During embryogenesis, patterning is one of the key processes by which the body plan of the embryo becomes established. Patterning of the A-P axis is accomplished by the products of the Hox gene family. In mammals, there are 39 genes in the Hox family that have been grouped into four clusters (A-D) by virtue of their chromosome location. Cross-species studies have confirmed the conservation of the Hox genes during evolution. In vivo, the products of the Hox genes function as transcription factors. The genes have a highly conserved sequence called the homeobox, which translates into a 60 amino acid homeodomain. The homeodomain is a DNA-binding domain made up of three alpha helices and an N-terminal arm which precedes helix 1. Since most HOX homeodomains bind a common core sequence (TAAT), the mechanism by which these proteins achieve specificity in target gene regulation was unknown for some years. This was resolved by the identification of extradenticle (exd). Genetic analysis of zygotic and maternal effect mutations of exd demonstrated that it is a required cofactor for the Drosophila Hox gene products. Examination of exd mutations showed posterior and anterior transformations with alteration in segmental identities. These transformations were similar to those caused by Hox genes. Further analysis of the Hox and exd mutations in vivo, substantiated by in vitro biochemical evidence showed that exd acts in concert with homeotic gene products by cooperatively binding DNA. The mammalian homologue of exd is PBX. PBX functions analogously to its Drosophila counterpart by modulating the DNA-binding specificity of HOX proteins. In mammals, PBX interacts with members of the first 10 paralog group HOX proteins. A second cofactor, MEIS with a high degree of homology to PBX was identified very recently. Both PBX and MEIS belong to the three amino acid loop extension (TALE) family of homeodomain proteins. The homeodomain of these proteins differ from the HOX homeodomains in t

Featherstone, M. S. (Supervisor)