Nuclear Envelope in Development and Disease

脊椎动物核层是一种与内膜核面相关的蛋白质网。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。层的主要成分是中间的丝状蛋白，即核层蛋白，层蛋白分为a型和b型两类。b型层蛋白由2个基因编码并组成表达，而a型层蛋白是由单个基因（Lmna）拼接而成的变体，其表达受发育调控。为了确定A型层粘连蛋白在胚胎发生中的功能，我们获得了A型层粘连蛋白表达缺失的小鼠。纯合子到断奶时发育正常。但8周后全部死亡。

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.