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Morphogenesis and function of somatosensory axon ensheathment by epidermal cells

表皮细胞体感轴突鞘的形态发生和功能

基本信息

批准号：
10683163
负责人：
Alvaro Sagasti
金额：
$ 36.71万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-05-15 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10683163
关键词：
Adherens Junction Adult Affect Animals Axon Basal Cell Behavioral Assay CRISPR screen CRISPR/Cas technology Caenorhabditis elegans Cell membrane Cell physiology Cells Chemicals Cholesterol Complement Dendrites Desmosomes Development Disease Drosophila genus Epidermis Epithelial Cells Epithelium Event F-Actin Fishes Functional disorder Grant Human Image Individual Integral Membrane Protein Larva Lipids Mammals Mechanics Mediating Membrane Methods Microscopy Modeling Molecular Morphogenesis Mutagenesis Neck Nervous System Physiology Neurites Neuroglia Neurons Neurophysiology - biologic function Nociception Nociceptors Pain Periderm Peripheral Play Process Proliferating Property Proteins Reporter Role Schwann Cells Sensory Signal Transduction Site Skin Stimulus Structure Study models Subcellular structure Supporting Cell System Testing Touch sensation Transgenic Organisms Vertebrates Work Zebrafish cell type epidermis cell experimental study fly innovation keratinocyte knock-down neural circuit neuron development optogenetics pain sensation plakoglobin protein distribution receptor recruit repaired response seal sensor somatosensory superresolution imaging temporal measurement tool transcriptome virtual

项目摘要

PROJECT SUMMARY Selective interactions between neurons and non-neuronal cells are crucial for the development and function of neural circuits. Pain-sensing somatosensory neurons project peripheral axons to the skin, where they branch extensively amongst epithelial epidermal cells. Although these sensory terminals are called “free endings”, recent studies have revealed that they are often wrapped by epidermal cells, which enclose them into ensheathment channels reminiscent of those formed by non-myelinating Remak Schwann cells. Although underappreciated, epidermal ensheathment channels have been observed in worms, flies, fish, and mammals, indicating that ensheathment is a conserved feature of epidermal sensory endings, and thus likely plays critical roles in the development and function of nociceptive axons. Little is known about the morphogenetic process of axon ensheathment by epidermal cells, and nothing is known about how these structures contribute to sensory function or disease in vertebrate animals. This proposal investigates the morphogenetic mechanisms that create epidermal ensheathment channels and how they contribute to sensory function in zebrafish larvae. Their external development and the availability of unique transgenic tools make zebrafish an ideal model for studying this dynamic morphogenetic process. Preliminary work using live fluorescent reporters for subcellular structures in zebrafish skin cells identified a sequence of events leading up to ensheathment and suggested a step-wise morphogenetic process. First, axons growing into this epidermis induce the formation of specialized lipid microdomains at skin cell-axon contact sites. Second, F-actin is recruited to these microdomains, likely promoting membrane invagination to initiate the ensheathment process. Finally, adherens junctions and desmosomes form at “necks” of ensheathment channels to tightly seal the channels. The first two aims of this proposal use innovative microscopy approaches for high spatial and temporal resolution live imaging, cell-specific molecular manipulations, and CRISPR/Cas9-mediated mutagenesis to determine how axons and skin cells establish selective interactions and execute the ensheathment process. These studies will illuminate morphogenetic mechanisms relevant not just to axon ensheathment by epidermal and glial cells, but also to basic cellular processes, like the formation of membrane signaling domains and junction assembly. The third aim combines imaging and behavioral assays to reveal how axon ensheathment impacts neuronal structure and function. These studies have the potential to uncover a critical feature of the touch-sensing apparatus and suggest how ensheathment contributes to disease conditions affecting pain and touch sensation.

