The zebrafish reveals dependence of the mast cell lineage on Notch signaling in vivo
The zebrafish reveals dependence of the mast cell lineage on Notch signaling in vivo
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DOI：
10.1182/blood-2011-10-385989
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发表时间：
2012-04-12
期刊：
影响因子：
20.3
通讯作者：
Berman, Jason N.
中科院分区：
文献类型：
--
作者：
Da'as, Sahar I.;Coombs, Andrew J.;Berman, Jason N.
我们利用斑马鱼提供的机会来确定调节体内肥大细胞发育的上游途径，并确定其细胞来源。共定位研究表明，斑马鱼notch受体表达的细胞表达羧肽酶A5（cpa 5），斑马鱼肥大细胞特异性标志物。Notch途径的抑制导致用γ-分泌酶抑制剂化合物E处理的思维炸弹突变体和野生型胚胎中cpa 5表达的降低。一系列的吗啉敲除研究明确指出notch 1b和gata 2是调节肥大细胞命运的关键因子。此外，hsp 70：：GAL 4; UAS：：nicd 1a转基因胚胎过度表达notch 1的激活形式nicd 1a，显示cpa 5，gata 2和pu.1表达增加。cpa 5表达的这种增加可以使用化合物E以剂量依赖性方式逆转并降低至基线水平以下。最后，在没有造血干细胞的情况下cpa 5表达与lmo 2共定位的证据表明，定形肥大细胞最初是从红骨髓祖细胞中分离出来的。这些研究确定了Notch信号在脊椎动物肥大细胞发育中的主要作用，并建立了该谱系的发育起源。此外，这些发现假定靶向Notch途径作为肥大细胞疾病的治疗策略。（血。2012;119（15）：3585-3594）
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 gamma-secretase inhibitor, Compound E. Aseries 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. (Blood. 2012;119(15):3585-3594)