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Seeing the Cytoskeleton in a Whole New Light

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It’s been 25 years since researchers coaxed a bacterium to synthesize an unusual jellyfish protein that fluoresced bright green when irradiated with blue light. Within months, another group had also fused this small green fluorescent protein (GFP) to larger proteins to make their whereabouts inside the cell come to light—like never before.

To mark the anniversary of this Nobel Prize-winning work and show off the rainbow of color that is now being used to illuminate the inner workings of the cell, the American Society for Cell Biology (ASCB) recently held its Green Fluorescent Protein Image and Video Contest. Over the next few months, my blog will feature some of the most eye-catching entries—starting with this video that will remind those who grew up in the 1980s of those plasma balls that, when touched, light up with a simulated bolt of colorful lightning.

This video, which took third place in the ASCB contest, shows the cytoskeleton of a frequently studied human breast cancer cell line. The cytoskeleton is made from protein structures called microtubules, made visible by fluorescently tagging a protein called doublecortin (orange). Filaments of another protein called actin (purple) are seen here as the fine meshwork in the cell periphery.

The cytoskeleton plays an important role in giving cells shape and structure. But it also allows a cell to move and divide. Indeed, the motion in this video shows that the complex network of cytoskeletal components is constantly being organized and reorganized in ways that researchers are still working hard to understand.

Jeffrey van Haren, Erasmus University Medical Center, Rotterdam, the Netherlands, shot this video using the tools of fluorescence microscopy when he was a postdoctoral researcher in the NIH-funded lab of Torsten Wittman, University of California, San Francisco.

All good movies have unusual plot twists, and that’s truly the case here. Though the researchers are using a breast cancer cell line, their primary interest is in the doublecortin protein, which is normally found in association with microtubules in the developing brain. In fact, in people with mutations in the gene that encodes this protein, neurons fail to migrate properly during development. The resulting condition, called lissencephaly, leads to epilepsy, cognitive disability, and other neurological problems.

Cancer cells don’t usually express doublecortin. But, in some of their initial studies, the Wittman team thought it would be much easier to visualize and study doublecortin in the cancer cells. And so, the researchers tagged doublecortin with an orange fluorescent protein, engineered its expression in the breast cancer cells, and van Haren started taking pictures.

This movie and others helped lead to the intriguing discovery that doublecortin binds to microtubules in some places and not others [1]. It appears to do so based on the ability to recognize and bind to certain microtubule geometries. The researchers have since moved on to studies in cultured neurons.

This video is certainly a good example of the illuminating power of fluorescent proteins: enabling us to see cells and their cytoskeletons as incredibly dynamic, constantly moving entities. And, if you’d like to see much more where this came from, consider visiting van Haren’s Twitter gallery of microtubule videos here:


[1] Doublecortin is excluded from growing microtubule ends and recognizes the GDP-microtubule lattice. Ettinger A, van Haren J, Ribeiro SA, Wittmann T. Curr Biol. 2016 Jun 20;26(12):1549-1555.


Lissencephaly Information Page (National Institute of Neurological Disorders and Stroke/NIH)

Wittman Lab (University of California, San Francisco)

Green Fluorescent Protein Image and Video Contest (American Society for Cell Biology, Bethesda, MD)

NIH Support: National Institute of General Medical Sciences

The Actin Superhighway

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Actin Superhighway

Credit: Andrew Lombardo and David Warshaw, University of Vermont, Burlington

What looks like a traffic grid filled with roundabouts is nothing of the sort: It’s actually a peek inside a tiny microchamber that models a complex system operating in many of our cells. The system is a molecular transportation network made of the protein actin, and researchers have reconstructed it in the lab to study its rules of the road and, when things go wrong, how it can lead to molecular traffic accidents.

This 3D super-resolution image shows the model’s silicone beads (circles) positioned in a tiny microfluidic-chamber. Suspended from the beads are actin filaments that form some of the main cytoskeletal roadways in our cells. Interestingly, a single dye creates the photo’s beautiful colors, which arise from the different vertical dimensions of a microscopic image: 300 nanometers below the focus (red), at focus (green), and 300 nanometers above the focus (blue). When a component spans multiple dimensions—such as the spherical beads—all the colors of the rainbow are visible. The technique is called 3D stochastic optical reconstruction microscopy, or STORM [1].

Lens Crafting

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Credit: Salma Muhammad Al Saai, Salil Lachke, University of Delaware, Newark

Live long enough, and there’s a good chance that you will develop a cataract, a clouding of the eye’s lens that impairs vision. Currently, U.S. eye surgeons perform about 3 million operations a year to swap out those clouded lenses with clear, artificial ones [1]. But wouldn’t it be great if we could develop non-surgical ways of preventing, slowing, or even reversing the growth of cataracts?  This image, from the lab of NIH-grantee Salil Lachke at the University of Delaware, Newark, is part of an effort to do just that.

Here you can see the process of lens development at work in a tissue cross-section from an adult mouse. In mice, as in people, a single layer of stem-like epithelial cells (far left, blue/green) gives rise to specialized lens cells (middle, blue/green) throughout life. The new cells initially resemble their progenitor cells, displaying nuclei (blue) and the cytoskeletal protein actin (green). But soon these cells will produce vast amounts of water-soluble proteins, called crystallins, to enhance their transparency, while gradually degrading their nuclei to eliminate light-scattering bulk. What remains are fully differentiated, enucleated, non-replicating lens fiber cells (right, green), which refract light onto the retina at the back of the eye.

Cool Videos: Pushing the Limits of Live-Cell Microscopy

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If you’re not watching recent work in biology, you might have thought that light microscopy hit its limits years ago.  After all, it’s been around a long time. But to the contrary, microscopic imaging technology just keeps getting better and better. Here you can look with unprecedented clarity at just one of the many dynamic processes going on within a living cell. Specifically, this video shows actin fibers (orange-red), which are key components of the cell’s cytoskeleton, slowly pulling clathrin-coated pits (green), which are basket-like structures containing molecular cargo, away from the cell’s external membrane and deeper within the cell.

This remarkable live-action view was produced using one of two new forms of extended-resolution, structured illumination microscopy (SIM). SIM is faster than other forms of super-resolution fluorescence microscopy. It’s also less damaging to cells, making it the go-to method for live-cell imaging. The downside has been SIM’s limited resolution—just twice that of conventional light microscopes. However, Nobel Prize-winner Eric Betzig and postdoc Dong Li of Howard Hughes Medical Institute, Janelia Research Campus, Ashburn, VA, along with colleagues including Jordan Beach and John Hammer at NIH’s National Heart, Lung, and Blood Institute, recently came up with two different solutions to enhance SIM’s spatial resolution.

Snapshots of Life: Cell Skeleton on the Move

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Credit: Torsten Wittmann, University of California, San Francisco

Cells are constantly on the move. They shift, grow, and migrate to new locations—for example, to heal a wound or to intercept an infectious agent as part of an immune response. But how do cells actually move?

In this image, Torsten Wittmann, an NIH-funded cell biologist at the University of California, San Francisco, reveals the usually-invisible cytoskeleton of a normal human skin cell that lends the cell its mobility. The cytoskeleton is made from protein structures called microtubules—the wispy threads surrounding the purple DNA-containing nucleus—and filaments of a protein called actin, seen here as the fine blue meshwork in the cell periphery. Both actin and microtubules are critical for growth and movement.

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