The Nuclear Envelope in Development and Disease

脊椎动物核膜是一种与内核膜核面相关的蛋白质网络。它为染色质结构域提供锚定位点，是间期核结构和DNA复制的重要决定因素。板层的主要成分是中间的丝状蛋白，核板层分为A型和B型两类。B型Lamins由2个基因编码，由2个基因组成表达，而A型lamins是单个基因(Lmna)的剪接变体，其表达受发育调节。为了确定A-型层蛋白在胚胎发育中的功能，我们获得了A-型层蛋白表达缺失的小鼠。纯合子到断奶的发育看起来是正常的。然而，到了8周时，所有的动物都灭绝了。 层粘连蛋白缺失的小鼠会出现某种形式的肌肉营养不良，白色脂肪很少或没有，心脏也不正常。最近有研究表明，在人类中，Lamin A基因的不同突变至少与三种遗传性疾病有关，即Emery-Dreifuss肌营养不良的常染色体变异、扩张型心肌病和家族性部分脂肪营养不良。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三种疾病状态。我们还在研究拉明缺乏对细胞复制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，它们可能对了解HIV感染患者是如何发生这种情况特别有用的，这些患者正在接受HIV蛋白酶抑制剂类药物的治疗。

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 currenlty analyzing our mice to determine whether they exhibit all 3 disease states. We are also looking at what effects Lamin deficiency has on a cellis 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.