DDecon

Distributed

Deconvolution

Student

Projects

Cells use actin filaments in the cytoskeleton to provide structural strength, generate movements, and coordinate their shape and adhesion to form tissues and organs. Actin filaments are dynamic polymers that are intrinsically polarized with fast growing (barbed) and slow growing (pointed) ends. Control of assembly or disassembly at filament ends by actin regulatory proteins is critical for morphogenesis of cells and tissues during embryonic development, and for homeostasis and function of adult tissues and organs. We focus on regulation of actin filament pointed end assembly and disassembly by tropomodulin (Tmod) and tropomyosin (TM) families of proteins. We are particularly interested in the assembly and dynamics of the short actin filaments in the spectrin-based membrane skeleton, and of the long actin filaments in the sarcomeres of striated muscle. We utilize a variety of approaches, from biochemical and biophysical analyses of actin polymerization in vitro, to fluorescence microscopy of actin dynamics in living cells, to 3D confocal fluorescence microscopy of tissues, to developmental and physiological studies of transgenic mice. Our goal is to connect the dots: from actin dynamics regulation, to assembly and organization of actin cytoskeletal structures, to control of cell shapes and interactions, to morphogenesis of cells and tissues during development and growth, to physiological function and disease.

 

We are interested in the following broad questions:

 

• Do different Tmod isoforms have unique regulatory properties tailored to the short actin filaments in the membrane skeleton, or the long actin filaments in sarcomeres?

 

• How do interactions of Tmod and TM affect actin pointed end regulation, filament lengths and turnover in different cytoskeletal structures and in different cell types?

 

• Does Tmod capping of pointed ends synergize or antagonize activities of other actin regulatory proteins (ADF/cofilin, profilin, Arp2/3 complex, capping protein, formins)?

 

• How does actin filament pointed end regulation by Tmod influence the differentiation, morphogenesis, and function of striated muscle, red blood cells, or the eye lens?

 

• Do common underlying molecular mechanisms explain diverse Tmod-/- mutant phenotypes in the embryonic heart, skeletal muscle, red blood cells, and the eye lens?