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

细胞之间的通讯对一系列生物功能至关重要，从组织的形成和生长，到大脑功能回路的形成。细胞通过释放作用于相邻细胞的信号分子进行通讯。重要的是，受体细胞能够检测到这些释放的信号，因为位于细胞表面的分子称为受体，充当天线。一旦感受器或天线检测到释放的信号，它们就会激活细胞内的一系列分子事件，称为信号级联。这些级联反应的强度和持续时间决定了细胞反应的类型。因此，了解信号分子如何作用于受体细胞以及受体如何在细胞表面发挥作用，是细胞和发育生物学家、免疫学家和神经科学家关心的基本过程。在大脑中，突触的组装是形成功能回路的关键一步。突触是神经细胞或神经元之间的接触点。有关突触形成的细胞和分子机制的研究已经取得了很大进展。我们实验室之前的工作已经发现，神经元释放的特定因子，即Wnt蛋白，在大脑电路的形成中发挥着关键作用。WNT蛋白通过与细胞内传递信息的表面受体相互作用而引起不同的反应。例如，我们的研究发现了Frizzled5(Fz5)，它是Wnt7a的关键受体，Wnt7a是一种促进突触形成的Wnt蛋白。我们还发现，缺少Fz5受体的神经元无法对Wnt7a产生反应来形成突触。最近，我们发现了一种新的机制，可以调节细胞表面Fz5受体的水平，以及它促进突触形成的能力。在这个项目中，我们将研究Fz5水平在细胞表面被调控的精确分子机制。我们将使用一种多学科的方法，使用生化方法、最先进的活细胞成像技术以及对发育中大脑中基因功能的调节。该项目将为受体如何定位并保持在细胞表面以控制基本细胞功能提供新的机械见解。

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.