Joe Howard, PhD
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Research Summary
Mechanics of Motor Proteins and the Cytoskeleton
The Howard lab is fascinated by the question of how small molecules like proteins, lipids and nucleotides self-assemble into cells and tissues that are thousands to millions of times larger than molecular dimensions. How do the molecules know where they are, whether the structures they make have the right size and shape, and whether they function correctly? By combining highly sensitive techniques to visualize and manipulate individual biological molecules, with theory and modeling, the Howard lab is trying to understand the interaction rules that allow molecules to work together to form highly organized yet dynamic cellular structures.
The Howard lab is approaching these questions in the context of the microtubule cytoskeleton. They are interested in the molecular properties of motor proteins, especially how they operate as molecular machines to drive motion and regulate the growth, shrinkage and severing of microtubules. In addition to biochemical and single-molecule approaches, the lab also studies a number of cellular systems including the branching of neurons during development and the motility of cilia.
Extensive Research Description
Motor and Cytoskeletal Systems: From molecules to cells
Tubulin exchange in and out of the microtubule wall and its role in severing, rigidity & dynamics
Microtubules are tubular polymers whose protein subunits, tubulin, associate in a head-to-tail geometry to form protofilaments, thirteen of which form the microtubule’s cylindrical wall. The pipe-like geometry gives the microtubule high rigidity for its protein mass. High bending rigidity is essential for the structural roles that microtubules play in cellular architecture: as tracks for motor proteins such as kinesins and dyneins, and as scaffolds that support force-generating organelles such as the mitotic spindle and the cilium (Howard 2001).
Microtubules grow and shrink by addition and subtraction of tubulin dimers at their ends, processes that are regulated by a host a microtubule associated proteins (Howard and Hyman 2007, Bowne-Anderson et al. 2015). Recently, however, it has become clear that, in addition to removal and addition of tubulin at microtubule ends, significant tubulin exchange also occurs within the wall of the microtubule. Removal can be mediated by microtubule severing enzymes such as spastin and katanin (Kuo & Howard 2021, Kuo et al. 2022), by motor proteins such as kinesins and dyneins, and by mechanical forces applied to the microtubule. Removal of tubulin from the microtubule lattice leads to holes, whose enlargement leads to microtubule softening and eventual breakage, and whose repair by incorporation of new GTP-tubulin from solution can promote microtubule growth. Together, the growth and repair of these defects can profoundly rearrange the microtubule cytoskeleton in cells.
We are developing new techniques for visualizing microtubule defects and to study the kinetic and structural mechanisms of microtubule severing.
Branching morphogenesis of neurons
The architecture of the brain and its constituent neurons is staggeringly complex. This complexity is enabled by the highly branched morphologies of dendrites and axons, which allow each neuron to connect to thousands of other neurons. We recently showed, using Drosophila sensory neurons as a model system, that the branching, growth, and retraction of dendrite tips can generate many of the morphological features of dendrites including the rate of growth of their arbors during development, and the average length, density, and orientation of their branches (Shree et al. 2022, Ouyang et al. in preparation). Branch diameters, another important morphological feature of neurons, change systematically across branch points, which facilitates the distribution of materials and nutrients through the network (Liao et al. 2019). Furthermore, neuronal dendrites have a scale-invariant network architecture that optimizes their function and metabolism (Liao et al. 2023).
Currently, we are using genetic perturbations and high-resolution imaging to elucidate the role of the microtubule cytoskeleton in generating dendrite morphology.
The motility of cilia and flagella
A major open question in cell motility is how the dynein motors, which power the bending of cilia and flagella, are coordinated to give the periodic beating patterns that drive cell motion (Howard et al. 2022). We are using the single-celled alga Chlamydomonas reinhardtii as a model system to test different models of motor coupling (Geyer et al. 2016, Sartori et al. 2016, Geyer 2022).
Currently, we are analyzing waveforms of different mutants by high-speed light microscopy and high-resolution electron cryo-microscopy.
Coauthors
Research Interests
Biophysics; Cilia; Microtubules; Mitosis; Neurobiology; Physics; Developmental Biology; Molecular Motor Proteins; Nanotechnology
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Selected Publications
- Topology recapitulates morphogenesis of neuronal dendritesLiao M, Bird A, Cuntz H, Howard J. Topology recapitulates morphogenesis of neuronal dendrites. Cell Reports 2023, 42: 113268. PMID: 38007691, PMCID: PMC10756852, DOI: 10.1016/j.celrep.2023.113268.
- Dynamic microtubules slow down during their shrinkage phaseLuchniak A, Kuo Y, McGuinness C, Sutradhar S, Orbach R, Mahamdeh M, Howard J. Dynamic microtubules slow down during their shrinkage phase. Biophysical Journal 2023, 122: 616-623. PMID: 36659852, PMCID: PMC9989939, DOI: 10.1016/j.bpj.2023.01.020.