项目总结神经元和非神经元细胞之间的选择性相互作用对神经细胞的发育和功能至关重要神经回路。痛感躯体感觉神经元将外周轴突投射到皮肤，在那里它们会分支广泛分布在上皮性表皮细胞中。尽管这些感官终末被称为“自由末梢”，最近的研究表明，它们经常被表皮细胞包裹，表皮细胞将它们包裹在包膜通道类似于无髓鞘的Remak Schwann细胞形成的通道。虽然被忽视的是，在蠕虫、苍蝇、鱼和哺乳动物中观察到了表皮包膜通道，表明包膜是表皮感觉末梢的一种保守特征，因此可能起关键作用。在伤害性轴突发育和功能中的作用。人们对它的形态发生过程知之甚少轴突被表皮细胞包裹，这些结构如何对感觉起作用尚不清楚脊椎动物的功能或疾病。该方案研究了形成表皮被膜通道的形态发生机制和它们如何对斑马鱼幼体的感觉功能做出贡献。它们的外部发展和可获得性独特的转基因工具使斑马鱼成为研究这种动态形态发生过程的理想模型。使用实时荧光记者对斑马鱼皮肤细胞亚细胞结构的初步研究发现导致包膜的一系列事件，并暗示了一个逐步的形态形成过程。第一, 长入该表皮的轴突诱导皮肤细胞轴突形成特化的脂质微域联系地点。第二，F-肌动蛋白被招募到这些微区，可能促进膜内陷到启动包扎过程。最后，粘连连接和桥粒形成在细胞的“颈部” 包裹通道，以将通道紧密密封。这项提案的前两个目标是使用创新用于高空间和时间分辨率实时成像的显微镜方法，细胞特异性分子操纵和CRISPR/Cas9介导的突变以确定轴突和皮肤细胞如何建立选择性相互作用，并执行包膜过程。这些研究将阐明形态发生学机制不仅与表皮细胞和神经胶质细胞的轴突包裹有关，而且与基础细胞有关。过程，如膜信号域的形成和连接组装。第三个目标结合了成像和行为分析，以揭示轴突包膜如何影响神经元结构和功能。这些研究有可能揭示触觉设备的一个关键特征，并建议如何包膜有助于影响疼痛和触觉的疾病状况。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Zebrafish expression reporters and mutants reveal that the IgSF cell adhesion molecule Dscamb is required for feeding and survival.

DOI：
10.1080/01677063.2018.1493479
发表时间：
2018-12
期刊：
Journal of neurogenetics
影响因子：
1.9
作者：
Julien DP;Chan AW;Barrios J;Mathiaparanam J;Douglass A;Wolman MA;Sagasti A
通讯作者：
Sagasti A

Sensory axons induce epithelial lipid microdomain remodeling and determine the distribution of junctions in the epidermis.

DOI：
10.1091/mbc.e22-09-0396
发表时间：
2023-01-01
期刊：
MOLECULAR BIOLOGY OF THE CELL
影响因子：
3.3
作者：
Rosa, Jeffrey B.;Nassman, Khaled Y.;Sagasti, Alvaro
通讯作者：
Sagasti, Alvaro

Fish Scales Dictate the Pattern of Adult Skin Innervation and Vascularization.

DOI：
10.1016/j.devcel.2018.06.019
发表时间：
2018-08-06
期刊：
Developmental cell
影响因子：
11.8
作者：
Rasmussen JP;Vo NT;Sagasti A
通讯作者：
Sagasti A

Vertebrate epidermal cells are broad-specificity phagocytes that clear sensory axon debris.

脊椎动物表皮细胞是清除感觉轴突碎片的广泛特异性吞噬细胞。

DOI：
10.1523/jneurosci.3613-14.2015
发表时间：
2015
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
0
作者：
Rasmussen,JeffreyP;Sack,GeorgeannS;Martin,SeannaM;Sagasti,Alvaro
通讯作者：
Sagasti,Alvaro

Live Imaging of Axonal Dynamics After Laser Axotomy of Peripheral Neurons in Zebrafish.

斑马鱼周围神经元激光轴突切除术后轴突动力学的实时成像。