Defining the role of post-translational modifications of Frizzled-5 receptor: implications in cell signalling and synapse formation

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Communication between cells is crucial for a range of biological functions, from tissue formation and growth, to the formation of functional circuits in the brain. Cells communicate by releasing signalling molecules that act on neighboring cells. Importantly, recipient cells are able to detect these released signals because of molecules located at the cell surface, called receptors, that act as antennas. Once the receptor, or antennas, detect the released signals, they activate a series of molecular events inside the cell, called signalling cascades. The intensity and duration of these cascades determine the type of cellular response. Thus, understanding how signalling molecules act on recipient cells and how receptors behave on the cell surface are fundamental processes that concerns cell and developmental biologists, immunologists and neuroscientists. In the brain, the assembly of synapses, sites of contact between nerve cells, or neurons, is a crucial step in the formation of functional circuits. Great progress has been made in understanding the cellular and molecular mechanisms that contributes to synapse formation. Previous work from our lab has led to the discovery that specific factors released by neurons, called Wnt proteins, play a critical role in the formation of brain circuits. Wnt proteins elicit different responses through their interaction with surface receptors that transmit information inside cells. For instance, our studies led to the identification of Frizzled-5 (Fz5), a key receptor for Wnt7a, a Wnt protein that promotes synapse formation. We also found that neurons missing the Fz5 receptor are unable to respond to Wnt7a to form synapses. More recently, we discovered a novel mechanism that modulates the level of Fz5 receptors at the cell surface and its ability to promote the formation of synapses. In this project, we will examine the precise molecular mechanisms by which Fz5 levels are regulated at the cell surface. We will use a multidisciplinary approach that uses biochemical approaches, state-of-the-art live-cell imaging techniques combined with modulation of gene function in the developing brain. This project will provide novel mechanistic insights into how receptors are localised and retained to the cell surface to control fundamental cell functions.