The Nuclear Envelope in Development, Disease and Ageing

脊椎动物核纤层是与内核膜（INM）的核面相关的蛋白质网络。它为染色质结构域提供锚定位点，并且是间期核结构、DNA复制和染色质组织的重要决定因素。核纤层的主要成分是核纤层蛋白，核纤层蛋白分为A型和B型两类。B型核纤层蛋白由2个基因编码并组成型表达，而A型核纤层蛋白是来自单个基因（Lmna）的剪接变体，并且它们的表达受发育调节。它们在早期胚胎或成体干细胞中不表达，并且它们的表达与各种谱系的终末分化相关。我们衍生出不表达A型核纤层蛋白的小鼠。核纤层蛋白缺失小鼠的发育明显正常，但到4-5周时，它们发展为严重的肌肉营养不良，心脏异常，并在8周时死亡。在人类中，核纤层蛋白A基因的不同突变导致至少8种遗传性疾病。这些包括2种形式的肌肉萎缩症、扩张型心肌病、2种类型的家族性部分脂肪营养不良（其中一种还影响骨骼发育）、周围神经病以及最近的称为吉尔福德早衰症的哈钦森早衰症。我们已经获得了Lmna基因突变的小鼠，这些突变对应于大多数这些疾病。我们已经产生了发展为肌营养不良症、扩张型心肌病和早衰表型的小鼠品系。患有早衰症的小鼠为衰老的基本方面以及细胞核的结构如何发育调节细胞增殖提供了新的见解。对核纤层蛋白病的分析为了解核结构对其功能的重要性提供了新的见解。这是特别相关的，因为除了与核纤层蛋白相关的疾病（核纤层蛋白病）之外，至少有2种其他疾病与核膜相关蛋白的突变有关。此外，最近对核膜组分的蛋白质组学分析表明，另外14种疾病也可能与核膜蛋白的改变有关。除了这些疾病，我们还在研究核纤层蛋白缺乏对细胞复制其DNA、染色体分离/定位和染色质组织/基因调控的能力有什么影响，以及核纤层蛋白缺失是否会影响肿瘤的发展。

The vertebrate nuclear lamina is a protein meshwork associated with the nuclear face of the inner nuclear membrane (INM). It provides anchoring sites for chromatin domains, and is an important determinant of interphase nuclear architecture, DNA replication and chromatin organization. The major components of the lamina are the intermediate filament-like proteins, the nuclear lamins, The lamins are grouped into 2 classes, A-type and B-type. The B-type lamins are encoded by 2 genes and are constitutively expressed whereas the A-type lamins are spliced variants from a single gene (Lmna) and their expression is developmentally regulated. They are not expressed in early embryos or adult stem cell and their expression correlates with the terminal differentiation of various lineages. We derived mice that did not express the A-type lamins. Development of the Lamin null mice was overtly normal, but by 4-5 weeks they developed a severe form of muscular dystrophy, had abnormal hearts and were dead by 8 weeks. In humans different mutations in the Lamin A gene are responsible for at least 8 inherited diseases. These include 2 forms of muscular dystrophy, dilated cardiomyopathy, 2 types of Familial Partial Lipodystrohy, one of which also affects skeletal development, a peripheral neuropathy and most recently, the premature ageing condition called Hutchinson Gilford Progeria. We have derived mice with mutations in the Lmna gene that correspond to most of these diseases. We have produced mouse lines that develop muscular dystrophy, dilated cardiomyopathy, and a progeric phenotype. The mice with progeria are providing novel insights into fundamental aspects of aging and how the structure of the nucleus developmentally regulates cell proliferation. The analysis of the laminopathies is providing novel insights into how the structure of the nucleus is important to its function. This is particularly relevant, as in addition to the diseases associated with the lamins (the laminopathies), at least 2 other disease have been linked to mutations in proteins associated with the nuclear envelope. Furthermore, a recent proteomics analysis of the components of the nuclear envelope suggested that an additional 14 diseases might also be linked to altered nuclear envelope proteins. In addition to these diseases we are also looking at what effects Lamin deficiency has on a cells ability to replicate its DNA, chromosome segregation/location and chromatin organization/gene regulation and whether lamin loss may affect tumor development.