Mechanism of Xenopus Cranial Neural Crest Cell Migration

非洲爪蟾颅神经嵴细胞迁移机制

基本信息

批准号：
7575150
负责人：
DOMINIQUE R ALFANDARI
金额：
$ 32.8万
依托单位：
UNIVERSITY OF MASSACHUSETTS AMHERST
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-03-01 至 2011-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7575150
关键词：
Anterior Antisense Oligonucleotides Asthma Cell Adhesion Cell Death Cell Proliferation Cell surface Cells Cephalic Cleaved cell Data Development Diagnosis Disintegrins Dominant-Negative Mutation Drug usage Embryo Embryonic Development Environment Epidermis Event Extracellular Matrix Face Fibronectins Histone H3 Human Immigration In Situ Hybridization In Situ Nick-End Labeling In Vitro Injection of therapeutic agent Jaw Label Lateral Lead Light Link Measures Mesoderm Messenger RNA Metalloproteases Modeling Neoplasm Metastasis Neural Crest Neural Crest Cell Oligonucleotides Pathway interactions Peptide Hydrolases Peripheral Nervous System Phenotype Phosphorylation Positioning Attribute Proteins Relative (related person)Research Personnel Signal Transduction Site Structure Testing Tissues Translations Work Xenopus adhesion receptor base cell motility craniofacial in vitro testing in vivo inhibitor/antagonist migration neural plate novel overexpression prevent programs protein function research study tumor

项目摘要

Proper cranial neural crest (CNC) cell migration is essential for the construction of the face, jaws and their peripheral nervous system connections. Despite this importance, little is known about how neural crest cell migration is regulated. During Xenopus embryo development the expression of ADAM13 (a protein containing A Disintegrin And Metalloprotease) correlates with the migration of the cranial neural crest cells from the lateral border of the neural plate to the ventral anterior station where they eventually form facial structures (Alfandari et al.,1997). Our on-going analyses of cranial neural crest cells expressing a dominant negative form of ADAM13 suggest that ADAM13 promotes and/or directs their migration in two of the three possible pathways. Our working hypothesis is that ADAM13 cleaves a protein that normally restricts cranial neural crest cell migration. This protein may either be inserted in the migration path as a stop signal to prevent cell passage or be expressed at the cranial neural crest cell surface to hold the cells in place as an anchor. To test these hypotheses and analyze whether other ADAM and related metalloproteases may also be involved in cranial neural crest cell migration we propose the following specific Aims. This proposal has three Aims to understand 1) if cells missing ADAM13 protein can use other ADAM and related metalloprotease to migrate, 2) if ADAM13 functions as a "drill" to open migration pathways, 3) if ADAM13 cuts an anchor that attaches cranial neural crest cells to their environment. Using specific morpholino oligonucleotides, we can prevent translation of ADAM proteins including ADAM13 in embryos and test how cranial neural crest cells migrate. This can be compared to the migration of cells in which ADAM13 function is blocked (using drug inhibitor). Using grafts we will test whether cranial neural crest cells missing ADAM13 activity can follow cells that have ADAM13. Finally, we will test if ADAM13 can cleave proteins that are known to anchor cells down. The proposed studies will increase our understanding of events that govern normal formation of the face, an essential step towards diagnosing and treating conditions that lead to abnormal development. Furthermore, information about ADAM contributions to cell migration could lead to new understanding of the function of these proteins in various cancer and metastasis. In particular these protein (ADAM) are likely to be involved in the escape of cells from the original tumor to new sites.

适当的颅神经rest（CNC）细胞迁移对于脸部，下巴及其的构建至关重要周围神经系统连接。尽管很重要，但对神经rest细胞的了解知之甚少迁移受到监管。在Xenopus胚胎发育期间ADAM13的表达（蛋白质包含崩解蛋白和金属蛋白酶）与颅神经细胞的迁移相关从神经板的外侧边界到腹前站，最终在那里形成面部结构（Alfandari等，1997）。我们正在进行的对颅神经rest细胞的分析，表达了主要的 ADAM13的负面形式表明ADAM13促进和/或指导其迁移到这三个中的两个可能的途径。我们的工作假设是ADAM13裂解了通常限制颅骨的蛋白质神经rest细胞迁移。该蛋白质可以插入迁移路径中，作为停止信号防止细胞通过或在颅神经rest细胞表面表达，以将细胞固定在适当的位置锚。测试这些假设并分析其他亚当和相关的金属蛋白酶是否也可能参与颅神经rest细胞迁移，我们提出以下特定目的。该提议有三个目的是了解1）如果缺少ADAM13蛋白的细胞可以使用其他ADAM和相关的细胞金属蛋白酶迁移，2）如果ADAM13用作打开迁移途径的“钻”，3）如果ADAM13 切开将颅神经rest细胞连接到其环境的锚。使用特定的吗啡寡核苷酸，我们可以防止胚胎中包括ADAM13在内的亚当蛋白的翻译，并测试如何颅神经rest细胞迁移。可以将其与ADAM13功能的细胞迁移进行比较被阻止（使用药物抑制剂）。使用移植物我们将测试颅神经rest细胞是否缺少ADAM13 活性可以跟随具有ADAM13的细胞。最后，我们将测试ADAM13是否可以切割蛋白质已知可以将细胞锚定。拟议的研究将增加我们对管理事件的理解面部正常形成，这是诊断和治疗导致条件的重要一步异常发展。此外，有关亚当对细胞迁移贡献的信息可能会导致对这些蛋白质在各种癌症和转移中的功能的新理解。特别是这些蛋白质（亚当）可能参与细胞从原始肿瘤逃避到新部位的逃生。