Axon Guidance at the CNS Midline: Changing Responses to External Cues
The wiring of the central nervous system (CNS) is composed of axons, specialized extensions of neurons that transmit electrical impulses to other cells. During development, axons navigate long distances to their targets in the CNS. Thomas Kidd’s Lab uses the fruit fly model to study how axons navigate properly. In the fly equivalent of the spinal cord, axons are attracted to the center of symmetry, the midline, by diffusible proteins called Netrins. Deletion of the genes encoding Netrin proteins prevents axons from crossing the midline, and expression of Netrin proteins at the midline is sufficient to rescue axon connectivity defects. Interestingly, Dr. Kidd found that one Netrin family member, Netrin-B, also promotes neuron survival, and that preventing cell death is sufficient to make neurons re-connect to other neurons even in the absence of guidance cues. Thus therapeutics designed to keep neurons alive after injury may be able to stimulate neurons to re-grow or sprout new connections.
Q: What is the big picture of your field?
TK: “People think that axon guidance is a solved problem. Axon guidance was a hot topic in the 90’s when the idea first came out. Some might say that now we are just filling in the details, but I still think that there are a lot of things that need to be understood. First of all, we don’t know enough about the function of molecules to explain the processes going on in our brain. Second, we have very little idea about how these molecules work together and how the machinery responds. For example, if you are dealing with a wiring problem in the CNS and neurons are dying, you might think the cause has nothing to do with navigation, but indeed there are some connections. Understanding the mechanisms neurons use to navigate is of great interest, not only for understanding how our brains develop, but also as a starting point to generate ideas that can be used to stimulate the re-growth of axons after injury such as spinal cord injury.”
Q: Is there a relationship between axon guidance and the aging field?
TK: “Axon guidance molecules also play an important role in cancer, and molecules such as Robo/Slit and Netrins are increasingly being implicated as tumor suppressor molecules. So the mechanism could be that when you make the right navigation decisions, you live; when you make the wrong decisions, you die. For cancer cells, axon guidance molecules may have other functions like controlling cell growth and division. A great example is the Netrin proteins, which we know are required the cell survival. In tumors, Netrins are often overexpressed and the receptors that trigger cell death are not working. Overall, abnormal changes in axon guidance molecules and their signaling pathways are an underlying cause of connectivity issues and aging-associated diseases.”
Q: You have experience in both academia and industry. What are the pros and cons from both sides?
TK: “I went into industry because I have always been interested in applications. I love basic research, but I think there is a huge amount of intellectual creativity in the application field. There are so many smart ideas out there. I went to industry at the start of dotcom boom, around 1999. At Exelixis, I screened for genetic modifiers of the insulin receptor. This project was very different from what I previously studied, but I found it very interesting and exciting. However, what I didn’t like was how things could change overnight without my knowledge or input. The defining moment for me was when I was sitting in a meeting, and I realized that everyone in the room knew that my group’s project had changed but no one had the courage to tell me. In industry, these are situations that you cannot control. I decided to return to academia because I wanted to be somewhere that I could help raise my family. The University of Nevada is beautiful, and being at a smaller university takes a lot of the pressure off. My suggestion for postdocs who are choosing between academia and industry, is to pick one path and stick to it. Just know that in industry, things change very fast, and you will probably end up doing something completely different than what you started doing.”