Our laboratory is interested in regulatory mechanisms governing the process of cell fate determination, with a focus on the identification of novel transcription factors that control osteoblast differentiation and adaptation in response to diseases. We use osteoblasts, the bone forming cells, chondrocytes, cartilage forming cells, cancer cells, the as model systems to understand how the program of cell proliferation and differentiation are controlled at the transcription level. Osteoblasts and chondrocytes are originated from the same mesenchymal progenitors which also differentiate into a variety of other cell types, each of which expressing distinct sets of genes controlled by different transcription factors and extracellular signals. By performing loss-of-function experiments in vivo, several essential osteoblast-specific factors have been identified. Recently, we have identified ATF4, another transcription factor that is essential for terminal osteoblast differentiation. Deletion of Atf4 in mice leads a severe osteoporosis due to a lack of mature osteoblasts in both embryos and adults and a decrease in the synthesis of Type I collagen, the main constituent of bone matrix protein. We are currently using a variety of approaches to define the mechanisms by which ATF4 governs the terminal osteoblast differentiation and to identify regulatory proteins with which it interacts.
ATF4 is also the target for several signal transduction cascades that induce and repress osteoblast differentiation. We are investigating how ATF4 may respond to various extracellular signals through phosphorylation and other types of post-translational modification and the role of these events in the control of ATF4's function.