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by Tim Kennedy, PhD

A human brain contains something like 1,000,000,000,000 nerve cells (neurons). A relatively easy way to remember this number, a one followed by twelve zeros, is that it correspond to one million million neurons. An easier way is to simply acknowledge that it is a lot of neurons. It is so many neurons that it is essentially unimaginable, at least using the power of one human brain. The circuitry of the nervous system is defined by the specialized connections that these cells make with each other, the synapses where one cell bumps up against another. To an important extent, the pattern of synaptic connections and neuronal circuits determines how the nervous system works, and in a potent way defines who each of us are. In my laboratory, we are interested in how these neural circuits are built during development and how they are maintained in the mature adult brain.

In mammals, the development of the circuitry of the nervous system begins during embryogenesis and continues for a short time after birth. One neuron may form a synapse on a neighbouring cell, while another may extend a long thin process, called an axon, great distances, growing past thousands of cells, until the appropriate partner is reached and a synaptic connection is formed. The process of an axon finding its way to its ultimate synaptic target is referred to as axon guidance.

The past 20 years have provided an unprecedented amount of insight into the molecules in the developing embryo that direct axons to their targets. In my laboratory, a major focus of our work involves a family of proteins called netrins. The name “netrin” is derived from the Sanskrit verb “netr” meaning “to guide”. Netrins do just that. Gradients of netrin protein form patterns in the early embryo. Some axons are attracted and grow up these gradients, while others are repelled, heading off in the opposite direction. Without netrins, brain development is severely abnormal, demonstrating that netrins play an essential role early in brain development.

Although netrins are required for complex mammalian brains to develop, the first netrin identified was not found in a human, or even a rat or mouse. Rather, it was discovered in C. elegans, a small approximately 1 millimetre long nematode worm. This little worm is a favourite animal for studying how genes influence development. Among its attributes, it is translucent, with its cellular workings readily visible for easy inspection under a microscope. It also has a relatively short life span and a rapid generation time, which helps when examining the consequences of inheritance. For the neuroscientist, while our brains contain twelve zeros worth of neurons, the entire nervous system of a C. elegans worm is composed of a more manageable 302 neurons. A series of studies carried out by researchers studying C. elegans discovered that mutation of certain genes resulted in worms that didn’t wiggle quite right. Some of the mutations that cause worms to grow up uncoordinated were found to disrupt the development of the nervous system. These genes were named UNCs, for the obvious reason. Some UNCs profoundly affected axon guidance. Among the hundreds of UNCs identified, number 6 on the list, UNC-6, was the first netrin to be found.

While the UNCs were being identified in C. elegans, I was a post-doctoral fellow working with a small group of developmental neurobiology colleagues to identify a protein that promotes axon growth in the embryonic chicken spinal cord. We purified and identified two new proteins with closely related gene sequences. Both caused axons in the embryonic spinal cord to grow, and although this was axon growth associated with a complex vertebrate nervous system, it was also clear that both of these new proteins were closely related to the UNC-6 protein recently described in C. elegans. We realized that we had found a novel family of proteins with an axon guidance function that was highly conserved across a massive span of evolutionary time. We named them netrin-1 and netrin-2. Related members of the extended family of netrins have since been identified in a diverse list of animals that includes insects and anemones, frogs and fish, mice and humans.

At the Neuro, working with my own students and post-docs to understand the function of netrin-1 in the nervous system, we were surprised to find that netrin-1 is not only expressed during development, but that it is produced by cells in the mature adult mammalian brain, including yours and mine. A major focus of our research over the past decade has been to try to understand why. These studies caused us to focus on oligodendrocytes. These are the cells in the mammalian CNS that make myelin, the wrapping that electrically insulates axons. In demyelinating diseases like multiple sclerosis, oligodendrocytes die, myelin is lost, and nervous system function is disrupted in part because without the appropriate insulation the axonal ‘wires’ essentially short circuit. We found that mature oligodendrocytes make netrin-1, and that without netrin-1, myelin begins to fall apart. These studies identified a new mechanism that maintains myelin and provided the first insight into why netrin-1 is made by cells in the adult CNS. Due to the potential relevance of such a mechanism to demyelinating disease, we are now working to identify the biochemical mechanisms involved, and to determine if these might be appropriate targets for drugs that could promote remyelination and prevent myelin from being lost.

Five hundred million years ago, give or take a few hundred million years, present day humans and present day C. elegans shared a common ancestor, which likely looked something much like a C. elegans does today: a small bilaterally symmetrical roundworm, making its way in the world with its collection of something like 300 neurons. When I first opened my lab at the Neuro, I imagined us studying the function of an exciting new family of axon guidance proteins, but I wasn`t thinking of myelin. Not the least among the reasons for this was that C. elegans, in which we knew netrin plays a critical role, doesn’t have myelin. 500 million years ago myelin hadn`t happened yet. The animals that make myelin had yet to evolve. Evolution has been described as a tinkerer, constrained to generate new things by working with and modifying what’s available. Netrin provides an example of a protein that evolved to perform an essential function in early development, directing growing axons to their targets, but was then co-opted into a profoundly different yet equally essential new role as life became more complex. Evolution, like life, is full of surprises. So is research - and the surprises are often the best part.