Dysfunctional Connections Between the Nucleus and the Actin and Microtubule Networks in Laminopathic Models
Dysfunctional Connections Between the Nucleus and the Actin and Microtubule Networks in Laminopathic Models
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DOI：
10.1529/biophysj.108.139428
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发表时间：
2008-12-01
影响因子：
3.4
通讯作者：
Wirtz, Denis
中科院分区：
文献类型：
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作者：
Hale, Christopher M.;Shrestha, Arun L.;Wirtz, Denis
核纤层蛋白病涵盖了一系列与LMNA基因上分散的突变相关的人类疾病，LMNA是一个编码A型核纤层蛋白的单基因。这种基因改变如何转化为细胞缺陷并产生如此多样的疾病表型仍然是个谜。近期的研究已经确定了核膜蛋白——伊默菌素以及核骨架与细胞骨架连接蛋白（LINC）复合物，它们将核纤层与细胞骨架连接起来。在此，我们定量检测了来自两种核纤层蛋白病小鼠模型（包括哈钦森 - 吉尔福德早衰综合征（Lmna(L530P/L530P)）和埃默里 - 德赖富斯肌营养不良症（Lmna(-/-)））的细胞的核膜组成，以及细胞骨架的结构和功能。还包括了来自X连锁埃默里 - 德赖富斯肌营养不良症的明显无表型模型（Emd(-/y)）的细胞。我们发现中心体从细胞核脱离，阻止了流动条件下细胞中的中心体极化，这些缺陷是由核膜上伊默菌素的缺失所介导的。此外，虽然基础肌动蛋白和粘着斑结构受到轻度影响，但RhoA激活、细胞 - 基质粘附以及细胞质弹性大幅降低，且仅在LINC复合物被破坏的核纤层蛋白病模型中出现。这些结果表明伊默菌素在细胞极化中有新的功能，并提示核纤层蛋白病与细胞极化能力的丧失并无直接关联，而是与细胞质软化以及由核膜上LINC复合物的破坏所介导的粘附减弱有关。
Laminopathies encompass a wide array of human diseases associated to scattered mutations along LMNA, a single gene encoding A-type lamins. How such genetic alterations translate to cellular defects and generate such diverse disease phenotypes remains enigmatic. Recent work has identified nuclear envelope proteins-emerin and the linker of the nucleoskeleton and cytoskeleton (LINC) complex-which connect the nuclear lamina to the cytoskeleton. Here we quantitatively examine the composition of the nuclear envelope, as well as the architecture and functions of the cytoskeleton in cells derived from two laminopathic mouse models, including Hutchinson-Gilford progeria syndrome (Lmna(L530P/L530P)) and Emery-Dreifuss muscular dystrophy (Lmna(-/-)). Cells derived from the overtly aphenotypical model of X-linked Emery-Dreifuss muscular dystrophy (Emd(-/y)) were also included. We find that the centrosome is detached from the nucleus, preventing centrosome polarization in cells under flow-defects that are mediated by the loss of emerin from the nuclear envelope. Moreover, while basal actin and focal adhesion structure are mildly affected, RhoA activation, cell-substratum adhesion, and cytoplasmic elasticity are greatly lowered, exclusively in laminopathic models in which the LINC complex is disrupted. These results indicate a new function for emerin in cell polarization and suggest that laminopathies are not directly associated with cells' inability to polarize, but rather with cytoplasmic softening and weakened adhesion mediated by the disruption of the LINC complex across the nuclear envelope.