Molecular genetic analysis of the nested Drosophila melanogaster lamin C gene
Molecular genetic analysis of the nested Drosophila melanogaster lamin C gene
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DOI：
10.1534/genetics.105.043208
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发表时间：
2005-09-01
期刊：
影响因子：
3.3
通讯作者：
Wallrath, LL
中科院分区：
文献类型：
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作者：
Schulze, SR;Curio-Penny, B;Wallrath, LL
核纤层蛋白是排列在核膜内表面的中间纤维，提供结构支持并与染色质接触。存在两种类型的核纤层蛋白，A型和B型，其在结构和表达上不同。果蝇具有两种核纤层蛋白类型，由LamC（A型）和核纤层蛋白Dm（O）（B型）基因编码。LamC嵌套在必需基因ttv的内含子内。我们证明了LamC中的无效突变是致命的，并且野生型LamC转基因的表达挽救了LamC的致死性，但不是TTV突变体。人类A型核纤层蛋白基因的突变会导致核纤层蛋白病。为了确定果蝇是否可以作为一个有用的模型来研究核纤层蛋白生物学和疾病机制，我们产生了转基因果蝇表达突变体LamC蛋白模仿人类致病核纤层蛋白。这些转基因动物显示出与在哺乳动物细胞中表达人突变A型核纤层蛋白时观察到的核纤层蛋白聚集表型非常相似的核纤层蛋白聚集表型。LamC聚集体还引起核纤层蛋白Dm（O）的解体，表明两种核纤层蛋白类型对于适当的核纤层组装的相互依赖性。总之，这些数据提供了LamC基因的第一个详细的遗传分析，并支持使用果蝇作为模型来研究核纤层蛋白在疾病中的作用。
Lamins are intermediate filaments that line the inner surface of the nuclear envelope, providing structural support and making contacts with chromatin. There are two types of lamins, A- and B-types, which differ in structure and expression. Drosophila possesses both lamin types, encoded by the LamC (A-type) and lamin Dm(O) (B-type) genes. LamC is nested within an intron of the essential gene ttv. We demonstrate that null mutations in LamC are lethal, and expression of a wild-type LamC transgene rescues lethality of LamC but not ttv mutants. Mutations in the human A-type lamin gene lead to diseases called laminopathics. To determine if Drosophila might serve as a useful model to study lamin biology and disease mechanisms, we generated transgenic flies expressing mutant LamC proteins modeled after human disease-causing lamins. These transgenic animals display a nuclear lamin aggregation phenotype remarkably similar to that observed when human mutant A-type lamins are expressed in mammalian cells. LamC aggregates also cause disorganization of lamin Dm(O), indicating interdependence of both lamin types for proper lamina assembly. Taken together, these data provide the first detailed genetic analysis of the LamC gene and support using Drosophila as a model to study the role of lamins in disease.