Normal hematopoiesis after conditional targeting of RXRα in murine hematopoietic stem/progenitor cells
Normal hematopoiesis after conditional targeting of RXRα in murine hematopoietic stem/progenitor cells
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DOI：
10.1189/jlb.0206097
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发表时间：
2006-10-01
影响因子：
5.5
通讯作者：
Glass, Christopher K.
中科院分区：
文献类型：
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作者：
Ricote, Mercedes;Snyder, Cynthia S.;Glass, Christopher K.
由于视黄酸受体α (RAR α)基因参与急性早幼粒细胞白血病，RARs在造血中的重要作用现已得到充分证实。然而，相对较少的造血研究集中在类视黄醇X受体（RXRs）的作用上，RXRs是RARs的专性异二聚体伴侣。我们试图确定RXR α在早期造血祖细胞中的有条件靶向，理想情况下达到造血干细胞（HSC）水平，是否会损害造血功能。对于RXR α的造血靶向，我们表征了ifn诱导的mxre小鼠，用于研究RXR α在造血中的作用。我们发现mxre在造血祖细胞中重组loxp -侧翼的RXRa，导致造血细胞中RXR α的广泛和持续靶向。然而，我们没有发现缺乏RXR α的小鼠血液学损害的证据，这表明RXR α对于正常小鼠造血是必不可少的。尽管如此，甲基纤维素中培养的RXR α缺失骨髓细胞比对照小鼠的骨髓细胞更有效地形成集落。这一结果表明，尽管RXR α不是小鼠造血所必需的，但可能存在选择性地响应RXR α的造血信号通路，或者在RXR （α、β和γ）的联合表达受限的环境中。
Because of the retinoic acid receptor-alpha (RAR alpha) gene's involvement in acute promyelocytic leukemia, the important role of RARs in hematopoiesis is now well established. However, relatively few studies of hematopoiesis have focused on the role of the retinoid X receptors (RXRs), the obligate heterodimeric partners of the RARs. We sought to establish whether conditional targeting of RXR alpha in early hematopoietic progenitors, ideally to the level of the hematopoietic stem cell (HSC), would compromise hematopoiesis. For hematopoietic targeting of RXR alpha, we characterized IFN-inducible MxCre mice for use in studying the role of RXR alpha in hematopoiesis. We established that MxCre executes recombination of loxP-flanked RXRa in hematopoietic progenitors immunophenotypically enriched for HSC, leading to widespread and sustained targeting of RXR alpha in hematopoietic cells. However, we found no evidence of hematologic compromise in mice lacking RXR alpha, suggesting that RXR alpha is dispensable for normal murine hematopoiesis. Nonetheless, RXR alpha null bone marrow cells cultured in methylcellulose form colonies more efficiently than bone marrow cells obtained from control mice. This result suggests that although RXR alpha is not required for murine hematopoiesis, there may be hematopoietic signaling pathways that respond selectively to RXR alpha or settings in which combined expression of RXR (alpha, beta, and gamma) is limiting.