Molecular Regulation of Trigeminal Sensory Ganglia Development

这项拟议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的主要感觉神经，负责调节触觉、温度和痛觉。它是由迁移到共享组装部位的神经脊和胎盘前体形成的。这两个亚群分离到神经节的不同区域，并分化为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。尽管三叉神经感觉神经节起着重要的作用，但人们对其如何发育知之甚少。这项建议集中在三叉神经感觉神经元被招募到神经节组装部位的机制，以及两个前体群体如何分类到神经节的两个不同的区域。以斑马鱼为模型，我们将结合体内荧光标记的神经元前体成像与胚胎学和遗传学操作来分析神经元的组装和分离。在特定的目标1中，我们将确定趋化因子信号如何引导神经元到达组装位置。我们将测试以下假设：趋化因子信号本质上是长距离的，但由于环境的影响，它变成了短程信号。在具体目标2中，我们将确定细胞黏附如何调节神经节不同区域的神经元分类。我们发现，细胞黏附受体的表达将神经节划分为不同的区域。我们将检验这一假设，即神经元根据其黏附特性分类到神经节的不同区域。最后，我们将探讨趋化因子引导和细胞黏附如何协同作用来组织组装神经节。通过这些研究，我们希望不仅能提供对神经元如何组织成簇的见解，还能阐明三叉神经病的潜在机制，这些疾病可能导致痛苦的疾病折磨人类。

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.