Exencephaly in a subset of animals heterozygous for AP-2alpha mutation

Transcription factor AP-2alpha has been implicated as a cell-type-specific regulator of gene expression during vertebrate embryogenesis based on its expression pattern in neural crest cells, ectoderm, and the nervous system in mouse, chick, and frog embryos. AP-2alpha is prominently expressed in cranial neural crest cells, a population of cells migrating from the lateral margins of the neural folds during closure of the neural tube in E (embryonic day of development) 8-9 mouse embryos. Homozygous AP-2alpha mutant mice die perinatally with cranio-abdominoschisis, full facial clefting, and defects in cranial ganglia and sensory organs.

Mice heterozygous for the AP-2alpha mutation on a 129/Sv strain were crossed with wildtype mice from the strain 129/Ola. The resulting embryos were genotyped, examined and used for histological analysis.

A subset of animals heterozygous for the AP-2alpha mutation develop a midbrain exencephaly after the mutation was crossed for one generation in the 129/Ola mouse strain. Up to 14% of the animals show a failure of the cranial neural folds to close resulting in a partial exencephaly, all of them being heterozygous for the mutation. The affected animals show reduced rostrocaudal dimensions of the skull and malformations of the bones of the cranial vault. The neural tube defects vary from pure midbrain exencephaly to a forebrain/midbrain exencephaly where the proliferating neural tissue covers the eyes completely.

The results support a role of AP-2alpha in the etiology of exencephalic disorders. The phenotype observed might be due to a downregulation of the remaining allele suggesting the presence of an upstream modifier gene.