title: The JAK3 inhibitor WHI-P154 prevents PDGF-evoked process outgrowth in human neural precursor cells.
abstract: The prospect of manipulating endogenous neural stem cells to replace damaged tissue and correct functional deficits offers a novel mechanism for treating a variety of CNS disorders. The aim of this study was to investigate pathways controlling neurite outgrowth in human neural precursor cells, in particular in response to platelet-derived growth factor (PDGF). PDGF-AA, -AB and -BB were found to initiate calcium signalling and produce robust increases in neurite outgrowth. PDGF-induced outgrowth of Tuj1-positive precursors was abolished by the addition of EGTA, suggesting that calcium entry is a critical part of the signalling pathway. Wortmannin and PD098059 failed to inhibit PDGF-induced outgrowth. Clostridium Toxin B increased the amount of PDGF-induced neurite branching but had no effect on basal levels. In contrast, WHI-P154, an inhibitor of Janus protein tyrosine kinase (JAK3), Hck and Syk, prevented PDGF-induced neurite outgrowth. PDGF activates multiple signalling pathways with considerable potential for cross-talk. This study has highlighted the complexity of the pathways leading to neurite outgrowth in human neural precursors, and provided initial evidence to suggest that calcium entry is critical in producing the morphological changes observed.
authors.affiliation: The Neuroscience Research Centre, Merck Sharp and Dohme Research Laboratories, Harlow, Essex, UK. gillian_richards@merck.com
authors.forename: G R
authors.initials: GR
authors.lastname: Richards
authors.forename: A J
authors.initials: AJ
authors.lastname: Smith
authors.forename: P
authors.initials: P
authors.lastname: Cuddon
authors.forename: Q P
authors.initials: QP
authors.lastname: Ma
authors.forename: M
authors.initials: M
authors.lastname: Leveridge
authors.forename: J
authors.initials: J
authors.lastname: Kerby
authors.forename: H L
authors.initials: HL
authors.lastname: Roderick
authors.forename: M D
authors.initials: MD
authors.lastname: Bootman
authors.forename: P B
authors.initials: PB
authors.lastname: Simpson
mesh_terms: D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology*; D018929:Cell Culture Techniques / Q000379:methods; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D053616:Janus Kinase 3; D016501:Neurites / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D010982:Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology*; D033581:Stem Cell Transplantation / Q000379:methods; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D013744:Tetanus Toxin / Q000494:pharmacology; D014404:Tubulin / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D010982:Platelet-Derived Growth Factor; D011799:Quinazolines; D013744:Tetanus Toxin; D014404:Tubulin; C113888:WHI P154; C462941:beta3 tubulin, mouse; D011505:Protein-Tyrosine Kinases; C507933:JAK3 protein, human; C507935:Jak3 protein, mouse; D053616:Janus Kinase 3; D002118:Calcium