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钙黏蛋白-2 控制小脑颗粒神经元的定向链迁移。

Cadherin-2 controls directional chain migration of cerebellar granule neurons.

机构信息

Institute of Developmental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich-Neuherberg, Germany.

出版信息

PLoS Biol. 2009 Nov;7(11):e1000240. doi: 10.1371/journal.pbio.1000240. Epub 2009 Nov 10.

DOI:10.1371/journal.pbio.1000240
PMID:19901980
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC2766073/
Abstract

Long distance migration of differentiating granule cells from the cerebellar upper rhombic lip has been reported in many vertebrates. However, the knowledge about the subcellular dynamics and molecular mechanisms regulating directional neuronal migration in vivo is just beginning to emerge. Here we show by time-lapse imaging in live zebrafish (Danio rerio) embryos that cerebellar granule cells migrate in chain-like structures in a homotypic glia-independent manner. Temporal rescue of zebrafish Cadherin-2 mutants reveals a direct role for this adhesion molecule in mediating chain formation and coherent migratory behavior of granule cells. In addition, Cadherin-2 maintains the orientation of cell polarization in direction of migration, whereas in Cadherin-2 mutant granule cells the site of leading edge formation and centrosome positioning is randomized. Thus, the lack of adhesion leads to impaired directional migration with a mispositioning of Cadherin-2 deficient granule cells as a consequence. Furthermore, these cells fail to differentiate properly into mature granule neurons. In vivo imaging of Cadherin-2 localization revealed the dynamics of this adhesion molecule during cell locomotion. Cadherin-2 concentrates transiently at the front of granule cells during the initiation of individual migratory steps by intramembraneous transport. The presence of Cadherin-2 in the leading edge corresponds to the observed centrosome orientation in direction of migration. Our results indicate that Cadherin-2 plays a key role during zebrafish granule cell migration by continuously coordinating cell-cell contacts and cell polarity through the remodeling of adherens junctions. As Cadherin-containing adherens junctions have been shown to be connected via microtubule fibers with the centrosome, our results offer an explanation for the mechanism of leading edge and centrosome positioning during nucleokinetic migration of many vertebrate neuronal populations.

摘要

已在许多脊椎动物中报道了来自小脑上菱形唇的分化颗粒细胞的长距离迁移。然而，关于调节体内定向神经元迁移的亚细胞动力学和分子机制的知识才刚刚开始出现。在这里，我们通过活体斑马鱼（Danio rerio）胚胎的延时成像显示，小脑颗粒细胞以同源胶质细胞独立的方式以链状结构迁移。斑马鱼 Cadherin-2 突变体的时间挽救揭示了该粘附分子在介导链形成和颗粒细胞的相干迁移行为中的直接作用。此外，Cadherin-2 维持细胞极化在迁移方向上的取向，而在 Cadherin-2 突变体颗粒细胞中，前缘形成和中心体定位的位点是随机化的。因此，缺乏粘附导致定向迁移受损，并且 Cadherin-2 缺乏的颗粒细胞位置不当。此外，这些细胞不能正常分化为成熟的颗粒神经元。Cadherin-2 定位的体内成像揭示了该粘附分子在细胞运动过程中的动力学。Cadherin-2 通过膜内运输在单个迁移步骤的起始时在颗粒细胞的前缘短暂集中。Cadherin-2 在前缘的存在与观察到的中心体在迁移方向上的取向相对应。我们的结果表明，Cadherin-2 在斑马鱼颗粒细胞迁移中发挥关键作用，通过不断协调细胞-细胞接触和细胞极性，通过粘着连接的重塑。由于含有 Cadherin 的粘着连接已被证明通过微管纤维与中心体相连，因此我们的结果为许多脊椎动物神经元群体的核动力学迁移过程中前缘和中心体定位的机制提供了解释。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0e88/2766073/0db0a31c8ec1/pbio.1000240.g012.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0e88/2766073/13b5c55fc02b/pbio.1000240.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0e88/2766073/720fc37d1d61/pbio.1000240.g003.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0e88/2766073/696058551760/pbio.1000240.g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0e88/2766073/b1a6a73e7fc8/pbio.1000240.g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0e88/2766073/ca3a8ee60c81/pbio.1000240.g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0e88/2766073/4287deba315a/pbio.1000240.g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0e88/2766073/8d0963eb8d1a/pbio.1000240.g010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0e88/2766073/a0945f1bf2ef/pbio.1000240.g011.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0e88/2766073/0db0a31c8ec1/pbio.1000240.g012.jpg

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