Signals between cells are critical for embryonic development and for the differentiation of stem cells into various cell types. Identifying the signals that are needed for stem cell differentiation—and understanding how they produce their effect—are key to the overall goal of using stem cells for therapeutic purposes. This proposal focuses on one such signaling system, the Bmp pathway. Bmps, an acronym for Bone morphogenetic proteins, are a family of proteins that function in a variety of processes in embryonic development. They interact with cells through receptors on the cell surface. These interactions cause the receptors to activate proteins known as smads. Following a Bmp signal, Smad proteins enter the nucleus and cause changes in gene expression, which ultimately lead to changes in the identity or behavior of cells. An important function of Bmps is to promote differentiation of embryonic stem cells along certain pathways. Despite the importance of this activity in stem cell biology, very little is known about how it occurs in molecular terms. One idea is that Bmps promote ES cell differentiation by interfering with the function of a complex of proteins known as polycomb. The polycomb complex is though to help to maintain cells in a stem-like state by interfering with the expression of genes that promote cell differentiation. A number of genes that are Bmp targets are also polycomb targets. The major question of this proposal is how the Bmp pathway causes a loss of polycomb-mediated repression and how this effect relates to the differentiation of human embryonic stem cells into different cell and tissue types.
Embryonic stem cells hold great promise in the treatment of human disease. However the lack of basic information about the genetic programs that control the differentiation of these cells limits the extent to which they can be manipulated in culture, and thus their utility. The central aim of this proposal is to help elucidate how, in specific molecular terms, the genetic program controlling “stemness” is turned off and a set of programs controlling differentiation is turned on. The value these studies to the State of California is that they will contribute to the knowledge base that ultimately will enable human ES cells to be used to rescue defective cells in humans.