Growth factors in the development and physiology of geniculate taste neurons

舌的味觉最初是由味蕾传达的，味蕾是位于高度发达的感觉细胞群。 有组织的味觉乳头，化学感觉神经元，其细胞体位于膝状体， 岩神经节味蕾中的化学感受器细胞不断翻转并被替换 在生活中。指导味蕾发育神经支配的分子机制，以及 在整个生命过程中保持这些不断更新的功能连接，仍在被阐明。 神经营养因子对感觉系统的发育和终身维持至关重要。两 神经营养因子家族的成员BDNF和NT-4被公认为对神经营养因子的存活至关重要。 膝状体化学感觉神经元，以及它们对菌状味蕾的神经支配。的成员 第二个重要的神经营养因子家族，胶质细胞源性神经营养因子（GDNF）家族 配体（GFLs）在化学感觉神经支配期间在舌中表达。GFLs， 由GDNF，neurturin，artemin和persephin组成，是对神经细胞亚群有效的神经营养因子。 躯体感觉神经元、脊髓运动神经元和自主神经元。我们最近发现， GFLs的信号转导受体Ret在Phox 2B+化学感受膝状体中广泛表达 神经元在发育的早期，在它们支配舌头之前（在E13.5大于70%），然后 在成年期仅限于Phox 2B+化学感觉神经元的一个子集（约15%）。这 表达谱表明，GFL/Ret通路可能有两个不同的发育调节， 在膝状体化学感觉神经元的分化和维持中起作用，但它们在 外周味觉系统尚未被探索。根据本提案中提供的初步数据，我们的总体 一种假说认为GFL/Ret受体复合物对早期细胞命运至关重要 确定膝状体化学感觉神经元，以及用于终身维持和 这些神经元的生理上不同的亚群的功能。在具体目标1中，我们将测试 GDNF、NRTN和Ret对化学感受器发育特化至关重要的假说 膝状神经节的神经元，以及它们对菌状味蕾和中枢的外周神经支配 孤束核的神经支配。在具体目标2中，我们将检验GDNF/Ret 受体复合物对于舌感觉神经的一个子集的终身维持和生理学是必需的。 膝状神经节的神经元。Ret+舌传入神经元的生理功能将是 用鼓索神经记录对各种化学刺激和舌刺激的反应来确定 方式。对膝状体神经元中的GFL/Ret通路进行机制检查的基本原理是， 这有助于合理设计外周神经元疾病和损伤的治疗干预， 并将为外周味觉系统的发育和维持带来新的见解。

The lingual sense of taste is initially communicated by taste buds, clusters of sensory cells located in highly organized taste papillae, to chemosensory neurons whose cell bodies are located in the geniculate and petrosal ganglia. The chemosensory receptor cells in taste buds continuously turn over and are replaced throughout life. The molecular mechanisms that direct the developmental innervation of taste buds, and maintain these constantly renewing functional connections throughout life, are still being elucidated. Neurotrophic factors are essential for the development and lifelong maintenance of sensory systems. Two members of the neurotrophin family, BDNF and NT-4, are well established as being critical for the survival of geniculate chemosensory neurons, and for their innervation of fungiform taste buds. The members of a second important family of neurotrophic factors, the glial cell line-derived neurotrophic factor (GDNF) family ligands (GFLs), are expressed in the tongue during the period of chemosensory innervation. The GFLs, which consist of GDNF, neurturin, artemin and persephin, are potent neurotrophic factors for subpopulations of somatosensory neurons, spinal motor neurons and autonomic neurons. We recently discovered that the signal-transducing receptor for the GFLs, Ret, is widely expressed in Phox2B+ chemosensory geniculate neurons early in development prior to their innervation of the tongue (greater than 70% at E13.5) and then becomes restricted to a subset (approximately 15%) of Phox2B+ chemosensory neurons in adulthood. This expression profile suggests that the GFL/Ret pathway may have two distinct developmentally regulated functions in the differentiation and maintenance of geniculate chemosensory neurons, but their role in the peripheral taste system is unexplored. Based on preliminary data presented in this proposal, our overarching hypothesis is that the GFL/Ret receptor complex is critically important for the early cell fate determination of geniculate chemosensory neurons, as well as for the life-long maintenance and function of physiologically distinct subpopulations of these neurons. In Specific Aim 1 we will test the hypothesis that GDNF, NRTN and Ret are critical for the developmental specification of chemosensory neurons of the geniculate ganglion, as well as their peripheral innervation of fungiform taste buds and central innervation of the nucleus of the solitary tract. In Specific Aim 2 we will test the hypothesis that the GDNF/Ret receptor complex is necessary for the lifelong maintenance and physiology of a subset of lingual sensory neurons of the geniculate ganglion. The physiologic function of Ret+ lingual afferent neurons will be determined with chorda tympani nerve recordings in response to the various chemical stimuli and lingual modalities. The rationale for a mechanistic examination of the GFL/Ret pathway in geniculate neurons is that this may aid in the rational design of therapeutic interventions for diseases and injuries of peripheral neurons, and will bring novel insights to the development and maintenance of the peripheral taste system.