Cell-Cell Signaling in Development and Regeneration of Visual Connections

视觉系统的正确运作需要一套从眼睛到大脑的精确的轴突连接。 如果这些连接发育异常，或者后来因损伤或退化而受损，视力可能会 受损或丢失。该项目广泛的长期目标是识别和表征细胞间的信号。 参与视觉神经元连接的发展和再生的分子。 在成人的视觉系统中，像中枢神经系统的其他部分一样，轴突的再生能力非常有限。这 至少在一定程度上是由于内源性再生抑制物，导致了人们对可能 克服这些抑制物的作用，从而促进可塑性和再生。硫酸软骨素 蛋白多糖(CSPGs)长期以来一直被认为是一类重要的抑制剂，但没有与之对应的 受体已被鉴定出来，限制了这一领域的进一步分子进展。在最近的工作中，我们发现 蛋白酪氨酸磷酸酶Sigma(PTPsigma)作为CSPGs的受体，开辟了新的机会 研究再生机制和潜在的治疗策略。该受体在体内的作用 再生被PTPsigma基因缺失的影响所证实，PTPsigma基因缺失促进再生，包括 视神经中的视网膜轴突。在最近的其他工作中，我们已经证明PTPsigma作为一种配体- 特异性分子开关，不仅介导CSPG抑制，还介导硫酸乙酰肝素蛋白聚糖(HSPG) 促进轴突延伸，为理解CSPG和HSPG的相反影响提供了一个范例。 目标1有两个相互关联的目标：第一，更好地理解相互作用的基本生物学 PTPsigma及其蛋白多糖配体；第二，探索可促进轴突生长和 视神经再生。虽然目标1专注于PTPsigma的细胞外相互作用，但目标2探索 下游的跨膜和细胞内信号机制。鉴定HSPG和HSPG的前期工作 PTPsigma的CSPG配体为理解PTPsigma的下游机制基础开辟了新的机会 这些蛋白多糖的对比作用，同时在理解上取得了新的进展 受体PTP家族信号传导的基本机制。最后，目标3建议继续研究 淀粉样前体蛋白(APP)及其结合伙伴在发育中的视网膜顶盖系统中表达。 虽然已知APP对β-淀粉样蛋白的处理在病理中有重要作用，但正常的 APP的发育功能或调节其处理的机制尚未被很好地理解。 已经确定了APP的结合伙伴，它们在视网膜顶盖发育中显著表达， 并会影响视网膜轴突的生长和APP的处理。进一步的研究将提供更好的理解 这些分子相互作用对发育、退化和再生具有潜在的影响。

Correct functioning of the visual system requires a precise set of axonal connections from the eye to the brain. If these connections develop abnormally, or are later damaged by injury or degeneration, vision may be impaired or lost. The broad long-term objective of the project is to identify and characterize cell-cell signaling molecules involved in the development and regeneration of visual neuronal connections. In the adult visual system, like other parts of the CNS, axons show very limited capacity for regeneration. This is due, at least in part, to endogenous regeneration inhibitors, leading to great interest in strategies that might overcome the effect of these inhibitors, and thus promote plasticity and regeneration. Chondroitin sulfate proteoglycans (CSPGs) have long been known as an important class of inhibitors, but no corresponding receptor had been identified, limiting further molecular progress in this area. In recent work, we identified Protein Tyrosine Phosphatase sigma (PTPsigma) as a receptor for CSPGs, opening up new opportunities to study mechanisms in regeneration and potential therapeutic strategies. The role of this receptor in regeneration is confirmed by the effects of PTPsigma gene deficiency, which enhances regeneration, including of retinal axons in the optic nerve. In other recent work, we have shown that PTPsigma acts as a ligand- specific molecular switch, mediating not only CSPG inhibition but also heparan sulfate proteogylcan (HSPG) promotion of axon extension, providing a paradigm to understand opposing effects of CSPGs and HSPGs. Aim 1 has two inter-related goals: first, to better understand the basic biology of the interaction between PTPsigma and its proteoglycan ligands; and second, to explore compounds that can promote axon growth and optic nerve regeneration. Whereas Aim 1 focuses on extracellular interactions of PTPsigma, Aim 2 explores downstream transmembrane and intracellular signaling mechanisms. The prior work identifying HSPG and CSPG ligands for PTPsigma opens up new opportunities to understand the downstream mechanistic basis for the contrasting effects of these proteoglycans, and simultaneously to make new progress in understanding basic mechanisms of signaling by the receptor PTP family. Finally, Aim 3 proposes to continue studies of the Amyloid Precursor Protein (APP) and its binding partners expressed in the developing retinotectal system. While APP processing to beta-amyloid is known to have important roles in pathology, neither the normal developmental functions of APP nor the mechanisms that regulate its processing are yet well understood. Binding partners for APP have been identified which are prominently expressed in retinotectal development, and can affect retinal axon growth and APP processing. Further studies will provide improved understanding of these molecular interactions, with potential implications for development, degeneration and regeneration.