Neural circuit formation is a critical step of brain development, and disruption of neural circuit formation causes many birth conditions. The formation of a functional circuit requires the intricate orchestration of multiple steps, including fate determination, migration, axon/dendrite differentiation, axon growth, and synapse formation and elimination. However it is still unclear how individual neurons are assembled into the functional circuits during development. Here, we propose to use the development of a defined neuronal circuit in Caenorhabditis elegans-the RME circuit- to study molecular mechanisms of neural circuit formation. RME circuit development utilizes all the critical steps of mammalian cortex development and involves neuron- neuron, neuron-glia, and neuron-muscle interactions. This system has enabled us to analyze neural circuit formation from the birth of neurons to the maturation of functional circuits. In this proposal we focus on address two important questions: how do glial cells instruct neuronal polarity through gap junctions, and what is the local regulatory mechanism of the cell death pathway in synapse elimination. In our preliminary studies we uncovered a previous unknown function of glial cells during neuronal development in which glial cells form gap junctions with nearby neurons to regulate microtubule polarity and neuronal polarity. We propose studies of the molecular mechanism underlying this observation. The final step of the circuit formation is refinement of synaptic connections through synapse elimination. We found that local activation of the cell death pathway is required for synapse elimination, and this local activation needs the presence of mitochondria. In this application we outline a strategy to address the long time questions in the field: how the apoptotic pathway is locally activated without causing cell death, and what are the downstream targets of caspases in neuronal development. Completion of this proposal will lead to the discovery of novel mechanisms of neural circuit formation, establish the development of RME circuit as a powerful model to study neural circuit formation, and generate new tools for further studies. Given that many neural disorders are associated with defects in neural circuit formation, it is hopeful that this project will help to understand brain development under both physiological and pathological conditions.

Public Health Relevance

Neural circuit formation is a critical step of brain development, and disruption of neural circuit formation causes many birth conditions, including autism, Down syndrome, Prader-Willi syndrome, and fragile X syndrome. In this proposal, we take advantage of the model organism Caenorhabditis elegans to investigate novel mechanisms of neural circuit formation. Completion of our studies will likely provide new drug targets for potential clinical studies of neurodevelopmental and neurodegenerative disorders.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Neurodifferentiation, Plasticity, and Regeneration Study Section (NDPR)
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Riddle, Robert D
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Duke University
Schools of Medicine
United States
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E, Lezi; Zhou, Ting; Koh, Sehwon et al. (2018) An Antimicrobial Peptide and Its Neuronal Receptor Regulate Dendrite Degeneration in Aging and Infection. Neuron 97:125-138.e5
Meng, Lingfeng; Zhang, Albert; Jin, Yishi et al. (2016) Regulation of neuronal axon specification by glia-neuron gap junctions in C. elegans. Elife 5:
Meng, Lingfeng; Chen, Chia-hui; Yan, Dong (2016) Regulation of Gap Junction Dynamics by UNC-44/ankyrin and UNC-33/CRMP through VAB-8 in C. elegans Neurons. PLoS Genet 12:e1005948
Meng, Lingfeng; Mulcahy, Ben; Cook, Steven J et al. (2015) The Cell Death Pathway Regulates Synapse Elimination through Cleavage of Gelsolin in Caenorhabditis elegans Neurons. Cell Rep 11:1737-48