Researchers in University College Dublin (UCD) led by Conway Fellow, Dr Oliver Blacque have revealed new information about a gene implicated in Joubert syndrome and related cerebellar disorders (JSRDs) that are characterised by blindness, bone abnormalities, cystic kidneys, developmental delay and loss of muscle tone and control. The findings from this research, which is funded by Science Foundation Ireland, have been published today in a leading science journal, Journal of Cell Biology.
One of seven genes associated with JSRDs, Arl13b codes for a protein already known to play roles in the formation and/or function of cilia, which are hair-like projections extending from the surface of the cell. However, the precise molecular details of what exactly Arl13b is doing in cilia have remained unclear.
To address this question, the UCD team asked what this gene is doing in the cilia of tiny worms (Caenorhabditis elegans), and collaborated with scientists in the University of Tokyo who conducted parallel experiments in cultured human cells.
Together, they confirmed that Arl13b proteins uses lipid anchors to associate with the ciliary membrane. The UCD scientists then went on to demonstrate in C. elegans how disrupting the function of this protein can cause the ciliary membrane to bulge and become misshapen as well as affecting the ability of other proteins to properly distribute within the ciliary membrane.
They also found that a fully functional Arl13b protein is needed for the normal functioning of a protein transport system in cilia. This intraflagellar transport system makes contact with the ciliary membrane. These results have led the team to propose a new working model for Arl13b, where it functions at the ciliary membrane to regulate important ciliary membrane properties such as shape, transmembrane protein distributions and IFT.
Up to only 20 years ago, many believed most cilia to be redundant cellular organelles that have fallen victim to mammalian evolution - a type of cellular appendix. However, scientists now know that these cellular antennae serve fundamental roles in many motility and sensory functions, including signalling pathways critical to development.
Together with the fact that cilia are present on nearly all of our cells, it is now not surprising that defects in cilium structure and function are associated with an ever expanding range of human diseases and syndromes, collectively called ciliopathies, that have overlapping clinical features such as polycystic kidneys and livers, retinal degeneration, bone abnormalities, hydrocephalus, as well as complex traits including obesity, diabetes, mental retardation and even cancer.
Dr Oliver Blacque hopes that the findings published today on the mechanism of action of Arl13b will ultimately lead to a greater understanding not only of JSRDs, but also of closely related ciliopathies such as Meckel Gruber and Bardet-Biedl syndrome, as well as perhaps more common phenotypes associated with cilium dysfunction such as mental retardation and obesity.
Commenting on this research, Dr Blacque said, "That Arl13b associates with ciliary membranes and is required for cilium structure/function in both worms and mammals demonstrates the remarkable evolutionary conservation of how this small G-protein functions. For patients with Joubert syndrome, these findings provide a greater understanding of the pathomechanisms of the disease and refine our working hypothesises, thereby instructing future research into JSRDs and possibly other ciliopathies."