Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, United States.
Molecular Biology Institute, University of California, Los Angeles, Los Angeles, United States.
Elife. 2021 Oct 29;10:e67516. doi: 10.7554/eLife.67516.
Mechanistic studies of lymph gland hematopoiesis are limited by the availability of cell-type-specific markers. Using a combination of bulk RNA-Seq of FACS-sorted cells, single-cell RNA-Seq, and genetic dissection, we identify new blood cell subpopulations along a developmental trajectory with multiple paths to mature cell types. This provides functional insights into key developmental processes and signaling pathways. We highlight metabolism as a driver of development, show that graded Pointed expression allows distinct roles in successive developmental steps, and that mature crystal cells specifically express an alternate isoform of Hypoxia-inducible factor (Hif/Sima). Mechanistically, the Musashi-regulated protein Numb facilitates Sima-dependent non-canonical, and inhibits canonical, Notch signaling. Broadly, we find that prior to making a fate choice, a progenitor selects between alternative, biologically relevant, transitory states allowing smooth transitions reflective of combinatorial expressions rather than stepwise binary decisions. Increasingly, this view is gaining support in mammalian hematopoiesis.
淋巴器官造血的机制研究受到细胞类型特异性标记物可用性的限制。我们结合流式细胞分选细胞的批量 RNA-Seq、单细胞 RNA-Seq 和遗传剖析，沿着具有多种成熟细胞类型途径的发育轨迹识别新的血细胞亚群。这为关键发育过程和信号通路提供了功能见解。我们强调代谢是发育的驱动力，表明分级 Pointed 表达允许在连续的发育步骤中发挥不同的作用，并且成熟的晶体细胞特异性表达缺氧诱导因子（Hif/Sima）的另一种同工型。从机制上讲，Musashi 调节的蛋白 Numb 促进 Sima 依赖性非经典、抑制经典 Notch 信号。广泛地，我们发现，在做出命运选择之前，祖细胞在替代的、生物学上相关的、短暂状态之间进行选择，允许平稳过渡，反映出组合表达而不是逐步二进制决策。越来越多的证据表明，这种观点在哺乳动物造血中得到了支持。
