- Cell Biology & Anatomy
- Physiological Sciences
P.O. Box 245044
Tucson, AZ 85724
Research in our laboratory is focused on understanding the molecular regulation of early developmental processes in vertebrate embryos. We primarily use the chicken embryo as a model organism, and approach research questions from the dual perspective of how individual molecules function and how their functions can be integrated into network models. One present research emphasis is concerned with understanding epithelial to mesenchymal transition (EMT) during avian gastrulation. Microarray studies have shown that more than 1800 genes are upregulated in the epiblast adjacent to the primitive streak. Many of these genes are regulated by FGF signaling, including members of several other signaling pathways and at least thirty differentially expressed transcription factors. Fgf signaling therefore appears to be a key upstream regulator of EMT. Studies are investigating the intracellular signaling pathways downstream of Fgf receptor activation, including the MAPK, PI3K and AKT pathways. The MAPK pathway in particular directly regulates downstream gene transcription via activation of several transcription factors, including members of the Ets and T Box families. Studies are investigating downstream transcriptional targets of these factors.
Another long standing research interest in the lab is the mechanisms controlling early stages of cardiac myogenesis, from the emergence of premyocardial cells during gastrulation to formation of the primitive heart tube. Bmp and Fgf signaling are well known activators of genes in the cardiogenic pathway, however relatively few direct transcriptional targets of these signaling pathways have been identified. By combining classical experimental embryological approaches with genome wide microarray analyses, we are working to generate a large-scale model of cardiac myogenesis.
These studies are integrating with a parallel effort to generate broad approaches for developing network models of biological processes in vertebrates. This involves high throughput in situ hybridization and microarray gene expression analysis and large scale-collation of published information to generate preliminary network models. Models are then tested through parameter space using software tools such as Ingeneue. Results are integrated with an artificial intelligence software environment that evaluates results and can suggest network modifications for retesting. Promising candidate network models are then tested in vivo. Through successive reiterations between computational network modeling and model testing in vivo, progressively more representative networks can be generated. Initial efforts are focused on modeling EMT during gastrulation and cardiac myogenesis.
Our laboratory also hosts the GEISHA in situ hybridization database and website (http://geisha.arizona.edu). The GEISHA project (gallus expression in situ hybridization analysis) began in 1998 to investigate using high throughput whole mount in situ hybridization to identify novel, differentially expressed genes in chicken embryos. An initial expression screen of approximately 900 genes demonstrated feasibility of the approach, and also highlighted the need for a centralized repository of in situ hybridization expression data. Funding was eventually obtained for this purpose. The goals of the GEISHA project are to obtain whole mount in situ hybridization expression information for all differentially expressed genes in the chicken embryo between HH stages 1-25, to integrate expression data with the chicken genome browsers, and to offer this information through a user-friendly graphical user interface