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  • The Adaptation of the Cell Cycle in Multiciliated Cells

    Researchers at UCSF Discover Novel Function of Cell Cycle in Cilia Formation
    The process of cell division is fundamental in transforming a fertilized egg into a complex organism and in the pathological proliferation of cancer cells. This tightly regulated process, known as the cell cycle, has long been a cornerstone of biological understanding. However, recent findings from scientists at UC San Francisco (UCSF) have revealed a surprising adaptation of the cell cycle in the formation of cilia, hair-like projections essential for various physiological functions.

    A New Role for the Cell Cycle
    Traditionally, the cell cycle is known for its role in cell division, but UCSF researchers have discovered its involvement in the development of multiciliated cells. These cells, which possess numerous cilia, are vital for human health. In the lungs, cilia prevent mucus accumulation; in the reproductive system, they facilitate the movement of eggs through the fallopian tubes; and in the brain, they help remove cerebrospinal fluid. Malfunctions in these cells can lead to serious diseases.

    “The cell cycle has been studied intensively for decades and here, we’ve found it working in a new way. This old dog – the cell cycle – is capable of more tricks than we realized,” explained Jeremy Reiter, Ph.D., UCSF professor of biophysics and biochemistry, and leader of the study. “This old dog—the cell cycle—is capable of more tricks than we realized.”

    Investigating Multiciliated Cells
    The research team employed single-cell RNA sequencing to analyze the gene expression patterns in individual multiciliated cells in the lungs at various maturation stages. This technique allowed them to capture the genetic instructions necessary for cilia formation and revealed a pattern resembling the cell cycle.

    Previous research indicated that a few cell cycle proteins, such as cyclins, were active during cilia growth, along with centrioles, which anchor chromosomes during cell division. However, Reiter’s team discovered that many cell cycle genes, beyond just cyclins, were highly expressed in lung cells even though these cells were not dividing.

    “In developing multiciliated cells, we saw the same sequential expression of cell cycle regulators, like cyclins and CDKs, that we’d expect to see in stem cells,” said Semil Choksi, Ph.D., a researcher in the Reiter lab and first author of the paper.

    The Multiciliation Cycle
    This finding indicated a departure from the typical cell cycle. The researchers dubbed this alternative process the “multiciliation cycle,” which produces an unusually high number of centrioles, far exceeding the four centrioles typically generated during cell division.

    “If you have something go wrong in the cell cycle, and you make too many centrioles, it can lead to cancer,” Choksi explained. “Somehow, this strict cancer-preventing rule, no more than four centrioles per cell, is very specifically broken in multiciliated cells to make hundreds of centrioles.”

    The Role of E2F7
    Further investigation revealed that the multiciliation cycle in lung cells differed from the classic cell cycle in stem cells on a genetic level. The gene E2F7 emerged as a critical player. Its expression was moderate in stem cells but significantly elevated in maturing multiciliated cells. When E2F7 was knocked out in an animal model, multiciliated cells failed to develop correctly, resulting in brain abnormalities.

    “We thought one of the knobs that evolution might have turned was by upregulating E2F7, to change the canonical cell cycle into the multiciliation cycle,” said Reiter.
    The absence of E2F7 caused multiciliated cells to initiate DNA synthesis, a characteristic of cell division, and the centrioles meant for cilia construction became stuck in the cell body.

    Conclusion
    The discovery by UCSF researchers underscores the versatility of the cell cycle, demonstrating its adaptation beyond traditional cell division roles. As Reiter noted, “Evolution clearly has adapted the cell cycle to carry out a variety of cellular projects well beyond cell division. It’ll be exciting to see what else it’s capable of.”

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