Department of Materials Science and Engineering, Northwestern University, Evanston, IL 60208, USA.
Proc Natl Acad Sci U S A. 2013 Feb 26;110(9):3248-53. doi: 10.1073/pnas.1300215110. Epub 2013 Feb 11.
Much of the structural stability of the nucleus comes from meshworks of intermediate filament proteins known as lamins forming the inner layer of the nuclear envelope called the nuclear lamina. These lamin meshworks additionally play a role in gene expression. Abnormalities in nuclear shape are associated with a variety of pathologies, including some forms of cancer and Hutchinson-Gilford Progeria Syndrome, and often include protruding structures termed nuclear blebs. These nuclear blebs are thought to be related to pathological gene expression; however, little is known about how and why blebs form. We have developed a minimal continuum elastic model of a lamin meshwork that we use to investigate which aspects of the meshwork could be responsible for bleb formation. Mammalian lamin meshworks consist of two types of lamin proteins, A type and B type, and it has been reported that nuclear blebs are enriched in A-type lamins. Our model treats each lamin type separately and thus, can assign them different properties. Nuclear blebs have been reported to be located in regions where the fibers in the lamin meshwork have a greater separation, and we find that this greater separation of fibers is an essential characteristic for generating nuclear blebs. The model produces structures with comparable morphologies and distributions of lamin types as real pathological nuclei. Thus, preventing this opening of the meshwork could be a route to prevent bleb formation, which could be used as a potential therapy for the pathologies associated with nuclear blebs.
细胞核的大部分结构稳定性来自于中间丝蛋白的网格结构，这些中间丝蛋白被称为核纤层蛋白，形成核膜的内层，称为核纤层。这些核纤层网格结构还在基因表达中发挥作用。核形状的异常与各种病理有关，包括某些形式的癌症和 Hutchinson-Gilford 早老综合征，并且通常包括突起结构，称为核泡。这些核泡被认为与病理性基因表达有关；然而，对于泡的形成方式和原因知之甚少。我们开发了一个简化的连续弹性模型，用于研究核纤层网格的哪些方面可能导致泡的形成。哺乳动物核纤层网格由两种类型的核纤层蛋白 A 型和 B 型组成，据报道，核泡富含 A 型核纤层蛋白。我们的模型分别处理每种核纤层蛋白类型，因此可以为它们分配不同的属性。据报道，核泡位于核纤层网格中纤维分离度较大的区域，我们发现纤维的这种较大分离度是产生核泡的一个重要特征。该模型生成的结构具有与真实病理性核类似的形态和核纤层蛋白分布。因此，防止这种网格结构的打开可能是防止泡形成的一种途径，这可能被用作与核泡相关的病理的潜在治疗方法。
