Mammalian homeobox genes in normal development and neoplasia

This review aims at providing an evaluation of the currently available data concerning the role of homeobox genes in mammalian embryonic pattern formation, and their involvement in oncogenic processes. The literature dealing with mouse and human homeobox genes is covered, with some excursions into Xenopus and chicken work because studies regarding particular aspects of development in the latter systems often complement those in mammals. Other studies in amphibians, chicken, and fish are omitted as they fall outside the scope of this survey devoted to mammalian genes. Emphasis is placed on expression and regulation during normal embryogenesis, on present hypotheses regarding gene function, on effects on development of modifying the expression patterns, and on observed aberrations in structure or expression associated with and possibly causally linked to neoplasia. The studies specifically dealing with the structure of the homeodomain and the mechanism of its interactions with DNA, which have been recently reviewed, are not considered here. The most thoroughly studied mammalian homeobox genes bear sequence homology to the Drosophila Antennapedia (Antp) homeotic gene and are thought to be involved in determination of regional identity along the anteroposterior (A-P) axis. Studies on these genes, the HOX genes, are oftem compared with related investigations in flies. In addition to the HOX genes, a number of genes containing a homeobox related to that in other Drosophila developmental control genes have been isolated from the mammalian genome and are being intensively studied. Homeodomains divergent from the Antp prototype have been discovered in an increasing number of transcription factors. Some of these may play a crucial role in local pattern formation, while others are tissue-specific or ubiquitous transcription regulators. As is unsurprising of genes, whose products regulate transcription, some of the homeobox-containing genes have been associated with malignancy, usually on the basis of abnormal structure, or deletions found to occur in tumor cells. The degree of probability that these mutated forms were causative in the generation of the tumors in which they were found is discussed.