Deletion of a Csf1r enhancer selectively impacts CSF1R expression and development of tissue macrophage populations
Deletion of a Csf1r enhancer selectively impacts CSF1R expression and development of tissue macrophage populations
复制标题
DOI：
10.1038/s41467-019-11053-8
复制
发表时间：
2019-07-19
影响因子：
16.6
通讯作者：
Pridans, Clare
中科院分区：
文献类型：
--
作者：
Rojo, Rocio;Raper, Anna;Pridans, Clare
单核吞噬细胞的增殖、分化和存活依赖于巨噬细胞集落刺激因子受体CSF1R的信号。哺乳动物Csf1r位点含有一个高度保守的超级增强子，即fms内含子调控元件（FIRE）。本研究表明，小鼠中FIRE的基因组缺失选择性地影响CSF1R的表达和特定组织中组织巨噬细胞的发育。缺失FIRE可抑制小鼠胚胎干细胞中巨噬细胞的发育。Csf1r（Delta FIRE/Delta FIRE）小鼠在胚胎、脑小胶质细胞和皮肤、肾脏、心脏和腹膜中缺乏巨噬细胞。其他巨噬细胞群和单核细胞的稳态不受影响，但骨髓中的单核细胞及其祖细胞缺乏表面CSF1R。最后，Csf1r（Delta FIRE/Delta FIRE）小鼠健康且可生育，没有Csf1r（-/-）啮齿动物报道的生长、神经或发育异常。因此，Csf1r（Delta FIRE/Delta FIRE）小鼠为探索成年动物组织特异性巨噬细胞群体的稳态、生理和免疫功能提供了一个模型。
The proliferation, differentiation and survival of mononuclear phagocytes depend on signals from the receptor for macrophage colony-stimulating factor, CSF1R. The mammalian Csf1r locus contains a highly conserved super-enhancer, the fms-intronic regulatory element (FIRE). Here we show that genomic deletion of FIRE in mice selectively impacts CSF1R expression and tissue macrophage development in specific tissues. Deletion of FIRE ablates macrophage development from murine embryonic stem cells. Csf1r(Delta FIRE/Delta FIRE) mice lack macrophages in the embryo, brain microglia and resident macrophages in the skin, kidney, heart and peritoneum. The homeostasis of other macrophage populations and monocytes is unaffected, but monocytes and their progenitors in bone marrow lack surface CSF1R. Finally, Csf1r(Delta FIRE/Delta FIRE) mice are healthy and fertile without the growth, neurological or developmental abnormalities reported in Csf1r(-/-) rodents. Csf1r(Delta FIRE/Delta FIRE) mice thus provide a model to explore the homeostatic, physiological and immunological functions of tissue-specific macrophage populations in adult animals.