The Picower Institute for Learning and Memory, Department of Biology, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, United States.
Elife. 2023 Jun 27;12:RP88273. doi: 10.7554/eLife.88273.
Heparan sulfate proteoglycans (HSPGs) form essential components of the extracellular matrix (ECM) and basement membrane (BM) and have both structural and signaling roles. Perlecan is a secreted ECM-localized HSPG that contributes to tissue integrity and cell-cell communication. Although a core component of the ECM, the role of Perlecan in neuronal structure and function is less understood. Here, we identify a role for Perlecan in the maintenance of larval motoneuron axonal and synaptic stability. Loss of Perlecan causes alterations in the axonal cytoskeleton, followed by axonal breakage and synaptic retraction of neuromuscular junctions. These phenotypes are not prevented by blocking Wallerian degeneration and are independent of Perlecan's role in Wingless signaling. Expression of Perlecan solely in motoneurons cannot rescue synaptic retraction phenotypes. Similarly, removing Perlecan specifically from neurons, glia, or muscle does not cause synaptic retraction, indicating the protein is secreted from multiple cell types and functions non-cell autonomously. Within the peripheral nervous system, Perlecan predominantly localizes to the neural lamella, a specialized ECM surrounding nerve bundles. Indeed, the neural lamella is disrupted in the absence of Perlecan, with axons occasionally exiting their usual boundary in the nerve bundle. In addition, entire nerve bundles degenerate in a temporally coordinated manner across individual hemi-segments throughout larval development. These observations indicate disruption of neural lamella ECM function triggers axonal destabilization and synaptic retraction of motoneurons, revealing a role for Perlecan in axonal and synaptic integrity during nervous system development.
乙酰肝素蛋白聚糖 (HSPGs) 是细胞外基质 (ECM) 和基底膜 (BM) 的重要组成部分，具有结构和信号作用。Perlecan 是一种分泌型 ECM 定位 HSPG，有助于组织完整性和细胞间通讯。尽管是 ECM 的核心成分，但 Perlecan 在神经元结构和功能中的作用知之甚少。在这里，我们确定了 Perlecan 在维持幼虫运动神经元轴突和突触稳定性中的作用。Perlecan 的缺失会导致轴突细胞骨架发生改变，随后轴突断裂，神经肌肉接头的突触回缩。这些表型不能通过阻止 Wallerian 变性来预防，并且与 Perlecan 在 Wingless 信号中的作用无关。仅在运动神经元中表达 Perlecan 不能挽救突触回缩表型。同样，特异性地从神经元、神经胶质或肌肉中去除 Perlecan 不会导致突触回缩，表明该蛋白是从多种细胞类型分泌的，并且发挥非细胞自主功能。在周围神经系统中，Perlecan 主要定位于神经板，这是一种围绕神经束的特殊 ECM。事实上，在没有 Perlecan 的情况下，神经板被破坏，轴突偶尔会离开神经束的正常边界。此外，整个神经束会以时间协调的方式在幼虫发育过程中逐个半节段退化。这些观察结果表明，神经板 ECM 功能的破坏会引发轴突不稳定和运动神经元的突触回缩，揭示了 Perlecan 在神经系统发育过程中对轴突和突触完整性的作用。
