Kota Mizumoto

Associate Professor

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Theses completed in 2010 or later are listed below. Please note that there is a 6-12 month delay to add the latest theses.

Role of Wnt signaling in asymmetrical neurite pruning in Caenorhabditis elegans (2020)

Developmental neurite pruning is a phenomenon widely observed in different organisms including humans. Through this process, neurons selectively remove exuberant neurites by pruning to form a proper neurocircuit. Some neurites are pruned base on the competition of neuronal input, while others undergo stereotyped pruning which is controlled by morphogenic cues.We found that in Caenorhabditis elegans, a cholinergic motor neuron, PDB, undergoes stereotyped neurite pruning. During PDB development, we observed two posterior branches that are stereotypically pruned. Time-lapse imaging showed that these posterior branches are retracted while the anterior branch is extending. We also found a posteriorly expressed Wnt, LIN-44, and its receptor LIN-17/Frizzled (Fz) are responsible for the pruning of the posterior neurites. In lin-44 and lin-17 mutant animals, the posterior neurites often failed to be pruned. Furthermore, we discovered that the activation of LIN-44/Wnt is gradient independent, and membrane-tethered lin-44 is sufficient to induce asymmetrical posterior neurite pruning. LIN-17 and its downstream DSH-1/Dishevelled (Dsh/Dvl) proteins are recruited to the posterior neurites while either wildtype or membrane-tethered lin-44 is expressed. Our results showed a novel contact-dependent role of Wnt in asymmetric neurite pruning.

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Understanding the role of neuronal cell fate determinants in synapse pattern formation in C. elegans (2020)

Animal locomotion and behaviour are ultimately controlled by the precise neuronal circuit formation at the level of synaptic connection. Mutations in the genes that specify individual neuronal cell fate (or cell fate determinants) alter synaptic connections and circuit wiring which results in the malfunction of the nervous system. It is however not fully understood if the defects in these mutants are merely due to a consequence of cell fate transformation, or the cell fate determinants have specific functions in synapse pattern formation. Here we identify a novel role for a homeobox transcription factor UNC-4 and its co-repressor UNC-37/Groucho, in tiled synapse pattern formation of the cholinergic motor neurons (DA8 and DA9) in Caenorhabditis elegans. In unc-4 and unc-37 mutant animals, we observed large overlap between the synaptic domains of DA8 and DA9. Strikingly, we show using temperature-sensitive mutants and auxin-inducible degron system that unc-4 is not required during embryonic development when DA neurons cell fate is set but is required post-embryonically. In contrast, unc-37 is required embryonically and post-embryonically in DA neurons for a tiled synaptic innervation. Our result reveals a novel post-cell fate determination role of homeobox gene in neuronal pattern formation.

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Mechanism of Semaphorin-Plexin signaling in synaptic pattern formation in Caenorhabditis elegans (2017)

Fine motor coordination depends on the precise synaptic connection between individual motor neurons and muscles. Recent studies have revealed the roles of extracellular signals such as Wnt, Netrin, and Semaphorin in synapse specificity. Little is known about their intracellular mechanisms in synapse patterning.In C. elegans, DA class motor neurons form en passant synapses along their axon on the dorsal nerve cord. Each DA neuron innervates a unique and tiled segment of muscle field by restricting its synapse to a distinct subaxonal domain - a phenomenon we term synaptic tiling. SEMAs/Semaphorins and their receptor PLX-1/Plexin were previously shown to be critical for the tiled synaptic innervation pattern between two neighboring neurons DA8 and DA9. Recently, structural and biochemical studies have predicted that mammalian Plexin acts as a GTPase activating protein (GAP) for Rap small GTPases.In this study, among three rap genes in the C. elegans genome, rap-2 is found to be required for synaptic tiling and functions through cycling between GTP- and GDP-bound forms. The genetic study has illustrated that rap-2 acts downstream of plx-1 to regulate synaptic tiling, supporting that PLX-1 acts as a RapGAP to regulate the spatial activity of RAP-2. MIG-15 is identified as an effector of RAP-2 in synaptic tiling. mig-15 mutants display severe synaptic tiling defects due to the increased synapse number of DA8 and DA9.iiiMIG-15 overexpression experiments demonstrated that MIG-15 controls both the length of synaptic domain and the number of synapses, while Plexin and RAP-2 define the length of the synaptic domain. PLX-1 overexpression experiments indicated that PLX-1 specifies synapse distribution via RAP-2 small GTPase and MIG-15 kinase. Overall, this study identified two novel components of Plexin signaling in the spatial regulation of synaptic pattern formation.

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