Throughout a lifetime of an organism synapse addition and elimination is on-going to ensure proper function of neuronal circuits. Growing evidence have revealed complex interactions involving intrinsic and extrinsic factors in synapse refinement with temporal and neuronal-type specificity. Studies using C. elegans have continued to expand the understanding of molecular and genetic pathways with single- synapse resolution. The locomotor circuit consists of several classes of excitatory cholinergic motor neurons and two classes of GABAergic motor neurons, and is a highly tractable system to discover mechanisms underlying synapse formation and refinement. Each neuron forms stereotyped pattern and number of synapses, providing an accurate readout to examine how synapses are dynamically regulated. Moreover, the development of the mature locomotor circuit involves a precisely timed remodeling of the embryonically born GABAergic neurons, known as ?DD synapse remodeling?, in the absence of axonal morphological changes. We developed the first in vivo visualization approach to examine DD synapse remodeling. In our recent studies, we have defined critical roles of microtubule dynamics in promoting cargo and motor interaction in the formation of new synapses in DD remodeling. Our findings underscore the concept that microtubules are not passive tracks but play an active role in cellular signaling. In the specific Aim 1 of this renewal application we will leverage our expertise in genetic pathway dissection with in vivo imaging of microtubule components to dissect the roles of a novel kinase in DD synapse remodeling. In parallel, we have investigated the mechanisms regulating the cholinergic neuron synapses, and have uncovered roles of inter-tissue interaction mediated by a IgSF transmembrane domain protein ZIG-10. Our studies show that ZIG-10 regulates phagocytotic pathway via a SRC kinase in the adjacent non-neuronal tissues.
In specific Aim 2, we will tackle the cellular action and the physiological impact of this pathway using innovative technologies. We will further examine how neuronal activity regulates this pathway.
In Aim 3, we will investigate the role of a conserved MAGUK protein that may link the ZIG-10 pathway to phospholipid biosynthesis in synapse maintenance. Genetic mutations of homologous molecules in human have been linked to various neurological diseases. Together our findings will provide important insights to the underlying signaling network and advance our knowledge in the understanding of human diseases.

Public Health Relevance

Neurons maintain their ability to adapt to internal needs and external stimuli throughout the lifetime of an organism. Refinement of synaptic connections has broad roles to ensure operation of neuronal circuits. This application examines the molecular genetic mechanisms that regulate the number and function of synapses in a simple nervous system. The findings will advance our knowledge of how normal synaptic connection is maintained and shed light to how dys- regulation of synapses may contribute to neurological disorders.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Method to Extend Research in Time (MERIT) Award (R37)
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Synapses, Cytoskeleton and Trafficking Study Section (SYN)
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Talley, Edmund M
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University of California, San Diego
Schools of Arts and Sciences
La Jolla
United States
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Jin, Yishi; Qi, Yingchuan B (2018) Building stereotypic connectivity: mechanistic insights into structural plasticity from C. elegans. Curr Opin Neurobiol 48:97-105
Tang, Ngang Heok; Jin, Yishi (2018) Shaping neurodevelopment: distinct contributions of cytoskeletal proteins. Curr Opin Neurobiol 51:111-118
Gao, Shangbang; Guan, Sihui Asuka; Fouad, Anthony D et al. (2018) Excitatory motor neurons are local oscillators for backward locomotion. Elife 7:
Zhou, Keming; Cherra 3rd, Salvatore J; Goncharov, Alexandr et al. (2017) Asynchronous Cholinergic Drive Correlates with Excitation-Inhibition Imbalance via a Neuronal Ca2+ Sensor Protein. Cell Rep 19:1117-1129
Kurup, Naina; Yan, Dong; Kono, Karina et al. (2017) Differential regulation of polarized synaptic vesicle trafficking and synapse stability in neural circuit rewiring in Caenorhabditis elegans. PLoS Genet 13:e1006844
Noma, Kentaro; Goncharov, Alexandr; Ellisman, Mark H et al. (2017) Microtubule-dependent ribosome localization in C. elegans neurons. Elife 6:
Sharifnia, Panid; Kim, Kyung Won; Wu, Zilu et al. (2017) Distinct cis elements in the 3' UTR of the C. elegans cebp-1 mRNA mediate its regulation in neuronal development. Dev Biol 429:240-248
McCulloch, Katherine A; Qi, Yingchuan B; Takayanagi-Kiya, Seika et al. (2017) Novel Mutations in Synaptic Transmission Genes Suppress Neuronal Hyperexcitation in Caenorhabditis elegans. G3 (Bethesda) 7:2055-2063
Cherra 3rd, Salvatore J; Jin, Yishi (2016) A Two-Immunoglobulin-Domain Transmembrane Protein Mediates an Epidermal-Neuronal Interaction to Maintain Synapse Density. Neuron 89:325-36
Cherra 3rd, Salvatore J; Jin, Yishi (2015) Advances in synapse formation: forging connections in the worm. Wiley Interdiscip Rev Dev Biol 4:85-97

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