Cell Biology, Neurobiology & Anatomy

Training / Education
BS, University of Scranton, Pennsylvania, 1996
PhD, Michigan State University, East Lansing, Michigan, 2002

Research Area: Transcriptional control of liver and gut development and physiology

During embryonic development, the activation of specific gene expression programs causes cells to differentiate, ultimately creating functional organs. Studies of heart, liver, lung, and pancreas development indicate that specific transcription factors gradually activate a cascade of gene expression, which initiates and maintains cytodifferentiation. To identify and characterize the role that specific transcription factors play in liver and intestine development and function, our laboratory uses LoxP-Cre technology to eliminate these factors from specific organs during development. My work has focused on characterizing HNF4a, a transcription factor belonging to the nuclear hormone receptor family, and GATA4, a zinc finger DNA binding domain containing transcription factor. 

To determine how HNF4a functions to control epithelial morphogenesis in the developing liver, I used HNF4α conditional knockout mice to establish that HNF4α coordinates the developmental expression of an extensive array of proteins essential for diverse aspects of junction assembly and function during hepatogenesis. The finding that HNF4α is responsible for expression of such a large and diverse repertoire of cell adhesion and cell-junction proteins strongly supports the proposal that HNF4α acts as an orchestrator of epithelial morphogenesis in the developing liver primarily by coordinating the formation cell junctions and adhesions. These studies describe a molecular framework through which epithelial formation coincides with the onset of organ function during embryonic development.

GATA4 is expressed in the epithelial cells of the duodenum and jejunum of the small intestine, but not in the ileum or in the large intestine. Expression in the intestinal epithelium is detected at E13.5-14.5, the time at which intestinal morphogenesis begins, and it continues through the remainder of embryonic development and in adulthood. Others have shown in vitro that GATA4 can bind to sites in the promoters of several genes expressed in differentiated intestinal epithelial cell lines and that GATA4 can transactivate such promoters in reporter gene assays. Moreover, GATA4 is essential for development of extraembryonic endoderm. This tissue shares similar function with the GI tract in that it expresses a similar set of genes and is responsible for maintaining the optimal nutrient balance for the developing embryo. Based on these data, I proposed that GATA4 is essential for gastrointestinal development because it regulates the expression of genes whose products are critical in executing cell differentiation and morphogenesis. I used a conditional knockout approach to eliminate GATA4 specifically in the intestinal epithelium. I found that although GATA4 is dispensable for embryonic intestinal morphogenesis, GATA4 is required for efficient intestinal lipid uptake and that it is also likely required for cholesterol absorption and metabolism. This study implicates GATA4 as a transcription factor with a specific role in regulating the expression of genes required for lipid and cholesterol uptake and metabolism. I also found that jejunum lacking GATA4 transitions toward an ileal phenotype suggesting that GATA4 is important in defining the jejunal character of the intestine.

Publications

Battle, M.A., Konopka, G., Parviz, F., Gaggl, A. L., Yang, C., Sladek, F. M., and Duncan, S. A. (2006). Hepatocyte nuclear factor 4a orchestrates expression of cell adhesion proteins during the epithelial transformation of the developing liver. Proc Natl Acad Sci U S A 103, 8419-8424.

Garrison, W. D., Battle, M. A., Yang, C., Kaestner, K. H., Sladek, F. M., and Duncan, S. A. (2006). Hepatocyte nuclear factor 4a is essential for embryonic development of the mouse colon. Gastroenterology 130, 1207-1220.

Rufibach, L. E., Duncan, S. A., Battle, M.A., and Deeb, S. S. (2006). Transcriptional regulation of the human hepatic lipase (LIPC) gene promoter. J Lipid Res 47, 1463-1477.

Watt, A. J., Battle, M. A., Li, J., and Duncan, S. A. (2004). GATA4 is essential for formation of the proepicardium and regulates cardiogenesis. Proc Natl Acad Sci U S A 101, 12573-12578.

Battle, M. A., Maher, V. M., and McCormick, J. J. (2003). ST7 is a novel low-density lipoprotein receptor-related protein (LRP) with a cytoplasmic tail that interacts with proteins related to signal transduction pathways. Biochemistry 42, 7270-7282