Cytoskeletal organization by Toll-like receptors during epithelial morphogenesis

Sloan-Kettering Inst Can Research, New York NY

Investigators

Abstract

Cell fate and behavior are controlled by spatially and temporally regulated extracellular signals that are recognized by transmembrane receptors at the cell surface and relayed by cytosolic effectors to distinct locations within the cell. Disruption of receptor signaling can alter cell behavior and lead to developmental defects and diseases such as cancer. The Toll-like family of receptors signal to effectors that activate NF-κB and MAP kinase signaling to induce transcriptional changes required for innate immunity. By contrast, Drosophila Toll-related receptors have been shown to activate a localized tyrosine kinase signaling cascade through the activation of Src family nonreceptor tyrosine kinases, which recruit effectors that elicit spatially regulated changes in the activity of the actomyosin cytoskeleton. However, the effectors downstream of Toll receptor-mediated tyrosine kinase signaling that regulate actomyosin dynamics and cytoskeletal organization to promote polarized cell movements in the Drosophila embryo are not known. In this proposal, I will identify effectors that link Toll receptor signaling to actin regulators during axis elongation in the Drosophila embryonic epithelium and determine how these regulators contribute to spatiotemporally regulated actomyosin contractility and cell behavior. In Aim 1, I will analyze the dynamic localization of regulators of the actin cytoskeleton and actomyosin contractility and determine how they affect the rapid reorganization of cell polarity and behavior. In Aim 2, I will determine how these factors promote epithelial remodeling by characterizing how they affect the intracellular assembly of signaling complexes and their genetic and biochemical interactions with upstream regulators of actomyosin contractility. In Aim 3, I will investigate how components involved in cytoskeletal organization are spatiotemporally regulated at the cellular and molecular level and how these processes influence the dynamic signaling events that organize cell polarity and behavior. The proposed studies will take advantage of in vitro biochemistry and in vivo genetic tools, quantitative live imaging analysis, and super-resolution microscopy to understand how cell-surface receptors communicate with the actomyosin cytoskeleton to effect collective changes in cell polarity and behavior during embryonic development.