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The Caenorhabditis elegans gene unc-76 and its human homologs define a new gene family involved in axonal outgrowth and fasciculation.

ABSTRACT: The gene unc-76 (unc, uncoordinated) is necessary for normal axonal bundling and elongation within axon bundles in the nematode Caenorhabditis elegans. The UNC-76 protein and two human homologs identified as expressed sequence tags are not similar to previously characterized proteins and thus represent a new protein family. At least one of these human homologs can function in C. elegans, suggesting that it, like UNC-76, acts in axonal outgrowth. We propose that the UNC-76 protein, which is found in cell bodies and processes of all neurons throughout development, either has a structural role in the formation and maintenance of axonal bundles or transduces signals to the intracellular machinery that regulates axonal extension and adhesion.

SUBMITTER: Bloom L

PROVIDER: S-EPMC20384 | biostudies-literature | 1997 Apr

REPOSITORIES: biostudies-literature

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The Caenorhabditis elegans gene unc-76 and its human homologs define a new gene family involved in axonal outgrowth and fasciculation.

Bloom L L Horvitz H R HR

Proceedings of the National Academy of Sciences of the United States of America 19970401 7

The gene unc-76 (unc, uncoordinated) is necessary for normal axonal bundling and elongation within axon bundles in the nematode Caenorhabditis elegans. The UNC-76 protein and two human homologs identified as expressed sequence tags are not similar to previously characterized proteins and thus represent a new protein family. At least one of these human homologs can function in C. elegans, suggesting that it, like UNC-76, acts in axonal outgrowth. We propose that the UNC-76 protein, which is found ...[more]

PMID: 9096408

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Project description:Munc18-1/UNC-18 is believed to prime SNARE-mediated membrane fusion, yet the underlying mechanisms remain enigmatic. Here, we examine how potential gain-of-function mutations of Munc18-1/UNC-18 affect locomotory behavior and synaptic transmission, and how Munc18-1-mediated priming is related to Munc13-1/UNC-13 and Tomosyn/TOM-1, positive and negative SNARE regulators, respectively. We show that a Munc18-1(P335A)/UNC-18(P334A) mutation leads to significantly increased locomotory activity and acetylcholine release in Caenorhabditis elegans, as well as enhanced synaptic neurotransmission in cultured mammalian neurons. Importantly, similar to tom-1 null mutants, unc-18(P334A) mutants partially bypass the requirement of UNC-13. Moreover, unc-18(P334A) and tom-1 null mutations confer a strong synergy in suppressing the phenotypes of unc-13 mutants. Through biochemical experiments, we demonstrate that Munc18-1(P335A) exhibits enhanced activity in SNARE complex formation as well as in binding to the preformed SNARE complex, and partially bypasses the Munc13-1 requirement in liposome fusion assays. Our results indicate that Munc18-1/UNC-18 primes vesicle fusion downstream of Munc13-1/UNC-13 by templating SNARE complex assembly and acts antagonistically with Tomosyn/TOM-1.SIGNIFICANCE STATEMENT At presynaptic sites, SNARE-mediated membrane fusion is tightly regulated by several key proteins including Munc18/UNC-18, Munc13/UNC-13, and Tomosyn/TOM-1. However, how these proteins interact with each other to achieve the precise regulation of neurotransmitter release remains largely unclear. Using Caenorhabditis elegans as an in vivo model, we found that a gain-of-function mutant of UNC-18 increases locomotory activity and synaptic acetylcholine release, that it partially bypasses the requirement of UNC-13 for release, and that this bypass is synergistically augmented by the lack of TOM-1. We also elucidated the biochemical basis for the gain-of-function caused by this mutation. Thus, our study provides novel mechanistic insights into how Munc18/UNC-18 primes synaptic vesicle release and how this protein interacts functionally with Munc13/UNC-13 and Tomosyn/TOM-1.

Dataset Information

The Caenorhabditis elegans gene unc-76 and its human homologs define a new gene family involved in axonal outgrowth and fasciculation.

Publications

The Caenorhabditis elegans gene unc-76 and its human homologs define a new gene family involved in axonal outgrowth and fasciculation.

Similar Datasets

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