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Cilia growth regulator essential for lung development

Researchers at MRC Harwell have shown stumpy cilia in mice lacking a functional Atmin gene prevent proper lung development. This could have important implications for human ciliopathies.

Nodal cilia from wild type mice (left), compared to Atmin and Dynll1 mutants (middle and right). Shortened, stumpy cilia can be seen in the Atmin mutant, while Dynll1 cilia bulge at their base.

Ciliopathies are diseases that all share a common cause - defective cilia. Research led by Dominic Norris, published in Development, into the underlying genetics of mouse lines with short cilia and underdeveloped lungs has helped explain the essential role of the Atmin gene in lung development.

What are cilia?

Cilia are small hair-like protrusions that extend from the surface of cells, and are known to play diverse roles in the body, from being required for certain kinds of cell-to-cell signalling to acting as flow sensors. Some cilia are motile, such as those lining the wind pipe, which beat so as to clear mucus from the lungs. With these varied roles, it is perhaps unsurprising that the symptoms of ciliopathies can vary considerably. However, they often include developmental abnormalities.

Cilia consist of a central microtubule scaffold surrounded by the cell membrane. In order for cilia to grow, proteins must be carried to the tip, where they are added onto the cilium. Molecular motors ‘walk’ up and down the cilium to transport these proteins as cargo - kinesin transports cargo up to the tip (‘anterograde’ transport), whereas cytoplasmic-dynein-2 transports cargo down to the base (‘retrograde’ transport).

Atmin’s role in cilia

Atmin encodes a protein that regulates the transcription of the Dynll1 gene. This study revealed that DYNLL1 protein is an important component of cytoplasmic-dynein-2.  

Both Atmin and Dynll1 mutant cells had fewer and shorter cilia than normal, and any present appeared stunted. Yet when functional DYNLL1 protein was added to Atmin mutant cells, the cilia were ‘rescued’. They deduced from this that Atmin acts via Dynll1 to regulate cilia growth.

To explain how the stunted cilia in these mutant mice lead to abnormal lung development, the researchers considered their role in signalling. Normal development and patterning of the embryo requires various signalling pathways. One of these, the ‘hedgehog’ signalling pathway, is known to require fully developed cilia. This pathway and was found to be working less efficiently in their lungs, and deficient signalling due to stunted cilia almost certainly interfered with normal lung development in these embryos.

Baffling bulges   

Some questions still remain. Particularly puzzling was the bulges they observed at the bottom of the Dynll1 mutant cilia – if retrograde transport is disrupted, you would expect everything to get stuck at the tip of the cilia, and therefore would expect to see a bulge at the top. They suggest that this might be due to another motor protein component taking up the slack, or possibly that the only aspect disrupted is the release from the base of the cilium. Whatever the cause, it merits further investigation.

This discovery has begun to unravel the vital role of cilia in mammalian development and disease. As similar defects in retrograde transport are known to occur in the human skeletal ciliopathies, it potentially provides an important step in understanding these complex diseases. 

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