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Faculty Lecture Series
When |
Wednesday, May 11, 2011
5 PM - 6 PM |
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Valerie Timken Amphitheater
Green Hospital |
Who |
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Velia Fowler, Ph.D.
Professor
Department of Cell Biology
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Topic |
"Actin filament architecture constrains cell morphology and physiology: Insights from red cells, the lens and striated muscle" |
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Precise regulation of the actin cytoskeleton is essential for the mechanics and physiology of virtually all eukaryotic cells. Actin filaments are dynamic polymeric structures, characterized by actin monomer association and dissociation at the fast-growing (barbed) and slow-growing (pointed) ends. The kinetics of actin incorporation at filament ends is regulated by protein caps, which bind to filament ends and inhibit monomer association and dissociation. While a host of proteins are known to cap actin barbed ends, the tropomodulin (Tmod) family is the only well-characterized group of proteins that cap pointed ends. Four Tmod isoforms are expressed in a developmentally regulated and tissue-specific manner, where they control the dynamics, stability, lengths, and architecture of actin filaments. In turn, Tmods indirectly modulate the mechanical properties of the actin cytoskeleton and the physiological properties of cells. Tmod family members exhibit distinct actin monomer-binding and polymer-regulatory properties in vitro, as well as different binding partners (tropomyosin and actin isoforms, nebulin, filensin, or small ankyrin1.5), suggesting unique functions for each of the four vertebrate Tmods. In vivo studies of embryonic development in mouse knockouts demonstrate key requirements for Tmods in tissue morphogenesis, while studies of differentiated tissues in adult animals demonstrate structural requirements for Tmods in the spectrin-actin lattice of the membrane skeleton, which impacts cell shapes, mechanics and physiology.
The canonical membrane skeleton is the spectrin-actin lattice of red blood cells (RBCs), which is organized as a quasi-hexagonal network of long spectrin strands connecting vertices of Tmod1-capped short actin filaments, all of which are precisely the same length (33 ± 5 nm). Loss of Tmod1 in red blood cells (RBCs) leads to misregulated actin filament lengths and a spectrin-actin lattice with increased pore sizes, resulting in a compensated hemolytic anemia characterized by fragile RBCs with abnormal shapes and reduced deformability. Loss of Tmod1 in eye lens fiber cells leads to γ-tropomyosin reduction, actin filament instability, and membrane skeleton disruptions, resulting in abnormal fiber cell membrane protrusions, aberrant cell shapes, and a loss of hexagonal packing geometry, which worsens as the fiber cells age. In skeletal muscle, loss of Tmod1 from thin filament pointed ends leads to muscle weakness and fiber-type reprogramming, due in part to loss of Tmod3 from the sarcoplasmic reticulum (SR), which destabilizes SR-associated γ-actin filaments and mislocalizes small ankryin1.5, leading to aberrant SR swelling, depressed calcium release, and myofibril misalignment. By understanding Tmod isoform function in the context of its molecular properties, actin regulation, and binding partners, we can draw broad conclusions that can explain the diverse morphological and functional phenotypes that arise from Tmod perturbation experiments both in vitro and in vivo, and discern how the emergent properties of the actin cytoskeleton drive tissue morphogenesis and physiology. |
Publications |
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Nowak, R.B., Fischer, R.S., Zoltoski, R.K., Kuszak, J.R., Fowler, V.M. Tropomodulin1 is required for membrane skeleton organization and hexagonal geometry of fiber cells in the mouse lens. J. Cell Biol. 186, 915-928 (2009). |
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Yamashiro, S., Speicher, K.D., Speicher, D.W., Fowler, V.M. Mammalian tropomodulins nucleate actin polymerization via their monomer binding and filament pointed end-capping activities. J. Biol. Chem. 285, 33265-33280 (2010). |
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Moyer, J.D.*, Nowak, R.B.*, Kim, N.E., Larkin, S.K., Peters, L.L., Hartwig, J., Kuypers, F.A., Fowler, V.M. Tropomodulin1 null mice have a mild spherocytic elliptocytosis with appearance of tropomodulin3 in red blood cells and disruption of the membrane skeleton. Blood. 116, 2590-2599 (2010). (*These two authors contributed equally.) |
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Gokhin, D.S.*, Lewis, R.A.*, McKeown, C.R., Nowak, R.B., Kim, N.E., Littlefield, R.S., Lieber, R.L., Fowler, V.M. Tropomodulin isoforms regulate thin filament pointed end capping and skeletal muscle physiology. J. Cell Biol. 189, 95-109 (2010). (*These two authors contributed equally.) |
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Previous Speakers
Glen Nemerow , Ph.D.
Marisa Roberto, Ph.D.
James R. Williamson, Ph.D.
Phil Dawson, Ph.D.
John Tainer, Ph.D.
Jeffery Kelly, Ph.D.
Paul Schimmel, Ph.D.
Ann Feeney, Ph.D.
Benjamin F. Cravatt, Ph.D.
Ron Milligan, Ph.D.
Erica Ollmann Saphire, Ph.D.
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