Grant: Operating Grant

The intestinal tract begins life as a specialized group of cells, termed endoderm cells, that form early in development. These cells, initially homogenous in nature, eventually give rise to all of the constituents of the digestive tract, including the esophagus, stomach and small and large intestines, as well as a number of ancillary glands and organs such as the pancreas and liver. The development of the endoderm into this array of highly specialized structures relies on the coordinated activity of a number of signaling pathways, which allow cell-cell communication and regulated expression of various transcription factors which regulate the expression of genes which dictate the nature of a given cell. A number of these signaling pathways and transcription factor networks continue to operate in the adult, where they are critical in order to maintain a constant supply of mature cells to replace those cells which the intestine constantly sheds off. Lesions in the proper development of the endoderm can result a number of birth defects, typically with devastating consequence. In addition, defects in the pathways dictating intestinal homeostasis in the adult can lead to intestinal cancers or other disorders such as Crohn's disease. Our understanding of the pathways and processes involved in intestinal development and homeostasis is rudimentary. Recently, two transcription factors, Cdx1 and Cdx2, have been implicated in both intestinal development and cancer, however, their precise roles in these events is poorly understood. Novel genetic models developed by our group hold strong propose for a better understanding of the gene networks and pathways that are dependent on Cdx function. The information forthcoming from these studies will have important bearing on our understanding not only of basic processes related to intestinal development, but may also shed light on the basis for certain congenital defects and cancers prevalent in the human population.