Grant: Operating Grant

We now know quite a bit about how external chemical signals control the functions on the inside of cells. Such cues are prominently used in the developing embryo, for example, to instruct a progenitor cell to keep dividing to increase the size of an organ, or to make a cell stick to another to build a tissue, or to connect a neuron with its synaptic partner. Such individual signals and their receptors on the surface of cells have been identified, as have been the relay pathways that transmit those signal from the receptor to other compartments inside the cell or neuron. Many of these have been implicated in various diseases and drugs targetting such signalling events are being sought. What is also unclear is how pathways activated by different signals might work together to integrate the information about the extracellular environment. To answer this question, we are proposing to work in the developing nervous system, to understand the how signals from two very different families of secreted molecules are integrated. We gathered a lot of evidence that netrin and ephrin signals are important in the development of connections between neurons. We also discovered that when ephrin and netrin are presented simultaneously, nerves develop in a very different manner compared when each signal is presented alone. We propose to examine how this happens in neurons made from neuronal stem cells in vitro, using biochemical fractionation and protein complex formation measurement. Ephrin and netrin signals have been implicated in many diseases such as cancer and neurodegeneration. In the long term, once we understand ephrin-netrin signal integration, we would search for drugs that might boost or disrupt it.