Molecular Biology Institute, Department of Medicine, and Department of Human Genetics, University of California, Los Angeles, CA 90095, USA.
Proc Natl Acad Sci U S A. 2013 May 21;110(21):E1923-32. doi: 10.1073/pnas.1303916110. Epub 2013 May 6.
The role of protein farnesylation in lamin A biogenesis and the pathogenesis of progeria has been studied in considerable detail, but the importance of farnesylation for the B-type lamins, lamin B1 and lamin B2, has received little attention. Lamins B1 and B2 are expressed in nearly every cell type from the earliest stages of development, and they have been implicated in a variety of functions within the cell nucleus. To assess the importance of protein farnesylation for B-type lamins, we created knock-in mice expressing nonfarnesylated versions of lamin B1 and lamin B2. Mice expressing nonfarnesylated lamin B2 developed normally and were free of disease. In contrast, mice expressing nonfarnesylated lamin B1 died soon after birth, with severe neurodevelopmental defects and striking nuclear abnormalities in neurons. The nuclear lamina in migrating neurons was pulled away from the chromatin so that the chromatin was left "naked" (free from the nuclear lamina). Thus, farnesylation of lamin B1--but not lamin B2--is crucial for brain development and for retaining chromatin within the bounds of the nuclear lamina during neuronal migration.
蛋白质法尼基化在核纤层蛋白 A 生物发生和早老症发病机制中的作用已得到深入研究，但法尼基化对于 B 型核纤层蛋白 lamin B1 和 lamin B2 的重要性却很少受到关注。lamin B1 和 lamin B2 从发育的最早阶段就在几乎所有细胞类型中表达，并且它们已经涉及细胞核内的各种功能。为了评估蛋白质法尼基化对于 B 型核纤层蛋白的重要性，我们创建了表达非法尼基化 lamin B1 和 lamin B2 的基因敲入小鼠。表达非法尼基化 lamin B2 的小鼠正常发育且没有疾病。相比之下，表达非法尼基化 lamin B1 的小鼠在出生后不久就死亡，具有严重的神经发育缺陷和神经元中明显的核异常。迁移神经元中的核纤层被从染色质上拉开，使得染色质“裸露”（脱离核纤层）。因此，lamin B1 的法尼基化——而不是 lamin B2 的法尼基化——对于大脑发育以及在神经元迁移过程中使染色质保持在核纤层的范围内是至关重要的。
