Faculty Opinions recommendation of Cofilin-2 controls actin filament length in muscle sarcomeres.

Actin is one of the key structural components of the eukaryotic cytoskeleton that regulates cellular architecture and mechanical properties. Dynamic regulation of actin filament length and organization is essential for the control of many physiological processes including cell adhesion, motility and division. While previous studies have mostly focused on the mechanisms controlling the mean length of individual actin filaments, it remains poorly understood how distinct actin filament populations in cells maintain different size using the same set of molecular building blocks. Here we develop a theoretical model for the length regulation of multiple actin filaments by nucleation and growth rate modulation by actin binding proteins in a limiting pool of monomers. We first show that spontaneous nucleation of actin filaments naturally leads to heterogeneities in filament length distribution. We then investigate the effects of filament growth inhibition by capping proteins and growth promotion by formin proteins on filament length distribution. We find that filament length heterogeneity can be increased by growth inhibition, whereas growth promoters do not significantly affect length heterogeneities. Interestingly, a competition between filament growth inhibitors and growth promoters can give rise to bimodal filament length distribution as well as a highly heterogeneous length distribution with large statistical dispersion. We quantitatively predict how heterogeneity in actin filament length can be modulated by tuning F-actin nucleation and growth rates in order to create distinct filament subpopulations with different lengths.

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Tropomodulin 1-null mice have a mild spherocytic elliptocytosis with appearance of Tropomodulin 3 in red blood cells and disruption of the membrane skeleton

Blood ◽

10.1182/blood-2010-02-268458 ◽

2010 ◽

Vol 116 (14) ◽

pp. 2590-2599 ◽

Cited By ~ 59

Author(s):

Jeannette D. Moyer ◽

Roberta B. Nowak ◽

Nancy E. Kim ◽

Sandra K. Larkin ◽

Luanne L. Peters ◽

...

Keyword(s):

Actin Filament ◽

Actin Filaments ◽

Membrane Skeleton ◽

Actin Dynamics ◽

Filament Length ◽

Western Blots ◽

Rbc Membrane ◽

Cellular Dehydration ◽

Rbc Membrane Skeleton

Abstract The short actin filaments in the red blood cell (RBC) membrane skeleton are capped at their pointed ends by tropomodulin 1 (Tmod1) and coated with tropomyosin (TM) along their length. Tmod1-TM control of actin filament length is hypothesized to regulate spectrin-actin lattice organization and membrane stability. We used a Tmod1 knockout mouse to investigate the in vivo role of Tmod1 in the RBC membrane skeleton. Western blots of Tmod1-null RBCs confirm the absence of Tmod1 and show the presence of Tmod3, which is normally not present in RBCs. Tmod3 is present at only one-fifth levels of Tmod1 present on wild-type membranes, but levels of actin, TMs, adducins, and other membrane skeleton proteins remain unchanged. Electron microscopy shows that actin filament lengths are more variable with spectrin-actin lattices displaying abnormally large and more variable pore sizes. Tmod1-null mice display a mild anemia with features resembling hereditary spherocytic elliptocytosis, including decreased RBC mean corpuscular volume, cellular dehydration, increased osmotic fragility, reduced deformability, and heterogeneity in osmotic ektacytometry. Insufficient capping of actin filaments by Tmod3 may allow greater actin dynamics at pointed ends, resulting in filament length redistribution, leading to irregular and attenuated spectrin-actin lattice connectivity, and concomitant RBC membrane instability.

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Latrunculin B increases force fluctuation-induced relengthening of ACh-contracted, isotonically shortened canine tracheal smooth muscle

Journal of Applied Physiology ◽

10.1152/japplphysiol.01378.2003 ◽

2005 ◽

Vol 98 (2) ◽

pp. 489-497 ◽

Cited By ~ 35

Author(s):

M. L. Dowell ◽

O. J. Lakser ◽

W. T. Gerthoffer ◽

J. J. Fredberg ◽

G. L. Stelmack ◽

...

