title: The zebrafish reveals dependence of the mast cell lineage on Notch signaling in vivo.
abstract: We used the opportunities afforded by the zebrafish to determine upstream pathways regulating mast cell development in vivo and identify their cellular origin. Colocalization studies demonstrated zebrafish notch receptor expression in cells expressing carboxypeptidase A5 (cpa5), a zebrafish mast cell-specific marker. Inhibition of the Notch pathway resulted in decreased cpa5 expression in mindbomb mutants and wild-type embryos treated with the γ-secretase inhibitor, Compound E. A series of morpholino knockdown studies specifically identified notch1b and gata2 as the critical factors regulating mast cell fate. Moreover, hsp70::GAL4;UAS::nicd1a transgenic embryos overexpressing an activated form of notch1, nicd1a, displayed increased cpa5, gata2, and pu.1 expression. This increase in cpa5 expression could be reversed and reduced below baseline levels in a dose-dependent manner using Compound E. Finally, evidence that cpa5 expression colocalizes with lmo2 in the absence of hematopoietic stem cells revealed that definitive mast cells initially delineate from erythromyeloid progenitors. These studies identify a master role for Notch signaling in vertebrate mast cell development and establish developmental origins of this lineage. Moreover, these findings postulate targeting the Notch pathway as a therapeutic strategy in mast cell diseases.
authors.affiliation: Izaak Walton Killam Health Centre, Dalhousie University, Halifax, NS, Canada.
authors.forename: Sahar I
authors.initials: SI
authors.lastname: Da'as
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Coombs
authors.forename: Tugce B
authors.initials: TB
authors.lastname: Balci
authors.forename: Chloe A
authors.initials: CA
authors.lastname: Grondin
authors.forename: Adolfo A
authors.initials: AA
authors.lastname: Ferrando
authors.forename: Jason N
authors.initials: JN
authors.lastname: Berman
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D043422:Carboxypeptidases A / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D002454:Cell Differentiation / Q000235:genetics; D019070:Cell Lineage / Q000235:genetics*; D004625:Embryo, Nonmammalian; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D018398:Homeodomain Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D008407:Mast Cells / Q000378:metabolism / Q000502:physiology*; D060172:Morpholinos / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051881:Receptor, Notch1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology / Q000502:physiology; D015027:Zebrafish / Q000196:embryology / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D029961:Zebrafish Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
chemical_list: D018398:Homeodomain Proteins; D060172:Morpholinos; D009419:Nerve Tissue Proteins; C561596:Notch1b protein, zebrafish; D051881:Receptor, Notch1; D029961:Zebrafish Proteins; C437805:notch1a protein, zebrafish; D043422:Carboxypeptidases A