Rikkyo University

A cell’s nucleus stores genetic information in the form of DNA and plays an important role in protecting this information and ensuring it is expressed accurately. The nuclear lamina is a uniform mesh structure inside the nuclear envelope. However, the basic question of whether the uniformity of this mesh structure is essential to the functioning of the nucleus has long been unknown. In this study, the research group answered this basic question, revealing that the uniformity of the nuclear lamina provides support for the proper higher-order structure of chromosomes, gene expression, and the physical strength of the nucleus.

These findings are expected to contribute to our understanding of disease. That is, while it is known that laminopathy, a disease caused by mutation of the nuclear lamina, causes muscular dystrophy-like symptoms in humans, muscle tearing was also observed in Drosophila with abnormalities in the uniformity of the nuclear lamina, which led to muscular dystrophy-like symptoms. These findings will be of great help in trying to understand the causes of laminopathy that leads to muscular dystrophy. The study was published online in the American Journal of Cell Biology on January 23, 2024.

Cell nuclei store genetic information as DNA and play an important role in protecting this information and ensuring its accurate expression. Closely examining a cell nucleus shows that the outermost layer is surrounded by a double lipid membrane that forms the nuclear envelope. Inside this envelope is a mesh-like structure called the nuclear lamina (Figure 1A). Yet it has remained unclear whether the uniformity of the nuclear lamina is important.

In their paper, the research group reported that the loss of the PIGB protein located in the nuclear envelope resulted in the loss of uniformity in the nuclear lamina, which exhibited an irregular pattern as shown in Figure 1B. Moreover, we found that the locations of nuclear membrane proteins were also abnormal (Figure 2). Measurements of the physical strength of this abnormal nucleus showed a significant reduction in strength in the PIGB mutant (Figure 3). It is also known that the nuclear envelope plays an important role in forming the higher-order structures of chromosomes.

Based on these findings, the research group conducted a comprehensive examination of the higher-order structure of chromosomes in PIGB mutants compared to the wild type which showed abnormal chromosomal structures in the mutants. Because the higher-order chromosomal structure impacts gene expression, they next examined the expression of several genes in areas where PIGB mutants exhibited abnormal higher-order structures, particularly those involved in muscle development and maintenance. This analysis revealed abnormalities in the expression of several genes. When they examined the muscles of PIGB mutants, they found muscular dystrophy-like muscular abnormalities (Figure 4). As muscular dystrophy-like symptoms are observed in humans with laminopathy, which is caused by mutations in the nuclear lamina, these findings are expected to improve our understanding of this disease. Moreover, the variety of abnormalities that were observed indicates that PIGB is an important protein that supports several functions of the nucleus.

The importance of the cell nucleus, particularly the nuclear lamina structure that lines the nuclear envelope, has attracted attention from researchers around the world. However, little was known about the significance of the uniformity of the nuclear lamina. This study demonstrated for the first time the importance of this uniformity, showing that it helps maintain various functions of the nucleus. In addition, because abnormalities in this uniformity were observed alongside symptoms similar to those of laminopathy, these findings could contribute to our understanding of the pathogenesis of such disorders. Going forward, the research group plans to investigate other factors, such as the control of PIGB over the functions of the nucleus in humans and other mammals to determine whether abnormalities in these factors are involved in the development of laminopathy.