This week we profile a recent publication in eLife from the laboratory of Dr. Michel Leroux (pictured, left) at SFU.
Can you provide a brief overview of your lab’s current research focus?
The Leroux laboratory, situated in the Molecular Biology and Biochemistry Department at Simon Fraser University, is interested in understanding how the cilium, an evolutionary ancient antenna-like cellular compartment, is built, functions, and contributes to human health. Most human cells have cilia, and nearly 200 human genes are currently known to be associated with a wide variety of genetically-inherited ciliary disorders collectively termed ‘ciliopathies.’ The clinical ailments of ciliopathies include, but are not limited to, blindness, polycystic kidney disease, heart and other skeletal anomalies, brain malformations, and obesity. A central goal of our research is to uncover the molecular parts list and functions of two complex, multi-protein systems that operate within cilia. The first is intraflagellar transport (IFT), which uses the molecular motors kinesin and dynein to mobilise ciliary cargo into and out of the compartment. One important cargo molecule is tubulin, which forms part of the microtubule-based axoneme or ‘traintracks’ of the cilium. The second system is the transition zone (TZ), which works as a molecular barrier or ‘gate’ at the base of cilia. The IFT and TZ system work together to ensure that the dynamic protein composition is established and maintained.
What is the significance of the findings in this publication?
In this eLIFE publication, Catrina Loucks and Kwangjin Park from my laboratory, together with collaborators from the University of British Columbia, Ireland and the UK, identified roles for a protein called EFHC1 at both the cilium and the neuronal synapse, which is involved in relaying information to other cells. There are two major types of cilia. One is motile and for example helps to propel sperm and clear respiratory airways. The other is non-motile, and acts like a cellular antenna, capturing and propagating extracellular information; for example, rods and cone cilia in the eye detect light and allow vision, and olfactory cilia have receptors that enable the sensation of smell. EFHC1 was previously associated with the motility of cilia, but not sensory or signalling functions. The protein is of particular significance because its mutations in humans result in juvenile myoclonic epilepsy (JME). Using the nematode Caenorhabditis elegans as a model system, we found that EFHC1 operates specifically in ciliated cells and regulates dopamine signalling. Accordingly, we discovered that disruption of EFHC1 leads to defects in dopamine-mediated behavioural phenotypes. This discovery confirmed that this protein plays a role in neurons and cellular signalling. Interestingly, EFHC1 functions both within non-motile cilia, and at the synapse to regulate the release of dopamine at synapses. Such a dual role for a ciliary protein is novel and appear to hint at the molecular coordination of sensory input (cilia) and output (synapse).
What are the next steps for this research?
Most neuronal cells in vertebrates have non-motile, or sensory, cilia. However, exactly what their functions are remains virtually unknown. Our work suggests that neuronal cilia may function together with the synapse to regulate neuronal transmission of information. One hypothesis is that together, the cilium and synapse can be modulated to regulate the threshold of activation of neurons, and thus influence how sensory inputs can affect neuronal outputs, or behaviour. Clarifying the function of EFHC1, or other proteins within the cilium, could help the research field better understand the overall functions of cilia and neurons. For example, how cilia regulate satiety and leads to obesity when disrupted is an important unanswered question. In the case of EFHC1, its ability to regulate neuronal activation and dopamine signalling is relevant to not only how neurons function but also how defects can lead to a specific disease, namely epilepsy. More work from our lab, and other groups, will be required to understand how ciliary signalling influences neuronal thresholds and functions.
This work was funded by:
This research was funded by the Canadian Institutes of Health Research (CIHR), and the lead author acknowledges a senior scholar award from the Michael Smith Foundation for Health Research (MSFHR).
