Ferguson Gabriel B, Martinez-Agosto Julian A
Molecular Biology Interdepartmental Ph.D. Program, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Molecular Biology Interdepartmental Ph.D. Program, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Molecular Biology Institute, Jonsson Comprehensive Cancer Center, UCLA Broad Stem Cell Center, and Mattel Children's Hospital UCLA, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Curr Biol. 2014 Nov 17;24(22):2665-72. doi: 10.1016/j.cub.2014.09.081. Epub 2014 Oct 30.
Cellular microenvironments established by the spatial and temporal expression of specific signaling molecules are critical for both the maintenance and lineage-specific differentiation of progenitor cells. In Drosophila, a population of hematopoietic progenitors, or prohemocytes, within the larval lymph gland gives rise to three mature cell types: plasmatocytes, lamellocytes, and crystal cells. Removal of the secreted signaling molecules Hedgehog and PVF1 from the posterior signaling center (PSC), which acts as a niche, leads to a loss of progenitors and complete differentiation of the lymph gland. Here, we characterize a novel population of signaling cells within the lymph gland, distinct from the PSC, that are required for lineage-specific differentiation of crystal cells. We provide evidence that Yorkie and Scalloped, the Drosophila homologs of YAP and TEAD, are required in lineage-specifying cells to regulate expression of Serrate, the Notch ligand responsible for the initiation of the crystal cell differentiation program. Genetic manipulation of yorkie and scalloped in the lymph gland specifically alters Serrate expression and crystal cell differentiation. Furthermore, Serrate expression in lineage-specifying cells is eliminated in the lymph gland upon the immune response induced by wasp parasitization to ensure the proper differentiation of lamellocytes at the expense of crystal cells. These findings expand the roles for Yorkie/Scalloped beyond growth to encompass specific cell-fate determination in the context of blood development. Similar regulatory functions may extend to their homologs in vertebrate progenitor cell niches that are required for specifying cell fate.
由特定信号分子的时空表达所建立的细胞微环境对于祖细胞的维持和谱系特异性分化都至关重要。在果蝇中，幼虫淋巴腺内的一群造血祖细胞（即前血细胞）可分化为三种成熟细胞类型：浆细胞、片层细胞和晶细胞。作为小生境的后部信号中心（PSC）中分泌的信号分子Hedgehog和PVF1的缺失，会导致祖细胞的丧失以及淋巴腺的完全分化。在这里，我们鉴定出淋巴腺内一群不同于PSC的新型信号细胞，它们是晶细胞谱系特异性分化所必需的。我们提供的证据表明，果蝇中YAP和TEAD的同源物Yorkie和Scalloped在谱系指定细胞中是调节Notch配体Serrate表达所必需的，Serrate负责启动晶细胞分化程序。在淋巴腺中对yorkie和scalloped进行基因操作会特异性改变Serrate的表达和晶细胞的分化。此外，在黄蜂寄生诱导的免疫反应后，淋巴腺中谱系指定细胞中的Serrate表达被消除，以确保片层细胞的正常分化，而牺牲晶细胞。这些发现扩展了Yorkie/Scalloped在生长之外的作用，使其在血液发育的背景下涵盖特定的细胞命运决定。类似的调节功能可能扩展到它们在脊椎动物祖细胞小生境中用于指定细胞命运的同源物。
