The long term goal of this research is to understand the genetic and molecular mechanisms underlying organogenesis and function of the thymus. Human birth defects that affect fetal thymus development can have both genetic causes, as in DiGeorge Syndrome and velocardiofacial syndrome (occurring in 1/5000 live births), and environmental origins. The early steps of fetal thymus development involve epithelial-mesenchymal interactions between pharyngeal endoderm derived epithelial cells and neural crest derived mesenchymal cells. Through analysis of mutant mouse strains and gene expression studies, a number of candidate genes have been identified in the mouse that may be involved in these early steps. However, the relationships between these genes and their specific roles in this process are poorly understood. The Hoxa3 and Pax1 genes are transcription factors that have been shown to have a role in regulating thymus development. Hoxa3 is expressed in both the endodermal epithelium and neural crest mesenchyme that contribute to thymus development, while Pax1 is expressed only in the endodermal epithelium. Mice which are mutant for Hoxa3 do not form a thymus Pax1 mutant mice have a hypoplastic thymus, and are deficient in early steps in T cell selection. Using a genetic analysis, we have shown that these two genes act synergistically to affect thymus development and thymocyte selection. To our knowledge, this result is the first demonstration of a genetic interaction between Hox and Pax genes in mice. In addition, Pax1 expression is specifically down-regulated in Hoxa3 mutants. We will use genetic and molecular approaches in mice to test the hypothesis that Hoxa3 and Pax` are interacting specifically in the endoderm to direct early thymus organogenesis.
The specific aims of the proposed research are: 1) to express Hoxa3 specifically in either them endoderm or neural crest, to determine the tissue specificity of Hoxa3 action in thymus development, and to address whether Hoxa3 regulates Pax1 expression; 2) to investigate the origin of the thymic hypoplasia in Hoxa3. Pax1 compound mutants, and identify potential downstream targets for Hoxa3 and Pax1 in early thymus organogenesis; and 3) test the ability of exogenously added candidate growth factors to bypass the block in thymus organogenesis and function in these mutants. The proposed studies seek to define a genetic pathway the regulates this poorly understood developmental process.
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