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.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD030727-02
Application #
2203066
Study Section
Genetics Study Section (GEN)
Project Start
1993-09-01
Project End
1997-08-31
Budget Start
1994-09-01
Budget End
1995-08-31
Support Year
2
Fiscal Year
1994
Total Cost
Indirect Cost
Name
California Institute of Technology
Department
Type
Schools of Arts and Sciences
DUNS #
078731668
City
Pasadena
State
CA
Country
United States
Zip Code
91125
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