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[PMID]: | 28859089 |
[Au] Autor: | Gujar MR; Stricker AM; Lundquist EA |
[Ad] Endereço: | Department of Molecular Biosciences, Program in Molecular, Cellular, and Developmental Biology, The University of Kansas, Lawrence, KS, United States of America. |
[Ti] Título: | Flavin monooxygenases regulate Caenorhabditis elegans axon guidance and growth cone protrusion with UNC-6/Netrin signaling and Rac GTPases. |
[So] Source: | PLoS Genet;13(8):e1006998, 2017 Aug. | [Is] ISSN: | 1553-7404 |
[Cp] País de publicação: | United States |
[La] Idioma: | eng |
[Ab] Resumo: | The guidance cue UNC-6/Netrin regulates both attractive and repulsive axon guidance. Our previous work showed that in C. elegans, the attractive UNC-6/Netrin receptor UNC-40/DCC stimulates growth cone protrusion, and that the repulsive receptor, an UNC-5:UNC-40 heterodimer, inhibits growth cone protrusion. We have also shown that inhibition of growth cone protrusion downstream of the UNC-5:UNC-40 repulsive receptor involves Rac GTPases, the Rac GTP exchange factor UNC-73/Trio, and the cytoskeletal regulator UNC-33/CRMP, which mediates Semaphorin-induced growth cone collapse in other systems. The multidomain flavoprotein monooxygenase (FMO) MICAL (Molecule Interacting with CasL) also mediates growth cone collapse in response to Semaphorin by directly oxidizing F-actin, resulting in depolymerization. The C. elegans genome does not encode a multidomain MICAL-like molecule, but does encode five flavin monooxygenases (FMO-1, -2, -3, -4, and 5) and another molecule, EHBP-1, similar to the non-FMO portion of MICAL. Here we show that FMO-1, FMO-4, FMO-5, and EHBP-1 may play a role in UNC-6/Netrin directed repulsive guidance mediated through UNC-40 and UNC-5 receptors. Mutations in fmo-1, fmo-4, fmo-5, and ehbp-1 showed VD/DD axon guidance and branching defects, and variably enhanced unc-40 and unc-5 VD/DD axon guidance defects. Developing growth cones in vivo of fmo-1, fmo-4, fmo-5, and ehbp-1 mutants displayed excessive filopodial protrusion, and transgenic expression of FMO-5 inhibited growth cone protrusion. Mutations suppressed growth cone inhibition caused by activated UNC-40 and UNC-5 signaling, and activated Rac GTPase CED-10 and MIG-2, suggesting that these molecules are required downstream of UNC-6/Netrin receptors and Rac GTPases. From these studies we conclude that FMO-1, FMO-4, FMO-5, and EHBP-1 represent new players downstream of UNC-6/Netrin receptors and Rac GTPases that inhibit growth cone filopodial protrusion in repulsive axon guidance. |
[Mh] Termos MeSH primário: |
Orientação de Axônios/genética Proteínas de Caenorhabditis elegans/genética Caenorhabditis elegans/genética Oxigenases de Função Mista/genética Proteínas do Tecido Nervoso/genética
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[Mh] Termos MeSH secundário: |
Animais Animais Geneticamente Modificados Caenorhabditis elegans/crescimento & desenvolvimento Dinitrocresóis/metabolismo Mutação Netrinas Pseudópodes/genética Pseudópodes/metabolismo Transdução de Sinais Proteínas rac de Ligação ao GTP/genética
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[Pt] Tipo de publicação: | JOURNAL ARTICLE |
[Nm] Nome de substância:
| 0 (Caenorhabditis elegans Proteins); 0 (Dinitrocresols); 0 (Nerve Tissue Proteins); 0 (Netrins); 0 (UNC-6 protein, C elegans); 1604ZJR09T (4,6-dinitro-o-cresol); EC 1.- (Mixed Function Oxygenases); EC 3.6.5.2 (rac GTP-Binding Proteins) |
[Em] Mês de entrada: | 1710 |
[Cu] Atualização por classe: | 171116 |
[Lr] Data última revisão:
| 171116 |
[Sb] Subgrupo de revista: | IM |
[Da] Data de entrada para processamento: | 170901 |
[St] Status: | MEDLINE |
[do] DOI: | 10.1371/journal.pgen.1006998 |
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