Development and Patterning of the Enteric Nervous System

项目摘要 无论是在早产儿还是在胃肠道运动的背景下，胃肠运动开始时的功能障碍 精神障碍是儿科人群神经发育迟缓和死亡的一个重要原因。这个 肠道神经系统(ENS)是肠壁内的局部神经系统，是 胃肠动力。我们最近已经证明，肠神经元被组织成一个宏观结构， 周向取向的条纹，由随机分布的肠神经元逐渐重组而来 排列成神经元条纹。这一模式的功能意义尚不清楚，但胃肠道运动功能已被了解 直到神经元条纹建立的某个时间点才会出现。此外，对ENS结构的破坏， 在人类疾病中，如先天性巨结肠和某些小鼠模型中，都与胃肠道疾病有关 功能障碍。在这里，我们建议表征这种明显的结构-功能关系的发展 在胚胎和新生小鼠的ENS中。我们将进一步研究模式基因Taqpep在 ENS图案化和GI功能。Taqpep之前已经被证明可以调制条纹猫毛图案，以及 我们的初步数据表明，Taqpep也影响肠神经元纹的周期性。建立 结构和功能之间的关系在ENS发育过程中，我们将绘制GI运动，神经元 多样性，以及神经网络对发育中的ENS的渐进条纹图案的作用(目标1)。在……里面 此外，我们将研究Taqpep突变小鼠的ENS模式和GI运动，以确定其微妙程度 ENS图案化的改变会影响GI功能(目标2)。总体而言，这个项目将描述两国关系的特点 ENS结构和胃肠道运动之间的关系，以及揭示控制ENS图案化的分子机制 和胃肠动力。对ENS结构和功能的这种新的理解将产生对ENS的关键的基本见解 发展并提供了新的途径，以询问胃肠道未成熟和治疗的病理生理和治疗 儿童胃肠动力障碍。

Project Summary Failure in the onset of gastrointestinal (GI) motility, either in the context of prematurity or GI motility disorders, is a significant cause of neurodevelopmental delay and mortality in the pediatric population. The enteric nervous system (ENS), the local nervous system within the walls of the intestine, is the primary driver of GI motility. We have recently demonstrated that enteric neurons are organized into a macrostructure of circumferentially oriented stripes, which arise from progressive reorganization of enteric neurons from a random array into neuronal stripes. The functional significance of this patterning is not understood, yet GI motility does not arise until a timepoint when neuronal stripes have been established. Further, disruptions to ENS structure, as occur in human diseases like Hirschsprung’s disease and in certain mouse models, are associated with GI dysfunction. Here, we propose to characterize the development of this apparent structure-function relationship in the embryonic and neonatal mouse ENS. We will further investigate the role of the patterning gene Taqpep in ENS patterning and GI function. Taqpep has previously been shown to modulate striped cat coat patterning, and our preliminary data suggest that Taqpep also influences the periodicity of enteric neuronal stripes. To establish a relationship between structure and function during ENS development, we will map GI motility, neuronal diversity, and neural network function onto the progressive striped patterning of the developing ENS (Aim 1). In addition, we will investigate ENS patterning and GI motility in Taqpep mutant mice to determine how subtle alterations to ENS patterning affect GI function (Aim 2). Overall, this project will characterize the relationship between ENS structure and GI motility as well as uncover a molecular mechanism that controls ENS patterning and GI motility. This novel understanding of ENS structure and function will yield critical basic insights into ENS development and provide new avenues to interrogate the pathophysiology and treatment of GI immaturity and pediatric GI motility disorders.