This week we profile a recent publication in eLIFE from Dr. Kota Mizumoto (far left) at the University of British Columbia.
Can you provide a brief overview of your lab’s current research focus?
Our lab is interested in understanding the genetic and molecular basis of how our nervous system develops. Specifically, we try to understand how neurons communicate with each other during the process of neuronal development at the level of single neuron or synapse, which is a specialized interface that neurons use to send/receive information. As the nervous system in mammals is too complicated (humans have billions of neurons), we use roundworms (Caenorhabditis elegans) as a model organism to tackle this question. C. elegans has a simple nervous system consisting of only 302 neurons, and various genetic tools allow us to examine how each neuron interacts with it neighboring neurons/cells to establish stereotyped neurocircuits during development. Most importantly, genes/molecules that regulate the development and function of the nervous system are highly conserved between C. elegans and humans. It is therefore likely that knowledge obtained from C. elegans is directly relevant to human.
What is the significance of the findings in this publication?
Previously we reported that a well-known axon guidance cue, Semaphorin, and its receptor, Plexin, mediate inter-cellular communication between two neighboring neurons to control spatial distribution patterns of their synapses. While the roles of Semaphorins and Plexins in synapse pattern formation have been reported by several groups including us, little is known about how they regulate synapse patterns: in other words, what kind of proteins does Plexin control? Here, using a combination of C. elegans genetics and state-of-the-art microscopy (Fluorescent Lifetime Imaging Microscopy: FLIM), we show that Plexin controls synapse patterning by locally down-regulating the activity of a small GTPase, Rap2, in the axon. Furthermore, we found that a Rap2-binding kinase, TNIK, also acts downstream of Plexin in synapse patterning. Interestingly, TNIK seems to play a critical role in negatively regulating the synapse number in C. elegans: Knocking down the activity of the TNIK gene caused a significant increase in synapse number while its hyperactivation by over-expression resulted in severe reduction in synapse number, which caused locomotion defects of the worms. Importantly, mutations in Plexin, Rap2 and TNIK are known to be associated with several psychiatric conditions including schizophrenia and autism spectrum disorders. Our findings will help other researchers test if mutations in these genes cause similar synaptic defects in other model organisms with more complex nervous system, such as mice.
What are the next steps for this research?
One big question that remains to be answered is how TNIK regulates synapse patterning and synapse number. As TNIK is a protein kinase which phosphorylates other proteins, we believe that upon activation by Plexin and Rap2, TNIK phosphorylates a series of proteins that regulate synapse formation. We examined a known substrate of TNIK, JNK (c-Jun N-terminal kinase), but we did not find its role in synapse number or patterning. It is therefore likely that TNIK regulates synapse formation via phosphorylation of proteins that have not been shown to be TNIK substrates in previous work. We have set up the genetic system to look for these TNIK substrates in C. elegans, to further understand the roles of TNIK gene in neurodevelopment. We hope our work will lead to findings that ultimately lead to therapeutics for neurological conditions caused by mutations in the Plexin signaling pathway.
This research was funded by:
The major funding source of this study is the Human Frontier Science Program (HFSP) and CIHR.
