Axopodia and the cellular “arms” race

Anyone who has sat around a dinner table knows the importance of being able to grab food. Without the ability to reach out with our arms and pick up plates or food items, we would be constrained to eat whatever happened to be on our plate. Unicellular organisms, especially sessile ones, face the same situation. In most environments, food organisms are sparsely scattered in the water. Some organisms use cilia to create long-rang flows of fluid that can bring food to their mouths from many body-lengths away. But a wide range of organisms have taken a dinner-table like approach by evolving “arms” of various sorts, by means of which they can extend their reach and grab food over a larger distance.

Why is it important to have long arms? In the case of a dinner table, arms let you reach for specific food items. But actually the situation is quite different for a cell. Unlike a human diner, the cell does not in general know where the food is. Moreover, the food is not static but swimming around, often in randomly meandering trajectories. Somehow, the arms help to increase the collection of food through random collisions. How does this work?

The rate at which food can be eaten depends on the probability of a food organism randomly colliding with the cell. Bigger cells have more surface area, and so the chance of encountering a food organism by random collision will increase as the radius increases. At first glance, one may imagine that the likelihood of collision would be proportional to the surface area. Since surface area is proportional to the radius squared, even a small increase in radius would lead to a large change in surface area. However, this is one of those cases where our intuition fails us when it comes to diffusion. If we consider a particle diffusing in the vicinity of a spherical object, there are two possible outcomes: either the particle will collide with the object (and be captured if the object is a sticky cell) or else the particle will diffuse away, never to return. The chance that the same particle will come back again after diffusing far away is vanishingly small in three dimensions. Based on these considerations, it can be shown (Berg 1983) that the probability of capturing a particle before it diffuses away is proportional to the radius of the sphere, not to the surface area. This means that in order to significantly increase the chance of capturing food, the cell has to make its radius much larger, leading to a huge increase in cell volume. This volume increase would require a massive investment of biomass to the point that the cost of growing to such a size might exceed the value of increased food capture.

The solution to this dilemma is to cover the cell surface with long, thin protrusions, that cost little in biomass but can lead to a greatly increased capture radius. In his comprehensive review article in this issue of Cytoskeleton, Robert Bloodgood explores the wide variety of arm-like protrusions used for food capture across eukaryotic phyla. These cellular arms have many different names, such as axopodia, haptonema, and reticulopodia, but they all share a similar architecture in which a bundle of microtubules push out a protrusion of the plasma membrane. Motor proteins associated with the microtubules interact with membrane proteins of the arms to move patches of membrane back o the cell body, carrying attached food particles. We can immediately see why the use of microtubules is so widespread for this purpose – compared to actin or intermediate filaments, microtubules have greater mechanical rigidity, with persistence lengths on the order of millimeters. When several microtubules are cross-linked together, the stiffness increases still further. This stiffness allows the arms to stick straight out from the cell.

Assuming that the primary role of microtubules is to be rigid tracks on which motor proteins can move, the exact arrangement of the microtubules within the bundle may have little relevance. This fact may explain the wide range of ultrastructures seen inside these microtubule based arms, ranging from spirals and regular lattices in some species to apparently random disorder in others. The relative insensitivity to the detailed molecular architecture should also make such structures relatively easy to evolve. This may explain the widespread convergent evolution of the “heliozoa”, a group of unicellular organisms with spherical symmetry and radiating microtubule-based axopodia. The heliozoan were once thought to be a single phylum but now are recognized as a polyphyletic group composed of members from four completely unrelated eukaryotic phyla (Gast 2017).

Speaking of evolution, another interesting point raised in Bloodgood’s article is the similarity between food capture mechanisms using axopodia and those using cilia and flagella. The latter are also microtubule-based cellular arms, although they generally have a more complex organization of microtubules and often are able to actively move the arms in order to swim or generate fluid flows. But, like axopodia, cilia and flagella also have back and forth membrane movements on their surface that can be used for food capture. As with axopodia, the force generating mechanism is microtubule motor proteins. These similarities suggest one potential evolutionary pathway for cilia and flagella – perhaps they evolved in cells that initial contained axopodia, via addition of dynein arms to drive bending motility. (Mitchell 2004). Such a scheme might help address the criticism, often leveled by so-called “intelligent design” creationists, that cilia are “irreducibly complex”, meaning that since breaking any one component of the cilium makes it useless, there is no way that the complete structure could have evolved. Because axopodia have a comparatively low bar for being useful, in that all they need to have is some parallel microtubules and a motor, the irreducible complexity argument carries less force. Once the axopodium had evolved, it would have been a small step to add bending motility, and meanwhile the structure would retain its usefulness for food capture because the motile system of cilia is orthogonal to the motor system that drives food capture and surface movement.

I would like to close with a final question: are we sure that food capture is the primary purpose of cellular “arms”? Gliding motility is one additional function, discussed in the article, but maybe there is an even simpler function. Every unicellular organism is prey for other organisms. By covering the cell surface with long spiky arms, the cell makes itself effectively bigger and makes it harder to be ingested by predators that feed by engulfing their prey. The long arms would also make it harder for tardigrades or rotifers to get close enough to the cell surface to chew it with their nasty mouthparts. Similar strategies of growing cell surface protrusions to avoid predation have been reported in some ciliates which grow wing-like protrusions that have been shown to reduce predation (Kuhlmann et al. 1994). Such a purely defensive role might not, at first glance, suggest a need for surface motility. But imagine that a cell has encountered a predator who is trying to push through its array of axopodia, like a Carthaginian war-elephant trying to push through the spears of a Greek phalanx. Surface motility directed outwards towards the tip of the arms (centrifugal motility) would serve to push the predator and the cell apart. One cannot help but smile at the frustration a tardigrade must feel while trying to eat a piece of food that is able to constantly push itself away via axopodial surface motility.

Clearly, there is much to be learned from studying the molecular basis of food capture by cellular arms. While some may dismiss these questions as being of purely academic interest, it is worth pointing out that in addition to the evolutionary implications discussed above, and the revelations that these systems hold for basic mechanism of microtubule and motor interactions, the role of food capture systems in ecological food-webs is tremendous. Moreover, surface motility of mucus and pathogens on cilia in the human airway is of the utmost importance in respiratory tract physiology and disease. Now that the genomic tools are finally available to study axopodia and other cellular arms, the time is right to see what lessons these structures have to teach us.