- Cilia function as calcium-mediated mechanosensors that instruct left-right asymmetryDjenoune L, Mahamdeh M, Truong T, Nguyen C, Fraser S, Brueckner M, Howard J, Yuan S. Cilia function as calcium-mediated mechanosensors that instruct left-right asymmetry. Science 2023, 379: 71-78. PMID: 36603098, PMCID: PMC9939240, DOI: 10.1126/science.abq7317.
- Predicting the locations of force-generating dyneins in beating cilia and flagellaHoward J, Chasteen A, Ouyang X, Geyer VF, Sartori P. Predicting the locations of force-generating dyneins in beating cilia and flagella. Frontiers In Cell And Developmental Biology 2022, 10: 995847. PMID: 36303602, PMCID: PMC9592896, DOI: 10.3389/fcell.2022.995847.
- Dynamic instability of dendrite tips generates the highly branched morphologies of sensory neuronsShree S, Sutradhar S, Trottier O, Tu Y, Liang X, Howard J. Dynamic instability of dendrite tips generates the highly branched morphologies of sensory neurons. Science Advances 2022, 8: eabn0080. PMID: 35767611, PMCID: PMC9242452, DOI: 10.1126/sciadv.abn0080.
- The force required to remove tubulin from the microtubule lattice by pulling on its α-tubulin C-terminal tailKuo YW, Mahamdeh M, Tuna Y, Howard J. The force required to remove tubulin from the microtubule lattice by pulling on its α-tubulin C-terminal tail. Nature Communications 2022, 13: 3651. PMID: 35752623, PMCID: PMC9233703, DOI: 10.1038/s41467-022-31069-x.
- Counting fluorescently labeled proteins in tissues in the spinning–disk microscope using single–molecule calibrationsLiao M, Kuo Y, Howard J. Counting fluorescently labeled proteins in tissues in the spinning–disk microscope using single–molecule calibrations. Molecular Biology Of The Cell 2022, 33: ar48. PMID: 35323029, PMCID: PMC9265152, DOI: 10.1091/mbc.e21-12-0618.
- Ciliary beating patterns map onto a low-dimensional behavioural spaceGeyer V, Howard J, Sartori P. Ciliary beating patterns map onto a low-dimensional behavioural space. Nature Physics 2022, 18: 332-337. DOI: 10.1038/s41567-021-01446-2.
- Structures of outer-arm dynein array on microtubule doublet reveal a motor coordination mechanismRao Q, Han L, Wang Y, Chai P, Kuo YW, Yang R, Hu F, Yang Y, Howard J, Zhang K. Structures of outer-arm dynein array on microtubule doublet reveal a motor coordination mechanism. Nature Structural & Molecular Biology 2021, 28: 799-810. PMID: 34556869, PMCID: PMC8500839, DOI: 10.1038/s41594-021-00656-9.
- The narrowing of dendrite branches across nodes follows a well-defined scaling lawLiao M, Liang X, Howard J. The narrowing of dendrite branches across nodes follows a well-defined scaling law. Proceedings Of The National Academy Of Sciences Of The United States Of America 2021, 118: e2022395118. PMID: 34215693, PMCID: PMC8271565, DOI: 10.1073/pnas.2022395118.
- Cutting, Amplifying, and Aligning Microtubules with Severing EnzymesKuo YW, Howard J. Cutting, Amplifying, and Aligning Microtubules with Severing Enzymes. Trends In Cell Biology 2020, 31: 50-61. PMID: 33183955, PMCID: PMC7749064, DOI: 10.1016/j.tcb.2020.10.004.
- Heat Oscillations Driven by the Embryonic Cell Cycle Reveal the Energetic Costs of SignalingRodenfels J, Neugebauer KM, Howard J. Heat Oscillations Driven by the Embryonic Cell Cycle Reveal the Energetic Costs of Signaling. Developmental Cell 2020, 53: 492. PMID: 32428456, PMCID: PMC7374639, DOI: 10.1016/j.devcel.2020.04.023.
- Spastin is a dual-function enzyme that severs microtubules and promotes their regrowth to increase the number and mass of microtubulesKuo YW, Trottier O, Mahamdeh M, Howard J. Spastin is a dual-function enzyme that severs microtubules and promotes their regrowth to increase the number and mass of microtubules. Proceedings Of The National Academy Of Sciences Of The United States Of America 2019, 116: 5533-5541. PMID: 30837315, PMCID: PMC6431158, DOI: 10.1073/pnas.1818824116.
