Spinal Cord Development: Interplay Between Electrical Activity and Sonic Hedgehog

脊髓发育：电活动与 Sonic Hedgehog 之间的相互作用

• 批准号: 8290336
• 负责人: Laura Noemi Borodinsky
• 金额: $ 33.22万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8290336
• 关键词: Address; Affect; Biological; Biological Assay; Biosensor; Brain; Calcium; Calcium Spikes; Cell Proliferation; Cells; Childhood; Cilia; Complex; Cues; Development; Developmental Biology; Developmental Process; Dominant-Negative Mutation; Dorsal; Embryo; Epilepsy; Equilibrium; Erinaceidae; Event; Exhibits; Generations; Goals; Image; Investigation; Knowledge; Label; Lead; Life; Link; Luciferases; Mediating; Molecular; Natural regeneration; Nerve Regeneration; Nervous system structure; Neural tube; Neuronal Differentiation; Neurons; Neurosciences; Neurotransmitters; Outcome; Pathway interactions; Patients; Pattern; Phenotype; Positioning Attribute; Process; Production; Proteins; Recovery; Research; Research Project Grants; Role; Second Messenger Systems; Signal Transduction; Signal Transduction Pathway; Sonic hedgehog protein; Spinal; Spinal Cord; Spinal cord injury; Staging; Surface; Synapses; System; Testing; Thinking; Tissues; Transcriptional Regulation; Western Blotting; Xenopus; axon guidance; axonal pathfinding; base; cancer stem cell; cell injury; cell type; human SMO protein; in vivo; injured; innovation; migration; morphogens; nerve stem cell; nervous system development; nervous system disorder; novel; receptor; relating to nervous system; repaired; second messenger; smoothened signaling pathway; synaptogenesis; tissue repair

DESCRIPTION (provided by applicant): Nervous system development encompasses generation of neural cells, followed by their positioning and differentiation to culminate with establishment of specific connections that enable the execution of innumerable functions. Although both the developing and mature nervous system exhibit tremendous plasticity, comparatively, the former has a greater capacity for remodeling. When the neural tissue is injured or its function is imbalanced, as for patients suffering from spinal cord injury or epilepsy, recreating the remarkable plasticity of the developing nervous system towards repairing and regenerating damaged cells and connections is the ultimate goal. Understanding developmental processes becomes crucial to devising therapies targeting nervous system regeneration and repair. Two major developmental cues are key for nervous system development, the morphogentic protein, Sonic hedgehog (Shh), and early electrical activity. Although many aspects of their action are known, there has been no previous consideration of the interaction between them. This research project wil study the molecular mechanisms underlying the interplay between Shh and electrical activity and how their interaction affects nervous system development and maturation. This study will test the hypothesis that the Shh gradient across the dorsoventral axis of the nervous system contributes to establish a gradient of calcium-dependent electrical activity across the dorsoventral developing spinal cord that in turn regulates neuronal differentiation. Pharmacological and molecular manipulations of Shh gradient and signaling wil be implemented in developing Xenopus embryos. Calcium dynamics will be imaged in neurons on the dorsal and ventral surfaces of the neural tube of control and experimentally perturbed embryos. Reciprocally, manipulations of calcium spike activity will be carried out and the consequences to Shh signaling in the developing spinal cord will be assessed. To investigate the functional consequences of the interplay between Shh signaling and calcium spike activity, a crucial biological outcome will be studied: dorsoventral differentiation of developing spinal neurons. The involvement of calcium spike activity-dependent pathways in this process will be studied in vivo following pharmacological and molecular perturbations of Shh signaling and electrical activity. This project may lead to new ways of thinking of how the nervous system develops and how different pathways interact to promote its formation and maturation. When generation and differentiation of neural cells is needed to reestablish lost connections, the ability to direct the affected system toward the production of appropriate number and type of cells is paramount. This investigation of mechanisms underlying neuronal differentiation may set the basis for devising treatments for neurological disorders such as pediatric epilepsy and spinal cord injury, in which both the reestablishment of balanced excitability and the reposition of damaged cells are key events for promoting recovery.

描述（由申请人提供）：神经系统发育包括神经细胞的产生，随后是它们的定位和分化，最终建立特定的连接，使无数功能得以执行。尽管发育中的神经系统和成熟的神经系统都表现出巨大的可塑性，但相对而言，前者具有更大的重塑能力。当神经组织受损或其功能失衡时，如脊髓损伤或癫痫患者，重建发育中的神经系统对修复和再生受损细胞和连接的显著可塑性是最终目标。了解发育过程对于设计针对神经系统再生和修复的治疗方法至关重要。两个主要的发育线索是神经系统发育的关键，即形态发生蛋白、Sonic hedgehog （Shh）和早期电活动。虽然他们行动的许多方面是已知的，但以前没有考虑到他们之间的相互作用。该研究项目将研究Shh与电活动相互作用的分子机制，以及它们的相互作用如何影响神经系统的发育和成熟。这项研究将验证神经系统背腹侧轴上的Shh梯度有助于在背腹侧发育中的脊髓上建立钙依赖性电活动梯度，进而调节神经元分化的假设。Shh梯度和信号的药理学和分子操作将在非洲爪蟾胚胎发育中实施。钙动力学将在对照和实验扰动胚胎的神经管背侧和腹侧表面的神经元中成像。反过来，钙峰活动的操作将被执行，并对发育中的脊髓中Shh信号的后果进行评估。为了研究Shh信号和钙峰活性之间相互作用的功能后果，将研究一个关键的生物学结果：发育中的脊髓神经元的背腹侧分化。在Shh信号和电活动的药理学和分子扰动后，将在体内研究钙峰活性依赖通路在这一过程中的参与。这个项目可能会为神经系统如何发展以及不同途径如何相互作用以促进其形成和成熟提供新的思路。当需要神经细胞的产生和分化来重建失去的连接时，指导受影响的系统产生适当数量和类型的细胞的能力是至关重要的。对神经元分化机制的研究可能为设计治疗神经系统疾病（如小儿癫痫和脊髓损伤）奠定基础，在这些疾病中，兴奋性平衡的重建和受损细胞的重新定位都是促进恢复的关键事件。