Neurotrophin receptor regulation of taste development

项目概述：在发育过程中，味蕾的感觉神经支配受到严格的 两种神经营养因子脑源性神经营养因子(BDNF)和神经营养因子-4(NT4)的作用。 虽然这两个因子都调节味觉神经支配，但它们的具体功能与 彼此之间。BDNF在味觉上皮细胞中表达，并决定味觉神经元是否会 在发育过程中定位和支配味觉安慰剂，而NT4不。BDNF和NT4 调节味觉神经元和味蕾数量，但它们在不同的时间有影响 发展。这项研究的长期目标是了解细胞和分子 味蕾的神经支配和维持的调节机制 发展。建议的研究集中在这两种神经营养因子BDNF的机制上 和NT4，可以通过相同的受体TrkB和NT4影响神经支配的各个方面 第75页。拟议的研究使用了细胞计数、轨迹追踪、免疫组织化学和扫描 基因敲除小鼠的电子显微镜观察以确定何时需要trkB和p75 味觉发育的各个方面，包括轴突延伸到舌头，目标选择，以及 膝状神经元/味蕾存活。此外，这些研究结合了这些解剖学 具有复杂遗传工具的方法，允许单个磷酸化位点的功能 TrkB受体蛋白在体内被阻断。这些实验将确定哪个TrkB在细胞内 信号通路是轴突伸入舌、靶点选择和膝曲形成所必需的。 神经元/味蕾存活。这些研究一起检验了TrkB介导的效应的假设 BDNF和NT4，但这些神经营养因子的每一种功能都需要不同的细胞内 信号通路。而p75‘S，更微妙的作用是调节味觉的调节 神经营养因子的发育。因为这些实验检验了 神经营养因子如何通过Trk受体调节神经元存活和轴突靶向，该项目 这些信号机制在控制神经元治疗中的重要意义 再生期间的存活和轴突靶向。 。

Project Summary: During development, sensory innervation to taste buds is tightly regulated by the actions of two neurotrophins, brain-derived neurotrophic factor (BDNF) and neurotrophin-4 (NT4). Although both of these factors regulate gustatory innervation, their specific functions are different from one another. BDNF is expressed in gustatory epithelium and determines whether gustatory neurons will locate and innervate taste placodes during development, while NT4 does not. Both BDNF and NT4 regulate gustatory neuron and taste bud number, but they have their influences at different times during development. The long range goal of this research is to understand the cellular and molecular mechanisms that regulate the neural innervation to and the maintenance of taste buds during development. The proposed studies focus on mechanisms by which these two neurotrophins, BDNF and NT4, can influence various aspects of neural innervation through the same receptors, TrkB and p75. The proposed studies use cell counting, tract tracing, immunohistochemistry and scanning electron microscopy in gene knockout mice to determine when TrkB and p75 are required for specific aspects of gustatory development, including axonal extension into the tongue, target selection, and geniculate neuron/taste bud survival. Furthermore, these studies combine these anatomical approaches with sophisticated genetic tools allowing the function of single phosphorylation sites on the TrkB receptor protein to be blocked in vivo. These experiments will determine which TrkB intracellular signaling pathways are required for axonal extension into the tongue, target selection, and geniculate neuron/taste bud survival. Together these studies test the hypotheses that TrkB mediates the effects of both BDNF and NT4, but that each function of these neurotrophins requires a different intracellular signaling pathway. While p75's, more subtle role, is to modulate the regulation of gustatory development by neurotrophins. Because these experiments examine the fundamental mechanisms of how neurotrophins regulate neuronal survival and axon targeting via Trk receptors, this project has important implications for the therapeutic use of these signaling mechanisms in controlling neuron survival and axon targeting during regeneration. .