The role of the descending dopaminergic projection in spinal development and regeneration

多巴胺能下降投射在脊柱发育和再生中的作用

• 批准号: BB/L021498/1
• 负责人: Catherina Becker
• 金额: $ 42.47万
• 依托单位: University of Edinburgh
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2014
• 资助国家: 英国
• 起止时间: 2014 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FL021498%2F1
• 关键词: role; descending; dopaminergic; projection; spinal

Nerve cells (neurons) in the spinal cord may be lost after injury. In motor neuron diseases, motor neurons in the spinal cord also die, leading to progressive paralysis and death. The reason for the irreversibility of these conditions is that in the human spinal cord, stem cells fail to regenerate neurons. In contrast, we have shown that the zebrafish regenerates motor neurons and other neurons even in adults. It is therefore important to elucidate the signals that allow these animals such formidable tasks. We have recently described that a messenger molecule, dopamine, is able to augment the generation of motor neurons in zebrafish and in human embryonic stem cells in cell culture, indicating a degree of similarity of this signal between zebrafish and humans. Here we want to find out whether dopamine acts only on stem cells that generate motor neurons and which signals inside the stem cells, responsible for motor neuron generation, are involved. Moreover, we will determine how this dopamine signal allows correct movement patterns of the embryo to emerge during development and whether dopamine can be harnessed to improve swimming function after a loss of motor neurons. Our research thus aims to find new cascades of molecular signals that may be important to understand how the spinal cord in vertebrates develops and how these developmental signals can be re-deployed after injury or degenerative neuron loss, which may ultimately inform cell replacement therapies in injured or diseased patient spinal cords. Moreover, our research indicates that psycho-active drugs that act on dopamine signalling during critical phases of embryonic development may lead to permanent changes in spinal cord function of the embryo. This may inform future research into potentially harmful consequences of drug use during early stages of pregnancy.

脊髓中的神经细胞（神经元）可能在损伤后丢失。在运动神经元疾病中，脊髓中的运动神经元也死亡，导致进行性瘫痪和死亡。这些情况不可逆转的原因是，在人类脊髓中，干细胞不能再生神经元。相比之下，我们已经证明，即使在成年人中，斑马鱼也能再生运动神经元和其他神经元。因此，重要的是要阐明的信号，使这些动物这样艰巨的任务。我们最近描述了一种信使分子，多巴胺，能够增加斑马鱼和细胞培养中的人类胚胎干细胞中运动神经元的产生，表明斑马鱼和人类之间的这种信号具有一定程度的相似性。在这里，我们想知道多巴胺是否只作用于产生运动神经元的干细胞，以及干细胞内部负责运动神经元产生的信号是否参与其中。此外，我们将确定这种多巴胺信号如何允许胚胎在发育过程中出现正确的运动模式，以及多巴胺是否可以在运动神经元丢失后被利用来改善游泳功能。因此，我们的研究旨在发现新的分子信号级联，这对于了解脊椎动物的脊髓如何发育以及这些发育信号如何在损伤或退行性神经元丢失后重新部署可能很重要，这可能最终为受伤或患病患者脊髓的细胞替代疗法提供信息。此外，我们的研究表明，在胚胎发育的关键阶段作用于多巴胺信号的精神活性药物可能导致胚胎脊髓功能的永久性变化。这可能会为未来研究怀孕早期使用药物的潜在有害后果提供信息。

项目成果

Wnt signaling controls pro-regenerative Collagen XII in functional spinal cord regeneration in zebrafish.

• DOI: 10.1038/s41467-017-00143-0
• 发表时间: 2017-07-25
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Wehner D;Tsarouchas TM;Michael A;Haase C;Weidinger G;Reimer MM;Becker T;Becker CG
• 通讯作者: Becker CG

Spinal motor neurons are regenerated after mechanical lesion and genetic ablation in larval zebrafish.

• DOI: 10.1242/dev.129155
• 发表时间: 2016-05-01
• 期刊: Development (Cambridge, England)
• 作者: Ohnmacht J;Yang Y;Maurer GW;Barreiro-Iglesias A;Tsarouchas TM;Wehner D;Sieger D;Becker CG;Becker T
• 通讯作者: Becker T