DIFFERENTIATION FACTOR RECEPTORS AND NEURAL CELL FATE

拟议的研究的目的是确定在斑马鱼的分子机制的基础规范的第一个神经元，早期逃避反射。初级运动神经元和感觉神经元有相似的遗传程序，它们响应于不同的背腹信号而执行。我建议阐明这些程序是如何发出信号的，以及它们如何决定细胞的规格。我将通过检查发育过程中的表达模式来测试c-ret受体在局部信号传导中所起的作用。我将确定初级神经元的分化是否需要c-ret的表达，以及c-ret是否足以驱动初级运动和感觉神经元的分化。我还将确定假定的c-ret配体GDNF的表达模式，看看它是否是维持初级感觉和运动神经元所必需的。一些感觉神经元的程序性细胞死亡与甲状腺激素水平的降低相一致。我将测试其他初级神经元的特化和维持是否也依赖于长距离甲状腺激素信号的改变。最后，我将研究甲状腺激素受体和它们的二聚化伙伴，类维生素A X受体的表达模式。干扰的信号与受体拮抗剂应该揭示的要求激素作用的规格或维护斑马鱼初级神经元。

The objective of the proposed research is to determine in zebrafish the molecular mechanisms that underlie the specification of the first neurons, those of the early-escape reflex. Primary motor and sensory neurons have similar genetic programs that are executed in response to different dorsal- ventral signaling. I propose to elucidate how these programs are signaled and how they determine cell specification. I will test the role that the c-ret receptor plays in local signaling by examining the expression pattern during development. I will determine if the differentiation of primary neurons requires expression of c-ret, and if c-ret is sufficient to drive differentiation of primary motor and sensory neurons. I will also ascertain the expression pattern of the putative c-ret ligand, GDNF, to see whether it is required for maintenance of primary sensory and motor neurons. Programmed cell death of some sensory neurons is coincident with decreasing levels of thyroid hormone. I will test if the specification and maintenance of other primary neurons is also dependent on alterations in long-range thyroid hormone signaling. Finally, I will examine the expression pattern of thyroid hormone receptors and their dimerization partners, the retinoid X receptors. Perturbation of the signaling with receptor antagonists should reveal the requirement for hormone action in the specification or maintenance of zebrafish primary neurons.