Grant: Operating Grant

Background. The basic units of nervous systems are circuits formed by precisely interconnected neurons. Neurons connect by extending processes called "axons" that are guided to their targets over long distances. Loss of accuracy of this guidance can have disastrous effects on the wiring of our nervous system, including mental retardation and even death. Some studies have suggested that diseases such as autism and schizophrenia might be caused by inappropriate connections formed between specific regions of the brain. Knowing how our nervous system is wired is therefore extremely important if we want to understand how such diseases develop and what could be done to cure them. In this proposal I outline experiments that address the role of a guidance molecule called Netrin. Specific Objectives. (1) Determine how Netrin functions to guide motor neuron axons to muscles (2) Determine how Netrin receptors function in motor neuron axons. Hypothesis. Netrin can function both as an attractant and a repellent molecule to coordinate the guidance of motor axons. Methods. I will address this hypothesis by using the mouse and chick model systems. Both share similar spinal cord anatomy, and use very similar proteins in their development. The mouse has the advantage of the possibility of using animals with "knocked out" genes, but chick embryos are more accessible and can be manipulated while inside the egg. Expected Results: If Netrin is important for setting up connections in the simple system of motor neuron axons and muscles, I will be able to next test how multiple guidance proteins work together: my previous work has identified other guidance molecules important in this system. In the long-term, such studies could shed light on how our brains might become miswired. Also, since the same molecules that are guiding axons are also guiding the formation of blood vessels, research into axon guidance could have wide reaching benefits.