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Extracellular phosphorylation drives the formation of neuronal circuitry.
Harada, Hidekiyo; Farhani, Nahal; Wang, Xue-Fan; Sugita, Shuzo; Charish, Jason; Attisano, Liliana; Moran, Michael; Cloutier, Jean-Francois; Reber, Michael; Bremner, Rod; Monnier, Philippe P.
Afiliación
  • Harada H; Krembil Research Institute, Vision Division, Krembil Discovery Tower, Toronto, Ontario, Canada.
  • Farhani N; Krembil Research Institute, Vision Division, Krembil Discovery Tower, Toronto, Ontario, Canada.
  • Wang XF; Krembil Research Institute, Vision Division, Krembil Discovery Tower, Toronto, Ontario, Canada.
  • Sugita S; Krembil Research Institute, Vision Division, Krembil Discovery Tower, Toronto, Ontario, Canada.
  • Charish J; Krembil Research Institute, Vision Division, Krembil Discovery Tower, Toronto, Ontario, Canada.
  • Attisano L; Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
  • Moran M; Department of Biochemistry, Donnelly Center, University of Toronto, Toronto, Ontario, Canada.
  • Cloutier JF; Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
  • Reber M; Montreal Neurological Institute, Montral, Quebec, Canada.
  • Bremner R; Krembil Research Institute, Vision Division, Krembil Discovery Tower, Toronto, Ontario, Canada.
  • Monnier PP; Department of Ophthalmology and Vision Sciences, Faculty of Medicine, University of Toronto, Ontario, Toronto, Canada.
Nat Chem Biol ; 15(11): 1035-1042, 2019 11.
Article en En | MEDLINE | ID: mdl-31451763
Until recently, the existence of extracellular kinase activity was questioned. Many proteins of the central nervous system are targeted, but it remains unknown whether, or how, extracellular phosphorylation influences brain development. Here we show that the tyrosine kinase vertebrate lonesome kinase (VLK), which is secreted by projecting retinal ganglion cells, phosphorylates the extracellular protein repulsive guidance molecule b (RGMb) in a dorsal-ventral descending gradient. Silencing of VLK or RGMb causes aberrant axonal branching and severe axon misguidance in the chick optic tectum. Mice harboring RGMb with a point mutation in the phosphorylation site also display aberrant axonal pathfinding. Mechanistic analyses show that VLK-mediated RGMb phosphorylation modulates Wnt3a activity by regulating LRP5 protein gradients. Thus, the secretion of VLK by projecting neurons provides crucial signals for the accurate formation of nervous system circuitry. The dramatic effect of VLK on RGMb and Wnt3a signaling implies that extracellular phosphorylation likely has broad and profound effects on brain development, function and disease.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Axones / Orientación del Axón Límite: Animals Idioma: En Revista: Nat Chem Biol Asunto de la revista: BIOLOGIA / QUIMICA Año: 2019 Tipo del documento: Article País de afiliación: Canadá Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Axones / Orientación del Axón Límite: Animals Idioma: En Revista: Nat Chem Biol Asunto de la revista: BIOLOGIA / QUIMICA Año: 2019 Tipo del documento: Article País de afiliación: Canadá Pais de publicación: Estados Unidos