Molecular Regulation of Trigeminal Sensory Ganglia Development

拟议的研究的长期目标是确定三叉神经感觉神经节发育的细胞，遗传和分子相互作用。三叉神经感觉神经节是脊椎动物头部中的主要感觉神经组，并介导触觉、温度和疼痛感觉。它是由迁移到一个共同的集合点的神经嵴和基板前体形成的。这两个亚群分离到神经节的不同区域，并分化成刺激特异性神经元亚型。三叉神经感觉神经节的畸形或损伤与神经痛有关，神经痛是一种复发性面部疼痛状况。尽管它的重要作用，很少有人知道如何三叉神经感觉神经节的发展。该建议的重点是三叉神经感觉神经元被招募到神经节组装位点的机制，以及两个前体群体如何分类到神经节的两个不同的域。以斑马鱼为模型，我们将结合胚胎学和遗传学操作的荧光标记神经元前体的体内成像来分析神经元的组装和分离。在具体目标1中，我们将确定趋化因子信号传导如何引导神经元到组装位点。我们将测试的假设，趋化因子信号是内在的长距离，但成为限制到一个短距离信号的环境。在具体目标2中，我们将确定细胞粘附如何介导神经元分选到神经节的不同区域。我们发现细胞粘附受体的表达将神经节分为不同的区域。我们将测试神经元根据其粘附特性分类到神经节不同区域的假设。最后，我们将询问趋化因子引导和细胞粘附如何合作来组织组装神经节。通过这些研究，我们希望不仅能深入了解神经元是如何组织成簇的，而且还能揭示三叉神经病变的潜在机制，这些机制可能会导致困扰人类的疼痛疾病。

The long-range goal of the proposed studies is to determine the cellular, genetic and molecular interactions that underlie trigeminal sensory ganglion development. The trigeminal sensory ganglion is the primary group of sensory nerves in the vertebrate head and mediates touch, temperature and pain sensations. It is formed from neural crest and placodal precursors that migrate to a shared assembly site. These two subpopulations segregate to different regions of the ganglion and differentiate into stimulus-specific neuronal subtypes. Malformations or injuries of the trigeminal sensory ganglion are associated with neuralgia, a recurrent facial pain condition. Despite its important role, very little is known about how the trigeminal sensory ganglion develops. This proposal focuses on the mechanisms by which trigeminal sensory neurons are recruited to the ganglion assembly site and how the two precursor populations sort to two distinct domains of the ganglion. Using zebrafish as a model, we will analyze neuron assembly and segregation by combining in vivo imaging of fluorescently labeled neuronal precursors with embryological and genetic manipulations. In Specific Aim 1, we will determine how chemokine signaling guides neurons to the assembly site. We will test the hypotheses that chemokine signaling is intrinsically long-range but becomes restricted to a short-range signal by the environment. In Specific Aim 2, we will determine how cell adhesion mediates sorting of neurons into different regions of the ganglion. We find that cell adhesion receptor expression divides the ganglion into different regions. We will test the hypothesis that neurons sort to different regions of the ganglion based on their adhesive properties. Lastly, we will ask how chemokine guidance and cell adhesion cooperate to organize the assembling ganglion. With these studies, we hope not only to provide insights into how neurons are organized into clusters, but also shed light onto the mechanisms underlying trigeminal neuropathies that can contribute to painful disease conditions afflicting humans.