(287c) Quantification and Modeling of BMP Signaling during Zebrafish Embryo Development

Bone Morphogenetic Proteins (BMPs) act in developmental pattern formation as a paradigm of extracellular information that is passed from an extracellular morphogen to cells that process the information and differentiate into distinct cell types based on the morphogen level. Numerous extracellular modulators and feedback regulators establish and control the BMP signaling distribution along the dorsal-ventral (DV) embryonic axis in vertebrates to induce space and time-dependent patterns of gene expression. To identify how the dynamic pattern is regulated during development, we have developed a seamless data-to-model integration and optimization strategy. First, the nuclear intensities of fluorescent stained Phosphorylated-Smad5 (P-Smad) are acquired for each nuclei in each embryo from staged populations to provide a quantitative time-course for the BMP signaling gradient. Next, the nuclei are segmented to yield quantitative point-clouds of P-Smad level at each nuclei. The individual point clouds are registered to similarly staged embryos using a process called Coherent Point Drift (CPD) and the registered populations provide rigorous quantification and comparison of phenotype. To delineate the mechanism of BMP signal inhibition by the secreted binding proteins Chordin (Chd), and Noggin (Nog) a mathematical model was developed and optimized against the population data for wild type and combinations of the Chd mutants with and without morpholino knockdown of Noggin and Follistatin. We found a model that reproduced the experimentally observed patterning in WT embryos as well as a number of tested mutants. Models consistent with experimental behavior require that Chordin has a greater range than Noggin, that Noggin is not as freely diffusible, and that the BMP ligands are freely diffusible.