The broad long-term objective is to understand at the molecular level how a gene cluster of the bithorax type is able to program the development of the body segments of higher organisms. This proposal focuses on the Abdominal-B (Abd-B) domain of the bithorax complex (BX-C) and more specifically on how it is regulated in cis. Several features of the organization of the cis-regulatory regions of this domain are highly unusual: a) over 95% of the DNA of the Abd-B domain exists in such regions; b) over 50% of these regions are located 3' rather than 5' to the coding region; and c) the regions are colinear in their chromosome order with their order of controlling Abd-B protein expression along the body axis.
Our specific aims are l) to develop new tools for dissecting various classes of elements within each cis-regulatory region; 2) to correlate the morphological effects of varying length deletions of these regions with the effects of such deletions upon the pattern of Abd-B expression; 3) to use transformation assays based on P-element constructs to discover classes of elements that are responsible for the wild-type pattern of Abd- B expression and; 4) to undertake a computational analysis of DNA sequence in the cis-regulatory regions to search for redundancy of specific motifs.
These aims will enable us to test the hypothesis that there are elements within each 3'cis-regulatory region that cause one of the ABD-B proteins (ABD-BI) to be expressed in a graded fashion that increases along the anterior/posterior body axis. A more global hypothesis that we plan to test with our studies is that the cis-regulatory regions have evolved from an ancestral region by tandem duplication and subsequent diversification by mutation. Our proposed studies are expected to have application to the molecular characterization of a variety of human genetic defects that involve faulty regulation of homeobox genes. In addition, there are expected to be applications to characterizing underlying defects that are responsible for tumorigenesis.
| Lewis, E B; Knafels, J D; Mathog, D R et al. (1995) Sequence analysis of the cis-regulatory regions of the bithorax complex of Drosophila. Proc Natl Acad Sci U S A 92:8403-7 |
| Fernandes, J; Celniker, S E; Lewis, E B et al. (1994) Muscle development in the four-winged Drosophila and the role of the Ultrabithorax gene. Curr Biol 4:957-64 |
