Clearing the Air on Cilia Development

A*STAR researchers have uncovered the sequence of genetic events behind the development of motile cilia in airways.

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Like janitors who keep corridors and walkways clean, multiciliated cells (MCC)—cells with hair-like structures known as cilia—keep the airways of land-dwelling animals free of particulate matter and disease-causing bacteria. MCCs perform a sweeping motion to prevent unwanted material from entering the lungs, and individuals with defective MCCs are at increased risk of respiratory diseases.

In the present study, scientists led by Sudipto Roy at A*STAR’s Institute of Molecular and Cell Biology (IMCB), wanted to understand how MCCs develop. “Two regulatory proteins— GMNC and MCIDAS—have been shown to be required for MCC development in previous studies,” said Roy. “However, what remains unclear is how the proteins actually function in MCC development: do they function together at the same developmental point in the MCC differentiation pathway, or at different steps?”

To answer those questions, the researchers generated MCIDAS mutant mice and found that MCIDAS-defective MCCs produced only a single cilium, unlike normal mice whose MCC bear hundreds of cilia. In addition, they discovered that MCIDAS-defective MCCs could not form multiple basal bodies—the structures found at the base of cilia.

Because basal body formation is known to be controlled by a signaling pathway called the deuterosome-dependent (DD) pathway, Roy’s team proceeded to investigate the interaction between MCIDAS and the DD pathway. MCIDAS overexpression in cells strongly activated the expression of genes in the DD pathway to trigger basal body formation. Another regulatory protein involved in cilia formation, GMNC, similarly activated the DD pathway, albeit to a weaker extent.

The researchers further showed that although GMNC was able to induce MCIDAS expression, the reverse was not true. This suggests that GMNC acts at an earlier developmental step to MCIDAS.

“Our results show that there is a genetic hierarchy in that GMNC functions upstream of MCIDAS. Therefore, they are deployed in a stepwise manner for regulating the gene expression programme during MCC differentiation,” said Roy. His team is currently studying MCIDAS mutant cells to assess which pathways are dysregulated in the absence of MCIDAS function.

“Both GMNC and MCIDAS have the ability to programme MCC development, which makes them good candidates for devising therapeutic strategies that restore damaged ciliary epithelia in severe lung disease,” Roy concluded.

The A*STAR-affiliated researchers contributing to this research are from the Institute of Molecular and Cell Biology (IMCB).