Linking an activity-dependent BMP pathway to synapse structure and function

 描述(由申请人提供)：这项提案研究了生长因子信号通路如何与突触结构和功能相联系。生长因子是强有力的神经调节剂，在突触中发挥着不同的作用。它们调节突触生物学的基本特征，包括基线递质释放、突触形态和可塑性。鉴于它们指导突触组织的重要性，确定突触生长因子信号与突触和神经元活动耦合的分子和细胞机制是很重要的。骨形态发生蛋白/转化生长因子β家族成员是突触结构和功能的进化保守调节者。特别是，骨形态发生蛋白/转化生长因子β途径在果蝇NMJ具有神经营养途径活性。BMP途径突变体在NMJ的形态和功能上表现出明显的缺陷。值得注意的是，不同的配基池独立地调节这些突触特征。我们证明，突触前池调节突触的结构和功能，而突触后池指导NMJ终末的整体生长。了解这些信息通道是如何在内源性突触上分离的，对于理解不同的突触功能是如何独立控制是至关重要的。我们这项工作的切入点是一种新型的神经元跨膜蛋白Crimpy。我们已经证明，Crimpy能够区分突触前和突触后的BMP池。CrimPy结合了一种名为GBB的BMP同系物，并将其输送到突触前致密核心小泡(DCV)。如果没有Crimpy，DCV中不再存在GBB，突触前活动也不会释放GBB。在没有Crimpy的情况下，无法区分突触前和突触后的配体池，NMJ的特征是以突触前突触组织线索为代价的异常营养信号。在这个提议中，我们建立在我们新的初步发现的基础上，以确定活动诱导的突触前BMP信号在突触结构和功能中的作用。首先，我们定义突触前和突触后信号的分子同一性。由于Crimpy是标记突触前池的关键，我们将从生物化学的角度定义Crimpy在BMP信号转导中的作用。其次，我们将阐明活性依赖的BMP信号如何引导突触组织。我们检验了Crimpy介导的突触前GBB信号是局部和急性线索指导性线索驱动突触组织的假设。第三，我们将定义下行信令级联。我们有令人兴奋的初步证据表明，一种新的BMP受体转导活性依赖的信号。我们将确定受体在该途径中的作用，并表征非典型活性依赖的BMP级联的新下游成分。

 DESCRIPTION (provided by applicant): This proposal examines how a growth factor signaling pathway is linked to synapse structure and function. Growth factors are potent neuromodulators and play diverse roles at synapses. They regulate fundamental features of synaptic biology including baseline transmitter release, synapse morphology, and plasticity. Given their importance directing synapse organization, it is important to define the molecular and cellular mechanisms coupling synaptic growth factor signaling to synapses and neuronal activity. BMP/TGFβ family members are evolutionarily conserved regulators of synapse structure and function. In particular, a BMP/TGFβ pathway has neurotrophic pathway activity at the Drosophila NMJ. BMP pathway mutants display striking defects in NMJ morphology and function. Remarkably, distinct ligand pools independently regulate these synaptic features. We demonstrate that the presynaptic pool regulates synaptic structure and function, while the postsynaptic pool directs overall growth of the NMJ terminal. Understanding how these information channels are separated at an endogenous synapse is essential to understand how distinct synaptic features are independently controlled. Our entry point to this work is the novel neuronal transmembrane protein Crimpy. We have demonstrated that Crimpy enables discrimination between pre- and postsynaptic BMP pools. Crimpy binds a BMP homolog called Gbb and traffics it to presynaptic dense core vesicles (DCVs). Without Crimpy, Gbb is no longer found in DCVs and is not released by presynaptic activity. In the absence of Crimpy, pre- and postsynaptic ligand pools cannot be distinguished, and the NMJs are characterized by aberrant trophic signaling at the expense of the presynaptic synapse-organizing cue. In this proposal, we build on our novel preliminary findings to define the role of activity-induced presynaptic BMP signaling in synapse structure and function. First, we define the molecular identity of the pre- and postsynaptic signals. Because Crimpy is key for marking the presynaptic pool, we will define biochemically the role of Crimpy in BMP signal transduction. Second, we will elucidate how activity-dependent BMP signals direct synapse organization. We test the hypothesis that the Crimpy-mediated presynaptic Gbb signal is a local and acute cue instructive cue driving synapse organization. And third, we will define the downstream signaling cascade. We have exciting preliminary evidence that a novel BMP receptor transduces the activity-dependent signal. We will establish the receptor's role in the pathway and characterize novel downstream components of a non-canonical activity-dependent BMP cascade.