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Nat Chem Biol. 2019 Nov;15(11):1035-1042. doi: 10.1038/s41589-019-0345-z. Epub 2019 Aug 26.

Extracellular phosphorylation drives the formation of neuronal circuitry.

Author information

1
Krembil Research Institute, Vision Division, Krembil Discovery Tower, Toronto, Ontario, Canada.
2
Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
3
Department of Biochemistry, Donnelly Center, University of Toronto, Toronto, Ontario, Canada.
4
Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
5
Montreal Neurological Institute, Montral, Quebec, Canada.
6
Department of Ophthalmology and Vision Sciences, Faculty of Medicine, University of Toronto, Ontario, Toronto, Canada.
7
CNRS UPR3212, University of Strasbourg, Strasbourg, France.
8
Lunenfeld Tannenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.
9
Krembil Research Institute, Vision Division, Krembil Discovery Tower, Toronto, Ontario, Canada. pmonnier@uhnres.utoronto.ca.
10
Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada. pmonnier@uhnres.utoronto.ca.
11
Department of Ophthalmology and Vision Sciences, Faculty of Medicine, University of Toronto, Ontario, Toronto, Canada. pmonnier@uhnres.utoronto.ca.

Abstract

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.

PMID:
31451763
DOI:
10.1038/s41589-019-0345-z

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