How does a vertebrate animal body develop from a single cell is an overarching question of my research. Despite much progress, many basic mechanisms underlying embryogenesis remain poorly understood. I am particularly interested how the inductive and morphogenetic processes that establish the embryonic body plan are coordinated in space and time to ensure normal development. Specification of anteroposterior and dorsoventral embryonic axis in the zebrafish zygote involves microtubule dependent transport of factors promoting dorsal Wnt/?-catenin activity, which patterns germ layers and coordinates gastrulation movements. We showed that Ccl19.1 chemokine signaling through Ccr7 G protein-coupled receptor (GPCR) limits axis formation by downregulating ?-catenin. Using mutations in ccl19.1 and ccr7 zebrafish genes we will delineate the pathways through which they regulate calcium signaling and limit axis formation. We recently discovered that Dachsous (Dchs) cadherins regulate cytoskeleton in the zygote and during axis formation. Whereas Dchs is commonly known to interact with Fat cadherin and Fjx1 kinase, we will characterize Fat/Fjx1-dependent and independent roles of Dchs. We will identify proteins interacting with Dchs to define its functional links to cytoskeleton and other effectors. During gastrulation, convergence and extension (C&E) movements elongate the germ layers anteroposteriorly and narrow them dorsoventrally. Wnt/Planar Cell Polarity (Wnt/PCP) signaling is a conserved regulator of polarized cell behaviors driving C&E in vertebrates. Our studies posit that Wnt/PCP signaling works during gastrulation as a cellular compass coordinating polarity and behaviors of individual cells with anteroposterior embryonic polarity, in part by asymmetric distribution of PCP components at anterior and posterior cell membranes. To understand how the planar asymmetries of PCP components arise in dynamic mesenchymal cells, we will test the hypothesis that adhesion GPCR, Gpr125, a new PCP component, promotes formation of the posteriorly enriched membrane PCP complexes. We will determine whether Dchs works with Fat and Fjx1 during gastrulation to polarize microtubules and regulate Wnt/PCP signaling-dependent cell polarity. Finally, we will test whether the Dchs/Fat/Fjx1 system provides a mechanism to link Wnt/PCP signaling to global embryo patterning. To uncover additional chemokine GPCRs involved in axis formation and gastrulation, we will interrogate functions of the subset of 21 chemokine GPCRs expressed during embryogenesis by characterizing loss-of-function single and compound mutant phenotypes. As mutations in the components of the Wnt, Dchs/Fat and GPCR pathways cause miscarriages, birth defects and diseases; our studies can advance their understanding, diagnosis and facilitate development of therapies.
The inductive and morphogenetic processes that establish the vertebrate body plan must be coordinated in space and time to ensure normal development. We are discovering new regulators of these fundamental processes and mechanisms they employ, focusing on adhesion and chemokine G Protein- Coupled Receptor, Wnt/Planar Cell Polarity and Dachsous/Fat/Fjx1 pathways. As mutations in the components of these pathways cause miscarriages, birth defects and diseases, our studies can advance their understanding, diagnosis and facilitate development of therapies.
