The harmonious development of the human embryo is essential if individuals are to meet successfully the demands of several crucial life steps on (i.e., birth). Alterations of the normal developmental patterns can cause a wide variety of health problems ranging from undetectable or mild changes to severe malformations, even lethality. Therefore, it becomes critical to know how development occurs normally if we are ever going to be able to design rational preventive or therapeutic measures. The Hox genes have been implicated strongly in several aspects of normal development, and this proposal deals with experiments designed to study their normal role in vivo through the use of mouse mutants generated by gene targeting in embryonic stem (ES) cells. The long-term goal of this proposal is to carry out an elaborate genetic dissection of part of one of the mammalian Hox clusters, HoxB. The initial approach is to scan genetically the 5' end of the cluster (Hoxb-9, Hoxb, and Hoxb-7 genes) through the production and analysis of a series of overlapping deletion mutants (Specific Aim 1). Then, analysis of the phenotypic consequences of the different deletions will guide further molecular and genetic characterization (i.e., identification of new cDNAs and regulatory regions, generation of additional mouse mutants).
Specific Aims 2 and 3 will deal with a focused in vivo analysis of the role of the most 5' gene of the HoxB cluster, Hoxb-9.
Specific Aim 2 will describe the analysis of the coding region of the gene, and Specific Aim 3 will study the regulatory elements responsible for its proper expression during development. These experiments will involve gene targeting to generate mouse mutants, transgenic mice with lacZ reporter genes, and in vitro DNA- protein binding studies. All the in vivo work will include detailed phenotypic characterization (i.e., morphological and molecular criteria) with the intention of finding opportunities to develop assays to study the basic cellular mechanisms of Hox gene action.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29HD033729-03
Application #
2668598
Study Section
Human Embryology and Development Subcommittee 1 (HED)
Project Start
1996-03-01
Project End
2001-02-28
Budget Start
1998-03-01
Budget End
1999-02-28
Support Year
3
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Texas Agrilife Research
Department
Type
Schools of Earth Sciences/Natur
DUNS #
110521739
City
College Station
State
TX
Country
United States
Zip Code
77843