- Label‐free high‐speed wide‐field imaging of single microtubules using interference reflection microscopyMAHAMDEH M, SIMMERT S, LUCHNIAK A, SCHÄFFER E, HOWARD J. Label‐free high‐speed wide‐field imaging of single microtubules using interference reflection microscopy. Journal Of Microscopy 2018, 272: 60-66. PMID: 30044498, PMCID: PMC6486835, DOI: 10.1111/jmi.12744.
- A force-generating machinery maintains the spindle at the cell center during mitosisGarzon-Coral C, Fantana HA, Howard J. A force-generating machinery maintains the spindle at the cell center during mitosis. Science 2016, 352: 1124-1127. PMID: 27230381, PMCID: PMC6535051, DOI: 10.1126/science.aad9745.
- Dynamic curvature regulation accounts for the symmetric and asymmetric beats of Chlamydomonas flagellaSartori P, Geyer VF, Scholich A, Jülicher F, Howard J. Dynamic curvature regulation accounts for the symmetric and asymmetric beats of Chlamydomonas flagella. ELife 2016, 5: e13258. PMID: 27166516, PMCID: PMC4924999, DOI: 10.7554/elife.13258.
- XMAP215 Is a Processive Microtubule PolymeraseBrouhard GJ, Stear JH, Noetzel TL, Al-Bassam J, Kinoshita K, Harrison SC, Howard J, Hyman AA. XMAP215 Is a Processive Microtubule Polymerase. Cell 2008, 132: 79-88. PMID: 18191222, PMCID: PMC2311386, DOI: 10.1016/j.cell.2007.11.043.
- Yeast kinesin-8 depolymerizes microtubules in a length-dependent mannerVarga V, Helenius J, Tanaka K, Hyman AA, Tanaka TU, Howard J. Yeast kinesin-8 depolymerizes microtubules in a length-dependent manner. Nature Cell Biology 2006, 8: 957-962. PMID: 16906145, DOI: 10.1038/ncb1462.
- The depolymerizing kinesin MCAK uses lattice diffusion to rapidly target microtubule endsHelenius J, Brouhard G, Kalaidzidis Y, Diez S, Howard J. The depolymerizing kinesin MCAK uses lattice diffusion to rapidly target microtubule ends. Nature 2006, 441: 115-119. PMID: 16672973, DOI: 10.1038/nature04736.
- A Self-Organized Vortex Array of Hydrodynamically Entrained Sperm CellsRiedel IH, Kruse K, Howard J. A Self-Organized Vortex Array of Hydrodynamically Entrained Sperm Cells. Science 2005, 309: 300-303. PMID: 16002619, DOI: 10.1126/science.1110329.
- The force exerted by a single kinesin molecule against a viscous loadHunt AJ, Gittes F, Howard J. The force exerted by a single kinesin molecule against a viscous load. Biophysical Journal 1994, 67: 766-781. PMID: 7948690, PMCID: PMC1225420, DOI: 10.1016/s0006-3495(94)80537-5.
- Flexural rigidity of microtubules and actin filaments measured from thermal fluctuations in shape.Gittes F, Mickey B, Nettleton J, Howard J. Flexural rigidity of microtubules and actin filaments measured from thermal fluctuations in shape. Journal Of Cell Biology 1993, 120: 923-934. PMID: 8432732, PMCID: PMC2200075, DOI: 10.1083/jcb.120.4.923.
- Compliance of the hair bundle associated with gating of mechanoelectrical transduction channels in the Bullfrog's saccular hair cellHoward J, Hudspeth AJ. Compliance of the hair bundle associated with gating of mechanoelectrical transduction channels in the Bullfrog's saccular hair cell. Neuron 1988, 1: 189-199. PMID: 2483095, DOI: 10.1016/0896-6273(88)90139-0.
- Optics of the butterfly eyeNilsson D, Land M, Howard J. Optics of the butterfly eye. Journal Of Comparative Physiology A 1988, 162: 341-366. DOI: 10.1007/bf00606122.
- The intracellular pupil mechanism and photoreceptor signal: noise ratios in the fly Lucilia cuprinaHoward J, Blakeslee B, Laughlin S. The intracellular pupil mechanism and photoreceptor signal: noise ratios in the fly Lucilia cuprina. Proceedings Of The Royal Society B 1987, 231: 415-435. PMID: 2892201, DOI: 10.1098/rspb.1987.0053.
- Mechanical relaxation of the hair bundle mediates adaptation in mechanoelectrical transduction by the bullfrog's saccular hair cell.Howard J, Hudspeth AJ. Mechanical relaxation of the hair bundle mediates adaptation in mechanoelectrical transduction by the bullfrog's saccular hair cell. Proceedings Of The National Academy Of Sciences Of The United States Of America 1987, 84: 3064-3068. PMID: 3495007, PMCID: PMC304803, DOI: 10.1073/pnas.84.9.3064.