Eph Signaling Auditory Brainstem Development

Eph 信号听觉脑干发育

• 批准号: 7068007
• 负责人: Karina S Cramer
• 金额: $ 25.67万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7068007
• 关键词: auditory nuclei; axon; biological signal transduction; brain stem; chick embryo; cochlea; cochlear nerve; developmental neurobiology; electroporation; ephrins; growth factor; immunocytochemistry; laboratory mouse; ligands; neurogenesis; neuronal guidance; plasmids; protein tyrosine kinase; receptor expression; species difference; synapses

DESCRIPTION (provided by applicant): The proposed research addresses potential molecular mechanisms underlying the formation of precise synaptic connections in the auditory brainstem. The applicant has previously shown that several members of the Eph family of receptor tyrosine kinases are expressed in avian auditory brainstem nuclei and along the midline during the formation of synaptic connections. These receptors mediate cell-cell interactions during axon outgrowth, and gradients of Eph receptors and their ligands, the ephrins, are required for the formation of precise topographic maps in the visual system. The Specific Aims are to test the roles of Eph receptor signaling in the development of auditory brainstem projections. Each group of experiments includes both descriptive studies of developmental expression and functional studies using experimental manipulations. Inovo microelectroporation will be used to misexpress Eph receptors and an in vitro labeling method will be used to evaluate resulting axonal projections. The generality of findings from chicks will be examined in developing mouse brainstem. Specific Aim 1 proposes experiments to investigate whether gradients of Eph receptors and ephrins are essential for the development of the tonotopic projection from VllIth nerve axons to the avian cochlear nucleus, n. magnocellularis. Specific Aim 2 extends these studies to mammals. The Eph receptor EphA4 is expressed nonuniformly in the developing mouse cochlear nuclei. The role of EphA4 in the establishment of a homologous projection from the VIIIth nerve to the cochlear nucleus will be evaluated in mutant mice that lack EphA4. Axonal projections from n. magnocellularis branch so that an ipsilateral branch synapses in the dorsal region of the target, n. laminaris, while the contralateral branch grows across the dorsal midline and contacts the ventral region of contralateral n. laminaris. Experiments outlined in Specific Aim 3 will evaluate the role of Eph receptors in the guidance of cochlear nucleus axons at the midline in the avian brainstem. These experiments will test whether Eph signaling is extensively used in the development of pathways in the auditory brainstem, and will address whether the roles for Eph receptors in establishing synaptic specificity are similar across modalities and across species.

描述（由申请人提供）： 拟议的研究探讨了听觉脑干中精确突触连接形成的潜在分子机制。申请人之前已经表明，受体酪氨酸激酶Eph家族的几个成员在禽类听性脑干核中以及在突触连接形成过程中沿中线表达。这些受体在轴突生长过程中介导细胞间相互作用，并且 Eph 受体及其配体（肝配蛋白）的梯度是在视觉系统中形成精确地形图所必需的。具体目标是测试 Eph 受体信号传导在听觉脑干投射发育中的作用。每组实验包括发育表达的描述性研究和使用实验操作的功能研究。 Inovo 微电穿孔将用于错误表达 Eph 受体，并使用体外标记方法来评估由此产生的轴突投影。来自小鸡的研究结果的普遍性将在发育中的小鼠脑干中进行检验。具体目标 1 提出了实验来研究 Eph 受体和肝配蛋白的梯度是否对于从第 VIII 神经轴突到鸟类耳蜗核的音位投射的发展至关重要。大细胞藻。具体目标 2 将这些研究扩展到哺乳动物。 Eph 受体 EphA4 在发育中的小鼠耳蜗核中表达不均匀。 EphA4 在建立从第八神经到耳蜗核的同源投射中的作用将在缺乏 EphA4 的突变小鼠中进行评估。 n 的轴突投影。 magnocellularis 分支，以便同侧分支在目标的背侧区域形成突触，n。昆布，而对侧分支生长穿过背中线并接触对侧n的腹侧区域。昆布。具体目标 3 中概述的实验将评估 Eph 受体在引导禽类脑干中线耳蜗核轴突中的作用。这些实验将测试 Eph 信号传导是否广泛用于听觉脑干通路的发育，并将解决 Eph 受体在建立突触特异性方面的作用在不同模式和不同物种中是否相似。