These findings, published in Science Advances, help us understand the mechanisms that cause cilia to disassemble. This important process takes place right before cells divide. David Breslow, an associate professor of molecular, cellular and developmental biology at Yale who led the research. It emphasizes the critical importance of the F2R gene in a normal essential cellular process.
Under these conditions cilia disassemble, and when scientists overexpress the F2R gene it actively induces cilia to disassemble. Cilia are microtubule-based, hair-like appendages that protrude from the cell membrane. This natural phenomenon is critical for accurate cell division. When F2R is activated, it transduces its signal via G proteins, resulting in a dramatic loss of cilia.
Using CRISPR activation screens, Breslow and his research team were able to identify F2R. They found a second gene, SARM1, that activates cilia disassembly when overexpressed. These results imply that both genes are important players in elucidating how cilia dismantle before cells enter division.
To investigate potential inhibitors of F2R, the researchers looked at vorapaxar and DSRM-3716. As shown in , vorapaxar at 6 μM concentration suppressed F2R signaling almost as well as the reference F2R antagonist, BMS-200261. In the same vein, DSRM-3716 acts as an inhibitor at a 30 μM concentration. These inhibitors will likely be of great use as probes in future studies designed to manipulate cilia dynamics for different cellular contexts.
NIH-3T3 cells were used in the study as a model system to determine the effects of F2R overexpression on ciliary structure. This cell line is extensively characterized for cellular mechanism studies. It is a great candidate to assess the consequences of gene manipulation on cilia dynamics.
These new discoveries about the F2R pathway truly open a thrilling window into understanding how cilia disassemble. This landmark discovery extends our knowledge beyond how cells prepare for division. This understanding paves the way for a plethora of studies into other connected cellular behaviors. It paves the way to exciting new therapeutic targets for diseases caused by cilia dysfunction.