Cellular mechanisms controlling neural crest cell migration along the developing gut

在肠壁内，有大量的神经元，可能比脊髓中的更多。这些肠神经元在控制包括肠蠕动（内容物沿肠沿着推进）在内的许多肠功能中起重要作用。肠道中的大多数神经元，包括大肠中的神经元，都来自于从后脑迁移的前体，然后在发育过程中迁移到胃肠道并沿着胃肠道迁移。神经元前体在肠道的定植在小鼠中需要5天，在人类中需要6周。对控制神经元前体沿着肠道迁移的机制的研究提供了关于细胞迁移的基本信息。对人类和小鼠的遗传学研究已经确定了神经元前体沿着胃肠道迁移所必需的一些基因，但对于一些关键基因，它们的确切作用尚不清楚。我们最近开发了一种方法，通过胚胎小鼠肠道外植体迁移的活神经元前体成像。在目前的提案中，我们将融合成像和遗传学研究，以了解特定基因的突变如何导致迁移缺陷。特别是，特定的突变如何影响肠神经前体的迁移行为？我们以前也表明，神经元前体迁移沿着肠与轴突密切相关。我们将研究这些相互作用的性质-特别是，谁跟随谁，当细胞迁移和轴突生长分开时会发生什么？这些研究将调查神经前体迁移到发育中的肠道中以及沿着发育中的肠道迁移的许多关键方面，对于理解肠神经系统是如何沿着胃肠道沿着建立的至关重要。

Within the wall of the gut, there are a large number of neurons, probably more than are in the spinal cord. These enteric neurons play an essential role in controlling a number of gut functions including peristalsis (the propulsion of contents along the gut). Most of the neurons in the gut, including those in the large intestine, arise from precursors that emigrate from the hindbrain, and then migrate into and along the gastrointestinal tract during development. The colonization of the gut by neuron precursors takes 5 days in mice and 6 weeks in humans. Studies of the mechanisms controlling the migration of neuron precursors along the gut have provided fundamental information about cell migration in general. Genetic studies in humans and mice have identified some of the genes that are necessary for the migration of neuron precursors along the gastrointestinal tract, but for some of the key genes, their precise role is unknown. We have recently developed a method for imaging living neuron precursors migrating through explants of embryonic mouse gut. In the current proposal we will meld imaging and genetic studies to understand how mutations in particular genes lead to migration defects. In particular, how do particular mutations affect the migratory behaviour of enteric neural precursors? We have also previously shown that neuron precursors migrate along the gut in close association with axons. We will examine the nature of these interactions - in particular, who is following whom, and what happens when cell migration and axon growth are uncoupled? These studies, which will investigate a number of critical aspects of the migration of neural precursors into and along the developing gut, are central to understanding how the enteric nervous system is established along the gastrointestinal tract.