Targeted disruption of the murine int-1 proto-oncogene resulting in severe abnormalities in midbrain and cerebellar development

Abstract

THE int-1 proto-oncogene was first identified as a gene activated in virally induced mouse mammary tumours^1,2. Expression studies, however, suggest that the normal function of this gene may be in spermatogenesis and in the development of the central nervous system^3–5. Genes sharing sequence similarity with int-1 have been found throughout the animal kingdom. For example, int-1 has 54% amino-acid identity to the Drosophila segment polarity gene wingless (wg)⁶. Both the int-1 and wg gene products seem to be secreted proteins, presumably involved in cell–cell signalling^7–11. We have now explored the function of int–1 in the mouse by disrupting one of the two int-1 alleles in mouse embryo-derived stem cells using positive–negative selection¹². This cell line was used to generate a chimaeric mouse that transmitted the mutant allele to its progeny^13–16. Mice heterozygous for the int-1 null mutation are normal and fertile, whereas mice homozygous for the mutation may exhibit a range of phenotypes from death before birth to survival with severe ataxia. The latter pathology in mice and humans is often associated with defects in the cerebellum. Examination of int-l^–/int-l^– mice at several stages of embryo-genesis revealed severe abnormalities in the development of the mesencephalon and metencephalon indicating a prominent role for the int-1 protein is in the induction of the mesencephalon and cerebellum.