Mechanism of Xenopus Cranial Neural Crest Cell Migration

正确的颅神经脊细胞迁移对于面部、颌骨和颌骨的构建至关重要。 外周神经系统连接。尽管这很重要，但人们对神经脊细胞是如何 移民是受监管的。非洲爪哇胚胎发育过程中ADAM13蛋白的表达 含有去整合素和金属蛋白酶)与脑神经脊细胞的迁移有关 从神经板的外侧缘到腹前站，在那里它们最终形成面部 结构(Alfandari等人，1997年)。我们对表达显性基因的脑神经脊细胞的分析 ADAM13的阴性形式表明，ADAM13促进和/或引导它们在三种类型中的两种中迁移 可能的路径。我们的工作假设是，ADAM13切割了一种通常限制颅骨的蛋白质 神经脊细胞迁移。该蛋白质可以作为停止信号被插入到迁移路径中 阻止细胞通过或在颅神经脊细胞表面表达，以将细胞保持在适当的位置 抛锚。来检验这些假说，并分析是否其他ADAM和相关的金属蛋白酶也可能 为了参与脑神经脊细胞的迁移，我们提出了以下具体目标。这项建议具有 三个目的是了解1)缺失ADAM13蛋白的细胞是否可以使用其他ADAM及其相关蛋白 金属蛋白水解酶的迁移，2)如果ADAM13起到了打开迁移途径的“钻头”的作用，3)如果ADAM13 切断了将脑神经脊细胞连接到环境中的锚。使用特定的吗啉 寡核苷酸，我们可以阻止包括ADAM13在内的ADAM蛋白在胚胎中的翻译，并测试如何 脑神经脊细胞迁移。这可以与ADAM13发挥作用的细胞的迁移进行比较 被阻断(使用药物抑制剂)。使用移植物，我们将测试脑神经脊细胞是否缺失ADAM13 活动可以跟随带有ADAM13的细胞。最后，我们将测试ADAM13是否可以切割 已知可以将细胞固定在下面。拟议的研究将增加我们对事件的理解 面部的正常形态，是诊断和治疗导致 发育不正常。此外，有关亚当对细胞迁移的贡献的信息可能会导致 对这些蛋白在各种癌症和转移中的作用有了新的认识。尤其是这些 蛋白质(ADAM)可能参与细胞从原始肿瘤逃逸到新的位置。

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.