Supporting Online Material Materials and Methods Figs. S1 to S10 References Movies S1 to S3 Functional Compartmentalization and Viewpoint Generalization within the Macaque Face-processing System-猫眼课题宝

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A R Simard;D. Soulet;G. Gowing;J. P. Julien;S. Rivest;B Ajami;J. L. Bennett;C. Krieger;W. Tetzlaff;F. M. Rossi;S. P. Sorokin;R. F. Hoyt;D. G. Blunt;N. McNelly;G. Hoeffel;X. H. Zong;R. Basu;H. Ketchum;W. Freiwald;Doris Y. Tsao

而在这个时间点，在大脑雏形体内没有检测到标记细胞(图4A和图4)。S10A)。脑浸润性细胞只有在血液循环发展时才出现，在E9.5胚胎中，相当大比例的Lac-Z+细胞出现与血管相关并渗透到大脑雏形(图4B和图4)。S10B)。这些结果与先前的发现一致，即在E8.0左右，CSF-1R+细胞首先聚集在卵黄囊中，当血管在E9.0(27)左右发育时，CSF-1R+细胞渗透到胚胎本身。为了解决功能性血管的发育是否需要将髓系前体重新招募到大脑雏形中，我们使用了NCX-1-/-动物，这些动物由于钠钙交换器1的缺陷而缺乏心跳和功能血液循环(28)。我们发现，E9.5到E10.5NCX-1-/-胚胎的卵黄囊巨噬细胞水平与对照窝产仔相当或更高(图4，C和E)。相反，NCX-1-/-胚胎在大脑中没有可检测到的小胶质细胞，而NCX-1+/+对照胎在这个时间点已经在大脑中有大量的小胶质细胞(图4，D和E)。综上所述，这些结果表明，RUNX1+祖细胞在E8.5和E9.5之间通过血管从卵黄囊迁移到大脑。为了检验明确的造血对小胶质细胞动态平衡的贡献，我们在E8.5、E9.5和E10.5注射了4‘OHT。E8.5和E9.5激活的小鼠的EYFP+白细胞比例比E7.25到E7.5激活的小鼠高得多(高达40%对不到3%，n=10)(图3E和图3)。S9)。相比之下，在E8.5及以后激活的成年小鼠的大脑中几乎没有检测到EYFP+小胶质细胞(图3e)。E7.5和E8.5之间的贡献水平急剧下降，与E7.5后RUNX1+解剖位置对成年小胶质细胞谱系标记的贡献相反。总而言之，这些数据表明，明确的造血对成年小胶质细胞的发育的贡献很小，如果有的话。我们的结果提供了证据，原始的髓系前体细胞在稳定状态下产生了停留在成人中枢神经系统的小胶质细胞。原始巨噬细胞在哺乳动物、鸟类和斑马鱼的卵黄囊中在血液循环开始之前分化(14)。对斑马鱼的研究表明，卵黄囊来源的巨噬细胞在通过…侵入大脑之前在头部间充质中扩散。

whereas no labeled cells were detectable in the brain rudiment at this time point (Fig. 4A and fig. S10A). Brain-infiltrating cells appeared only when blood circulation developed, and a significant proportion of Lac-Z + cells appeared associated with blood vessels and infiltrated the brain rudiment in E9.5 conceptus (Fig. 4B and fig. S10B). These results are consistent with prior findings showing that CSF-1R + cells first accumulate in the yolk sac around E8.0 and infiltrate the embryo proper when blood vessels develop around E9.0 (27). To address whether the development of functional blood vessels was required for the recruitment of myeloid precursors into the brain rudiment, we used Ncx-1 –/– animals that lack a heartbeat and functional blood circulation because of a defect in sodium calcium exchanger 1 (28). We found that E9.5 to E10.5 Ncx-1 –/– embryos have yolk sac macrophages levels comparable or higher than control litter-mates (Fig. 4, C and E). In contrast, Ncx-1 –/– embryos have no detectable microglia in the brain, whereas Ncx-1 +/+ control littermates already have a substantial number of microglia in the brain at this time-point (Fig. 4, D and E). Altogether, these results suggest that Runx1 + progenitors migrate from the yolk sac into the brain through blood vessels between E8.5 and E9.5. To examine the contribution of definitive hem-atopoiesis to microglial homeostasis, we injected 4′OHT at E8.5, E9.5, and E10.5. The proportion of eYFP + leukocytes known to derive from definitive hematopoiesis was much higher in mice activated at E8.5 and E9.5 compared with mice activated at E7.25 to E7.5 (up to 40% versus less than 3%, n = 10) (Fig. 3E and fig. S9). In contrast , few eYFP + microglia were detected in the brains of adult mice activated after E8.5 and onward (Fig. 3E). The sharp descending contribution levels between E7.5 and E8.5 argue against the contribution of post-E7.5 Runx1 + anatomic locations to the labeling of the adult microglia lineage. Altogether, these data suggest minimal, if any, contribution of definitive hem-atopoiesis to the development of adult microglia. Our results provide evidence that primitive myeloid precursors give rise to microglia residing in the adult CNS in the steady state. Primitive macrophages differentiate in the yolk sac of mammals , birds, and zebrafish before the onset of blood circulation (14). Studies in zebrafish revealed that yolk sac–derived macrophages spread in the cephalic mesenchyme before invading the brain through …

Supporting Online Material Materials and Methods Figs. S1 to S10 References Movies S1 to S3 Functional Compartmentalization and Viewpoint Generalization within the Macaque Face-processing System

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