Radial patterning of smooth muscle in the vertebrate gut

脊椎动物肠道平滑肌的径向模式

• 批准号: 9320015
• 负责人: Tyler Huycke
• 金额: $ 3.16万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9320015
• 关键词: Address; Attention; Bone Morphogenetic Proteins; Chick Embryo; Cues; Data; Development; Digestion; Digestive System Disorders; Dysplasia; Embryo; Endoderm; Ensure; Enteral; Epithelium; Erinaceidae; Food; Gastrointestinal tract structure; Genetic; Impairment; Intestinal Obstruction; Ligands; Location; Mesenchyme; Mesoderm; Modeling; Molecular; Morphology; Mus; Muscle; Muscle Development; Muscle function; Neural Crest; Neurons; Nutrient; Organ; Pathway interactions; Pattern; Peristalsis; Positioning Attribute; Process; Radial; Resolution; Role; Signal Pathway; Signal Transduction; Signaling Protein; Smooth Muscle; System; Testing; Time; Tissues; To specify; Tube; Work; experimental study; improved; interest; loss of function; muscle form; response; smoothened signaling pathway; spatiotemporal

PROJECT SUMMARY Beginning as a simple tube of endoderm surrounded by mesenchyme, the gut is patterned early in development along its radial axis to generate discrete layers of smooth muscle with distinct orientations. Correct organization of these muscle layers into circumferential and longitudinal bands is required for peristalsis and to generate appropriate physical forces that drive folding of the gut lumen. Yet, how the radial pattern of muscle is determined with precise spatiotemporal resolution during development is not known. Building upon work from our lab and others, we predict that this precision is achieved through specific levels of Hedgehog (Hh) and BMP signaling activity within the gut mesenchyme. By modulating levels of Hh pathway activity, we show in preliminary studies that both low and high levels of Hh signaling inhibit differentiation of the early-forming circumferential smooth muscle layer. We predict that this inhibitory effect of Hh at high levels is due to increased Hh-dependent BMP signaling activity, which is activated at high threshold levels of Hh and acts to block muscle differentiation. Importantly, when Hh signaling is only slightly decreased smooth muscle smooth muscle forms adjacent to the endoderm. Given these data, we put forth and test model in Aim 1 in which the circumferential band of smooth muscle forms at an exact radial location where Hh signaling is sufficiently high, yet the inhibitory effects of BMP are low enough to not interfere. What then triggers the formation of the outer and inner longitudinal layers that form subsequent to the circumferential layer? Our preliminary results indicate that continuous BMP signaling acts to suppress the differentiation of the longitudinal layers, as exogenous Noggin causes their precocious differentiation. We additionally show that Noggin is expressed specifically by differentiating enteric neurons, and put forth a model wherein temporally specific and expression of Noggin in enteric neurons may serve to initiate the differentiation of longitudinal muscle at the correct place and time by locally antagonizing BMPs. In Aim 2, we test this model through embryological manipulations in chick and genetic loss of function in mouse to determine if Noggin from the NCCs is required for longitudinal muscle differentiation. Furthermore, we aim to identify the cellular origin of the longitudinal muscle. The results of the experiments proposed herein will establish a mechanistic model to explain smooth muscle patterning in the vertebrate gut and have the potential to improve our understanding of the mechanism underlying muscle dysplasias that impair digestion.

项目摘要 从一根简单的内胚层管开始，被间充质包围，肠道在 沿着径向轴发育，以产生具有不同方向的平滑肌的离散层。 将这些肌肉层正确组织成圆周和纵向带 蠕动并产生适当的物理力，以驱动肠腔折叠。但是，径向如何 肌肉的模式是在发育过程中精确的时空分辨率确定的。 在我们实验室和其他人的工作的基础上，我们预测这一精度是通过特定级别来实现的 刺猬（HH）和BMP信号传导活性。通过调节HH途径的水平 我们在初步研究中表明，低水平和高水平的HH信号传导抑制了分化 早期形成的圆周平滑肌层。我们预测，高水平HH的这种抑制作用是 由于HH依赖性的BMP信号活性增加，该活性在高阈值水平的HH和 可以阻止肌肉分化的行为。重要的是，当HH信号传导仅略微降低平滑肌时 平滑肌形式与内胚层相邻。鉴于这些数据，我们在AIM 1中提出并测试模型 平滑肌的圆周带形成在HH信号的精确径向位置 足够高，但是BMP的抑制作用足够低，以免干扰。然后是什么触发 在圆周层之后形成的外部和内部纵向层的形成？我们的 初步结果表明，连续的BMP信号传导可抑制分化 纵向层，因为外源性鼻子会引起早熟的分化。我们还表明 Noggin专门通过区分肠神经元来表达，并提出一个模型 肠神经元中Noggin的特异性和表达可能有助于引发纵向的分化 通过局部拮抗BMP，在正确的位置和时间的肌肉。在AIM 2中，我们通过 小鸡的胚胎学和小鼠功能的遗传丧失，以确定是否从 NCC是纵向肌肉分化所必需的。此外，我们旨在确定 纵向肌肉。本文提出的实验结果将建立一个机械模型 解释脊椎动物肠道中的平滑肌图案，并有可能提高我们对 肌肉发育不良的机制损害了消化。