A key process of asymmetric cell division preserves germline immortality


Chromosome-oriented fluorescence in situ hybridization (CO-FISH) is performed on Drosophila testis to experimentally distinguish sister chromatids (red vs blue). Credit: George Watase/Whitehead Institute

During cell division, chromosomes are replicated in two copies, one for each daughter cell. These copies, called sister chromatids, are generally considered to be identical. In fact, it is the two pairs of sister chromatids that form the symmetrical X-shape usually depicted when viewing chromosomes.

A 2013 paper from the lab of Whitehead Institute fellow Yukiko Yamashita showed that in the case of asymmetric cell division, such as when a stem cell divides into two different types of daughter cells (i.e. i.e. a stem cell and a differentiating daughter) – the sister chromatids of the sex chromosomes may actually contain separate information, and the dividing cell “chooses” which of the daughters receives a specific copy.

What this “choice” means, and how it is executed, has been a mystery until now. A new paper by Yamashita, who is also a professor of biology at the Massachusetts Institute of Technology and a researcher at the Howard Hughes Medical Institute, published in Scientists progress on July 27, sheds light on the mechanisms underlying non-random segregation of sister chromatids and suggests that the whole process may serve as a means of maintaining the amount of ribosomal DNA (or rDNA) that is passed on to subsequent generations. “Linking these two processes together—maintenance of rDNA copy number and non-random chromatid segregation—is an unexpected and exciting advance in our understanding of how germ cells are able to maintain their immortality,” he said. Yamashita.

George Watase, postdoctoral researcher at Yamashita Lab, led the study. Watase began his research with the intention of uncovering the genetic basis of non-random segregation of the X and Y chromosomes in the fruit fly Drosophila melanogaster. As he scanned the genome for genes essential for non-random segregation, it became clear that ribosomal DNA was key to the process.

When the rDNA was left intact, the sister chromatid with more rDNA was preferentially chosen by the daughter stem cell instead of the differentiating daughter cell. However, when rDNA was removed from the X and Y chromosomes, Watase found that sister chromatids randomly separate from daughter cells.

Ribosomal DNA, or rDNA, is made up of a long stretch of repeats of certain base pairs. rDNA provides the instructions and materials for making ribosomes, which are essential for cells to create proteins. “Most genes only exist in one copy, but in the case of rDNA, we have hundreds of copies in our genome,” Watase said. “The reason is that we need a massive amount of ribosomes to synthesize proteins to maintain the viability of our cells.”

As organisms age, most of their cells naturally lose some of these rDNA repeats, including germline stem cells. However, germ cells are sometimes called “immortal” – while all other cells in the body are renewed with each generation and die when an organism dies, germ cells such as sperm and egg must carry DNA between cells. generations. Therefore, stem cells that produce sperm and eggs cannot continue to lose rDNA repeats and must avoid the death of other cells by maintaining a high number of rDNA repeats over time.

By isolating proteins that bind rDNA, Watase discovered a specific gene, whose protein product bound rDNA and somehow assigned the sister chromatid with more rDNA repeats to the cell. daughter who was destined to remain a germline stem cell.

This particular gene had not been previously described, and Watase and Yamashita were now tasked with naming it. Fruit fly genes are named after what happens to the animal when the gene is removed. When this new gene was knocked down, germ cells of subsequent generations gradually lost the immortality that separates germ stem cells from their differentiated counterparts.

Watase wasn’t sure how to convey the intricacies of this result. In the end, it was Watase’s wife who came up with the perfect name: Indra. In Hindu scriptures, Indra, the lord of all deities, was given a garland of fragrant flowers by a sage called Durvasa. Indra placed the garland on his elephant’s trunk, but the animal was irritated by the smell of the flowers and threw the garland by trampling on it. When Durvasa saw this, he became enraged and cursed Indra, stripping him of his immortality.

The name also opened up a world of possibilities for naming future genes that are important in non-random segregation of sister chromatids. “People sometimes take inspiration from Roman or Greek myths when naming genes, but few people use names from Hindu myths,” he said. “And since this is new biology, if we identify other related genes in the future, we may once again be able to use the names from Hindu myths.”

Watase and Yamashita’s study opens new avenues for future research. For example, the article focused primarily on male fruit flies and sperm production by asymmetric division. Indra is also expressed in the female germline, and when the gene is knocked down in females, the resulting phenotype is much more severe. “There must be a mechanism in female germ cells to avoid rDNA copy number reduction,” Watase said. “We just don’t know what that mechanism is.”

In the future, Watase and Yamashita also hope to elucidate exactly how Indra interacts with the cell division machinery to influence which chromatid ends up in the stem cell and which in the differentiation cell, and beyond this mechanism, how the cell strain “selects” the longest chromatid.

“Many biologists study germ cells, but few specifically study how they maintain their immortality,” Yamashita said. “This study is a step towards understanding this fascinating property of germ cells. It’s a really fascinating area and we really need to keep digging deeper into this phenomenon.”

Clues to aging found in stem cell genomes

More information:
George J. Watase et al, Non-random sister chromatid segregation mediates rDNA copy number maintenance in Drosophila, Scientists progress (2022). DOI: 10.1126/sciadv.abo4443

Provided by Whitehead Institute for Biomedical Research

Quote: A Key Process in Asymmetric Cell Division Preserves Germline Immortality (2022, July 28) Retrieved August 28, 2022 from https://phys.org/news/2022-07-key-asymmetric-cell-division -immortality.html

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