Bone Morphogenic Protein (BMP) signaling is a conserved pathway used for development and homeostasis. In the model system Drosophila melanogaster patterning of the dorsal surface is controlled by Decapentapolegic (DPP), a BMP protein that robustly stimulates the BMP signaling pathway in a narrow domain of cells on the dorsal surface of the embryo. The levels of Dpp are estimated to be between 10-100 molecules / nucleus, which would predict a significant level of noise in Dpp signaling. However this is not observed, so there must be mechanisms that dampen noise in signaling pathways. I used molecular biology, genetics, and mathematical modeling to identify possible mechanisms for feedback control of BMP signaling and to elucidate mechanisms to dampen stochastic fluctuations in signaling molecules. I have identified a new novel allele of nejire with a stop codon in the 12th exon. This mutation truncates part of the glutamine rich domain at the end of the protein. This new allele has a highly variable phenotype with all embryos showing varying degrees of loss of Dpp signaling in the pre-cephalic furrow embryos, and half showing recovery just before and during gastrulation. I also studied the phenotype of Crossveinless-2 (Cv-2) during dorsal surface patterning. I found that cv-2 is a Dpp response gene that is a negative inhibitor of Dpp signaling during dorsal surface patterning. Cv-2 null embryos have a 20% wider area of Dpp signaling on the dorsal surface, and this change leads to a larger amnioserosa later in development. Interestingly loss of Cv-2 leads to a slight increase in noise in the width of pMad, the intracellular signaling of Dpp receptor activation. I followed up on this finding with a 3D stochastic model of Dpp for a single nuclear compartment which suggests that competition for BMP from the receptor could increase noise in signaling. In addition, the stochastic model suggests that endocytosis of Dpp bound receptors and nuclear accumulation of transcription factors may be mechanisms to decrease noise and increase robustness of Dpp signaling.
University of Minnesota Ph.D. dissertation. February, 2014. Major: Chemical Engineering. Advisors: Hans Othmer and Michael O'Connor. 1 computer file (PDF); xii, 193 pages.
Modulation of BMP signaling during Dorsal-Ventral patterning in Drosophila melanogaster.
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