Keyword(s):

Smooth Muscle ◽

Airway Smooth Muscle ◽

Actin Filament ◽

Isometric Force ◽

Muscle Length ◽

Tracheal Smooth Muscle ◽

Filament Length ◽

Latrunculin B ◽

Force Fluctuation ◽

Reference Length

We hypothesized that differences in actin filament length could influence force fluctuation-induced relengthening (FFIR) of contracted airway smooth muscle and tested this hypothesis as follows. One-hundred micromolar ACh-stimulated canine tracheal smooth muscle (TSM) strips set at optimal reference length ( Lref) were allowed to shorten against 32% maximal isometric force (Fmax) steady preload, after which force oscillations of ±16% Fmax were superimposed. Strips relengthened during force oscillations. We measured hysteresivity and calculated FFIR as the difference between muscle length before and after 20-min imposed force oscillations. Strips were relaxed by ACh removal and treated for 1 h with 30 nM latrunculin B (sequesters G-actin and promotes depolymerization) or 500 nM jasplakinolide (stabilizes actin filaments and opposes depolymerization). A second isotonic contraction protocol was then performed; FFIR and hysteresivity were again measured. Latrunculin B increased FFIR by 92.2 ± 27.6% Lref and hysteresivity by 31.8 ± 13.5% vs. pretreatment values. In contrast, jasplakinolide had little influence on relengthening by itself; neither FFIR nor hysteresivity was significantly affected. However, when jasplakinolide-treated tissues were then incubated with latrunculin B in the continued presence of jasplakinolide for 1 more h and a third contraction protocol performed, latrunculin B no longer substantially enhanced TSM relengthening. In TSM treated with latrunculin B + jasplakinolide, FFIR increased by only 3.03 ± 5.2% Lref and hysteresivity by 4.14 ± 4.9% compared with its first (pre-jasplakinolide or latrunculin B) value. These results suggest that actin filament length, in part, determines the relengthening of contracted airway smooth muscle.

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HSPB7 is indispensable for heart development by modulating actin filament assembly

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1713763114 ◽

2017 ◽

Vol 114 (45) ◽

pp. 11956-11961 ◽

Cited By ~ 18

Author(s):

Tongbin Wu ◽

Yongxin Mu ◽

Julius Bogomolovas ◽

Xi Fang ◽

Jennifer Veevers ◽

...

Keyword(s):

Heat Shock ◽

Heat Shock Protein ◽

Actin Filament ◽

Thin Filament ◽

Actin Polymerization ◽

Small Heat Shock Protein ◽

Embryonic Lethality ◽

Filament Length ◽

Actin Bundles ◽

Filament Bundles

Small heat shock protein HSPB7 is highly expressed in the heart. Several mutations within HSPB7 are associated with dilated cardiomyopathy and heart failure in human patients. However, the precise role of HSPB7 in the heart is still unclear. In this study, we generated global as well as cardiac-specific HSPB7 KO mouse models and found that loss of HSPB7 globally or specifically in cardiomyocytes resulted in embryonic lethality before embryonic day 12.5. Using biochemical and cell culture assays, we identified HSPB7 as an actin filament length regulator that repressed actin polymerization by binding to monomeric actin. Consistent with HSPB7’s inhibitory effects on actin polymerization, HSPB7 KO mice had longer actin/thin filaments and developed abnormal actin filament bundles within sarcomeres that interconnected Z lines and were cross-linked by α-actinin. In addition, loss of HSPB7 resulted in up-regulation of Lmod2 expression and mislocalization of Tmod1. Furthermore, crossing HSPB7 null mice into an Lmod2 null background rescued the elongated thin filament phenotype of HSPB7 KOs, but double KO mice still exhibited formation of abnormal actin bundles and early embryonic lethality. These in vivo findings indicated that abnormal actin bundles, not elongated thin filament length, were the cause of embryonic lethality in HSPB7 KOs. Our findings showed an unsuspected and critical role for a specific small heat shock protein in directly modulating actin thin filament length in cardiac muscle by binding monomeric actin and limiting its availability for polymerization.

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