha-tocopherol su pplementation 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 depende nt compounds in dysmorphogenesis. (C) 1995 Wiley-Liss, Inc.