Research News

How Do Microtubules Help Neurons Find Their Path?

Neurons or nerve cells are one of the longest cells in the body. They grow in rather precise directions and network with other neurons in order to transfer, integrate and process information. The molecular mechanisms and mechanics behind this defined directionality of neurons is an intriguing area of research.

Chaitanya Athale, who leads a research group at IISER Pune, approaches this area from the perspective of understanding how form and shape help achieve functionality. In a recent paper with Saurabh Mahajan, an undergraduate trainee in his lab (now at Delhi University), Athale has modeled the growing tip (growth cone) of an axon–the long wire-like projection from the cell body of a neuron.

One of the earliest cellular events during growth cone turning (which marks the initiation of a decision on direction of growth) is the activation of receptors on its membrane, either by mechanical or chemical cues. What follows is a complex network of signaling pathways, which remodel the actin and microtubule cytoskeletons, the structural networks across the cell which help in cell movement and in managing cell shape.

Pointing to the less understood role of microtubule cytoskeleton, Athale says, “The role of actin cytoskeleton has been better studied probably due to its force generating nature, but experiments show that intact microtubule cytoskeleton is equally important for neuronal growth cone guidance.”

Simulation snapshots of a neuronal growth cone. blue: microtubules; dots: C-domain motors; green arrow-heads: growing plus-ends of microtubules; red arrow-heads: shrinking plus ends of microtubules; magenta: radial filopodial arrays. Athale lab has modeled microtubules in 2D using a previously developed Langevin Dynamics simulation in a neuronal growth cone geometry. This is one of the first models in literature to simultaneously take into account two important phenomena involved in the process of growth cone turning: diffusion gradients of regulatory signals and microtubule dynamics/mechanics.

Simulation snapshots of a neuronal growth cone. blue: microtubules; dots: C-domain motors; green arrow-heads: growing plus-ends of microtubules; red arrow-heads: shrinking plus ends of microtubules; magenta: radial filopodial arrays. Athale lab has modeled microtubules in 2D using a previously developed Langevin Dynamics simulation in a neuronal growth cone geometry. This is one of the first models in literature to simultaneously take into account two important phenomena involved in the process of growth cone turning: diffusion gradients of regulatory signals and microtubule dynamics/mechanics (Image: Chaitanya Athale).

In order to recreate in silico the earliest events in microtubule network polarization in a neuronal system, the Athale lab has chosen to model the neuronal growth cones of Aplysia californica using information on its structure and dimensions available in literature. The model they developed (shown in the adjacent figure) fits all the available data on the mean angle of microtubule density as well as steady state angular distributions and flux of microtubules within different regions of Aplysia’s neuronal growth cone.

Saurabh Mahajan (left) and Chaitanya Athale, authors of a recent paper on the role of microtubules in neuronal pathfinding in Biophysical Journal (103:2432–2445)

Saurabh Mahajan (left) and Chaitanya Athale, authors of a recent paper on the role of microtubules in neuronal pathfinding in Biophysical Journal (103:2432–2445)

Using this platform, Mahajan and Athale carried out sensitivity analysis of the model to test the limits of neuronal microtubules. Here are a few questions they addressed: what is the distribution of microtubules across different regions of the growth cone, how does dynamic instability of a microtubule polymer contribute to growth of the microtubule polymer in a specific direction (referred to as microtubule polarization), and what is the nature of a minimal biochemical regulatory network that limits microtubule polarization.

Describing the results of this analysis, Athale says, “Our model predicts that receptor concentration is the strongest stimulus in changing the mean angle of microtubule density. Additionally, we find a feedback model of stathmin-microtubule interactions is sensitive to small fluctuations and does not polarize neuronal microtubules as strongly as a linear model. We also find microtubule polarization is significant only for a receptor polarization angle greater than or equal to 30 degrees.”

The predictions made in this study are experimentally testable and the Athale group is actively discussing with potential collaborators.

Aurnab Ghose, who leads a research group at IISER Pune working in the area of neuronal connectivity says the study now opens up the possibility of testing some very interesting predictions related to the role of motor protein complexes and temporal limits of the polarization response. Ghose adds, “The parameters in this study have been taken from Aplysia bag cell neurons which, though large in spatial spread, are extremely slow in terms of translocation rates. It will therefore also be of interest to fit parameters taken from fast moving growth cones onto this model”.

The paper titled “Spatial and temporal sensing limits of microtubule polarization in neuronal growth cones by intracellular gradients and forces” is authored by Saurabh Mahajan and Chaitanya Athale and has appeared in Biophysical Journal (103:2432–2445).

“The larger question we address in the lab is why certain cells and tissues acquire certain forms, not others, to achieve a given function. The famous book by D’arcy Wentworth Thompson On Growth and Form, where he analyzed the growth and form of biological phenomena in terms of physics and mathematics, continues to inspire and motivate our research,” says Athale.

Visit the Athale lab webpage to learn more about their research.

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