Project 457553

The growth of an organ requires production of the correct shape with the correct identity of cells. When the embryo develops, it accomplishes both processes in a remarkably synchronized fashion. How this synchrony occurs is largely an open question. In our lab, we have found that developing organs generate coordinated forces which are felt by individual cells of the tissue. It is known that within cells, a series of mechanical linkages connect the cell surface to structures within, including the nucleus. Within the nucleus is a condensed and packaged form of DNA known as chromatin. Chromatin contains the genes which define a cell's identity, but which genes are actually expressed depends on the conformation of said chromatin. It is believed that during the shaping of organs, the forces acting on cells are mechanically transmitted to the nucleus and can physically control chromatin conformation. The goal of my research is to test whether this physical control can alter the expression of genes required for cell identity. I will test this idea by using the early embryonic limb bud as a model system. The limb bud, which is the precursor to the arm/hand, is ideal because its development and tissue forces have been well studied. The limb bud is composed of proximal (away from hand) and distal (towards hand) cells that have distinct chromatin conformations and express different genes. Using mechanical tools our lab has made, I will apply compressive force to distal limb bud cells in developing mouse embryos and test whether the gene expression and chromatin conformation becomes more similar to proximal cells. I will also use genetic mouse engineering to remove the linkages connecting the nucleus to the cell surface, and test whether force transmission to chromatin is altered. This research will help us understand how the physical shaping of organs is related to cell identity, which in turn will improve our ability to engineer tissues and organs for regenerative medicine.