By Andrew Matamoros, PhD
My first memory of Dr. Baas (visit lab) is from his Core II lecture on microtubules. Armed with only a marker and a white board, Dr. Baas walked us through the biology and importance of microtubules in the nervous system. We had to devise experiments to answer questions regarding neuronal microtubules. I get excited about these types of classes, so I raised my hand several times during class. After class, Dr. Baas asked me to see him in his office. Truthfully, I thought I was in trouble! Luckily, I was not. He told me that he was happy to see my enthusiasm in class and wanted to discuss a project that had the potential to promote regeneration following a nerve injury by targeting microtubules. This was the start of my dissertation work in the Baas lab.
If a city were a cell, microtubules are like the support beams in buildings and the highways we travel on. Microtubules are especially important in neurons of the nervous system to maintain a structure called the axon. The axon is responsible for transmitting chemoelectrical signals from one cell to the next, and this cellular communication allows our body to function and our minds to think. If an axon is severed or injured, it is no longer capable of proper communication. The regenerative capacity of injured adult axons is limited, particularly in the central nervous system. Injured axons degenerate because they encounter obstacles such as scar tissue and inhibitory molecules, lack growth factors, and exhibit a much slower growth rate than a juvenile axon. Microtubules are an attractive target for therapy because they are crucial for the advance of a regenerating axon.
Microtubules in the axon consist of a stable region and a labile region, each of which has distinct properties and duties. The labile region is responsible for polymerizing more microtubule mass from free tubulin. My thesis work attempted to add labile microtubule mass to the regenerating axon by protecting the labile regions of the microtubules. This approach would mimic a state of axonal growth when labile microtubule mass is abundant. To accomplish this, I knocked-down a microtubule severing protein called fidgetin. You can think of fidgetin as gardening sheers that are used to prune plant growth; knocking-down fidgetin results in a notable boost in the microtubule mass of the axon via preservation of the labile mass from fidgetin’s severing activity. As a result, axons grow faster, even on unfavorable substrates associated with spinal cord injury (SCI) as well as in vivo following a nerve-crush injury.
There are many novel microtubule-associated proteins, and, along with fidgetin, several have been implicated in regulating the microtubules in the growth cones of axons. I created a medium-throughput workflow for other microtubule associated proteins to be tested in the Baas lab for augmenting nerve regeneration both in vitro and in vivo. Hopefully one day we will be able to utilize microtubules to help repair injured and degenerating axons. Microtubules are a lot like the bones in our body. If you break your arm, you must grow new bone for your arm to heal. If you injure an axon, you must restore microtubule mass for it to function properly and grow. Any therapy that helps an axon regenerate, must converge on microtubules. Approximately 50 years ago tubulin was first discovered and a variety of anti-cancer drugs that targeted microtubules followed. Hopefully, over the next 50 years, microtubules can help heal injured nerve cells.