THE NUCLEAR ENVELOPE IN DEVELOPMENT AND DISEASE

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，并且是间期核结构和DNA复制的重要决定因素。 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。 为了确定A型核纤层蛋白在胚胎发生中的功能，我们获得了A型核纤层蛋白表达缺失的小鼠。 纯合子到断奶的发育似乎正常。 然而，所有人都在8周内死亡。 核纤层蛋白缺失小鼠发展为一种形式的肌营养不良，具有很少或没有白色脂肪，并且具有异常的心脏。 最近已经表明，在人类中，核纤层蛋白A基因中的不同突变导致至少3种遗传形式的疾病，即埃默里-德赖富斯肌营养不良、扩张型心肌病和家族性部分脂肪营养不良的常染色体变体。 我们目前正在分析我们的小鼠，以确定它们是否表现出所有3种疾病状态。 我们也在研究核纤层蛋白缺乏对细胞复制DNA和在细胞分裂时分离染色体的能力有什么影响。 由于小鼠也可能是脂肪营养不良的，它们可能特别用于理解这种情况如何在正在用HIV蛋白酶抑制剂类药物治疗的HIV感染患者中出现。

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 and DNA replication. 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. To determine the function of the A-type lamins in embryogenesis we derived mice null for A type lamin expression. Development of the homozygotes to weaning appears normal. However all had perished by 8 weeks. The lamin null mice develop a form of muscular dystrophy, have little or no white fat and have abnormal hearts. Recently it has been shown that in humans different mutations in the Lamin A gene are responsible for at least 3 inherited forms of disease, the autosomal variant of Emery-Dreifuss muscular dystrophy, dilated cardiomyopathy and Familial Partial Lipodystrohy. We are currently analyzing our mice to determine whether they exhibit all 3 disease states. We are also looking at what effects Lamin deficiency has on a cell's ability to replicate its DNA and segregate chromosomes at cell division. As the mice may also be lipodystrophic they may be of particular use in understanding how this condition arises in HIV infected patients who are being treated with the HIV protease inhibitor class of drugs.