SB, M.I.T., Computer Science/Biology, 1976
PhD, M.I.T. & Woods Hole Oceanographic Inst., 1985
The lab approaches questions of pattern formation and cell fate specification in the fruit fly Drosophila melanogaster. Our current interests are the mechanisms underlying the patterning of the embryonic dorsal-ventral (D/V) axis and the asymmetric self-renewal divisions of adult stem cells.
The original focus of the lab was on the role of the Bone Morphogenetic Protein (BMP) family member Decapentaplegic (Dpp) in patterning the D/V axis. In the past, we demonstrated that the system that patterns the embryonic D/V axis is conserved between arthropods and chordates, identified the mechanism by which the Spemann organizer patterns the Xenopus body axis, and characterized essential and modulatory components of the Dpp signal transduction pathway.
We showed that, although Dpp is broadly transcribed dorsally, receptor-bound Dpp is only observed in a sharp stripe comprising the dorsal-most cells. We demonstrated that formation of this pattern of Dpp - receptor interactions involves two distinct processes. First, Dpp undergoes long-range extracellular movement facilitated by the Dpp-binding protein Sog. Second, an intracellular positive feedback circuit promotes Dpp - receptor interactions as a function of previous signaling strength. The two processes cooperate to produce the observed spatial bistability of Dpp-receptor interactions. More recently, we have identified a genetic network that acts to confer robustness to this patterning process. Specifically, both a component of the positive feedback circuity, and a negative regulator of BMP signaling are under the control of a single transcription factor. Loss of this robustness circuit results in high levels of variability in BMP signaling and tissue specification.
We have also begun to investigate processes underlying maintenance of the germ line stem cells (GSCs) in the adult ovary. Like most adult stem cells, the GSCs are present in an environmental niche, which provides signals necessary for their maintenance. Dpp is a niche signal required for GSC maintenance. We hypothesize that interactions between the GSC and the surrounding niche cells create an intrinsic polarity in the GSC. This polarity both controls the plane of GSC division and elevates responsiveness to Dpp within the GSC. These two characteristics ensure a robust pattern of asymmetric, self-renewal divisions.