Mechanisms that guide motor axon pathfinding

引导运动轴突寻路的机制

• 批准号: 7162150
• 负责人: CATHERINE Ellen KRULL
• 金额: $ 29.89万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-06-01 至 2009-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7162150
• 关键词: Axon; Cells; Chickens; Condition; Cues; DNA Sequence Rearrangement; Data; Defect; Development; Disease; Dorsal; Electroporation; Embryo; Ensure; Environment; Ephrin-B1; Ephrins; Event; GDNF gene; Goals; Growth; Hindlimb; In Vitro; Limb structure; Localized; Mediating; Mesoderm; Molecular; Motor; Motor Neurons; Muscle; Muscle fasciculation; Nerve; Nerve Regeneration; Pathway interactions; Pattern; Play; Population; Proteins; Rate; Research; Research Personnel; Role; Signal Transduction; Somites; Sorting - Cell Movement; Specificity; Testing; Time; Trauma; Work; axon growth; base; ephexin; gain of function; in vivo; insight; morphogens; prevent; programs; promoter; receptor; repaired; small hairpin RNA

DESCRIPTION (provided by applicant): The overall goal of our research is to identify the molecular cues that influence motor axons as they navigate long distances to their target muscles in the limb and define how they work mechanistically. The results of our studies should yield important insights into the factors that control neural regeneration and repair following disease or trauma. This proposal is a logical extension of our previous studies and focuses on the function of EphA4/ephrins, c- ephexin and c-Ret. Our general hypothesis is that these factors act at multiple steps in the development of motor axon projections to the limb, as directional cues involved in pathway selection, general promoters of growth or as stimulators of axon fasciculation. The specific aims of our studies are as follows: 1. Test the hypothesis that distinct ephrins in axons are vital for axon fasciculation, growth, and dorsoventral pathway selection. 2. Test the hypothesis that ephrins and EphA4 regulate segmental growth, limb entry, and pathway selection. 3. Test the hypothesis that c-ephexin is required in motor axons to select their muscle targets correctly. 4. Test the hypothesis that c-Ret acts as a positive factor to promote motor axon pathway selection of a dorsal trajectory. In chicken embryos, effects on axon fasciculation, growth, pathway selection and muscle target selection will be analyzed following loss- and gain-of-function manipulations targeted precisely to motor neurons, somitic mesoderm, and limb mesoderm using in ovo electroporation. Our strong preliminary studies demonstrate clearly that shRNA against c-ephexin reduces protein levels in vitro and in vivo, and results in phenotypic defects in the timing of axon entry into the limb. These data strongly support the usefulness of this approach in the proposed studies.

描述（由申请人提供）：我们研究的总体目标是确定在运动轴突在肢体中长距离距离目标肌肉时影响运动轴突的分子提示，并定义它们的机械工作方式。我们的研究结果应对控制神经再生和修复的因素产生重要的见解。该建议是我们以前的研究的逻辑扩展，并着重于epha4/ephrins，c- ephecin和c-ret的功能。我们的总体假设是，这些因素在运动轴突投射到肢体的发展中都在多个步骤中起作用，作为参与途径选择的方向提示，生长的一般启动子或作为轴突筋膜的刺激剂。我们研究的具体目的如下：1。检验以下假设：轴突中不同的晶状体对于轴突束缚，生长和背腹途径的选择至关重要。 2。检验以ephrins和epha4调节节段生长，肢体进入和途径选择的假设。 3。检验以下假设：在运动轴突中需要C-甲状腺素才能正确选择其肌肉靶标。 4。检验C-RET是促进背轨迹选择运动轴突途径选择的积极因素的假设。在鸡蛋中，将分析对运动神经元，躯体中胚层和肢体中胚层的损失和功能收益操作后，将对轴突诱变，生长，途径选择和肌肉目标选择的影响进行分析。我们的强有力的初步研究清楚地表明，针对C-甲状腺素的shRNA在体外和体内降低了蛋白质水平，并导致轴突进入肢体的时机中表型缺陷。这些数据在拟议的研究中强烈支持了这种方法的有用性。