O-fucose modulates Notch-controlled blood lineage commitment.
O-fucose modulates Notch-controlled blood lineage commitment.
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DOI：
10.2353/ajpath.2010.090702
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发表时间：
2010-06
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影响因子：
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通讯作者：
Q. Yan;D. Yao;Lebing Wei;Yuanshuai Huang;Jay T. Myers;Lihua Zhang;W. Xin;Jeongsup Shim;Yunfang Man;B. Petryniak;S. Gerson;J. Lowe;Lan Zhou
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作者：
Q. Yan;D. Yao;Lebing Wei;Yuanshuai Huang;Jay T. Myers;Lihua Zhang;W. Xin;Jeongsup Shim;Yunfang Man;B. Petryniak;S. Gerson;J. Lowe;Lan Zhou
Notch受体是细胞命运决定所必需的细胞表面分子。Notch信号在多个水平受到严格调控，包括通过O-连接岩藻糖基化对Notch受体进行翻译后修饰，这是一种由蛋白质O-岩藻糖基转移酶-1（Pofut 1）催化的反应。我们先前的研究在细胞岩藻糖基化有条件缺陷的小鼠中鉴定了骨髓增殖表型，其可归因于Notch依赖性骨髓生成抑制的丧失。在这里，我们报告说，造血干细胞在细胞岩藻糖基化缺陷显示频率降低和缺陷的再增殖能力，以及减少淋巴，但增加骨髓的发育潜力。这种表型可能归因于造血干细胞中Notch配体结合受抑制和Notch活性下游信号传导减少。与这一发现相一致，我们进一步证明了Notch 1（Notch 1（-/-））或Pofut 1（Pofut 1（-/-））缺陷的小鼠胚胎干细胞不能产生T淋巴细胞，但在体外与表达Notch配体的骨髓基质细胞共培养时分化为髓样细胞。此外，来自Notch 1（-/-）或Pofut 1（-/-）胚胎干细胞的CD 34（+）祖细胞的体内造血重建显示增强的粒细胞生成，伴有抑制的淋巴系发育。总之，这些结果表明Notch信号传导通过促进淋巴发育和抑制明显的骨髓生成来维持造血谱系稳态，部分地通过Notch受体的O-连接岩藻糖基化控制的过程。
Notch receptors are cell surface molecules essential for cell fate determination. Notch signaling is subject to tight regulation at multiple levels, including the posttranslational modification of Notch receptors by O-linked fucosylation, a reaction that is catalyzed by protein O-fucosyltransferase-1 (Pofut1). Our previous studies identified a myeloproliferative phenotype in mice conditionally deficient in cellular fucosylation that is attributable to a loss of Notch-dependent suppression of myelopoiesis. Here, we report that hematopoietic stem cells deficient in cellular fucosylation display decreased frequency and defective repopulating ability as well as decreased lymphoid but increased myeloid developmental potential. This phenotype may be attributed to suppressed Notch ligand binding and reduced downstream signaling of Notch activity in hematopoietic stem cells. Consistent with this finding, we further demonstrate that mouse embryonic stem cells deficient in Notch1 (Notch1(-/-)) or Pofut1 (Pofut1(-/-)) fail to generate T lymphocytes but differentiate into myeloid cells while coculturing with Notch ligand-expressing bone marrow stromal cells in vitro. Moreover, in vivo hematopoietic reconstitution of CD34(+) progenitor cells derived from either Notch1(-/-) or Pofut1(-/-) embryonic stem cells show enhanced granulopoiesis with depressed lymphoid lineage development. Together, these results indicate that Notch signaling maintains hematopoietic lineage homeostasis by promoting lymphoid development and suppressing overt myelopoiesis, in part through processes controlled by O-linked fucosylation of Notch receptors.