Baldeosingh Rajkumar, Gao Hongjuan, Wu Xiaorong, Fossett Nancy
Graduate Program in Life Sciences, University of Maryland School of Medicine, Baltimore, MD 21201, USA; Center for Vascular and Inflammatory Diseases and the Department of Pathology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
Center for Vascular and Inflammatory Diseases and the Department of Pathology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
Dev Biol. 2018 Sep 1;441(1):132-145. doi: 10.1016/j.ydbio.2018.06.020. Epub 2018 Jul 11.
Hematopoietic progenitor choice between multipotency and differentiation is tightly regulated by intrinsic factors and extrinsic signals from the surrounding microenvironment. The Drosophila melanogaster hematopoietic lymph gland has emerged as a powerful tool to investigate mechanisms that regulate hematopoietic progenitor choice in vivo. The lymph gland contains progenitor cells, which share key characteristics with mammalian hematopoietic progenitors such as quiescence, multipotency and niche-dependence. The lymph gland is zonally arranged, with progenitors located in medullary zone, differentiating cells in the cortical zone, and the stem cell niche or Posterior Signaling Center (PSC) residing at the base of the medullary zone (MZ). This arrangement facilitates investigations into how signaling from the microenvironment controls progenitor choice. The Drosophila Friend of GATA transcriptional regulator, U-shaped, is a conserved hematopoietic regulator. To identify additional novel intrinsic and extrinsic regulators that interface with U-shaped to control hematopoiesis, we conducted an in vivo screen for factors that genetically interact with u-shaped. Smoothened, a downstream effector of Hedgehog signaling, was one of the factors identified in the screen. Here we report our studies that characterized the relationship between Smoothened and U-shaped. We showed that the PSC and Hedgehog signaling are required for U-shaped expression and that U-shaped is an important intrinsic progenitor regulator. These observations identify a potential link between the progenitor regulatory machinery and extrinsic signals from the PSC. Furthermore, we showed that both Hedgehog signaling and the PSC are required to maintain a subpopulation of progenitors. This led to a delineation of PSC-dependent versus PSC-independent progenitors and provided further evidence that the MZ progenitor population is heterogeneous. Overall, we have identified a connection between a conserved hematopoietic master regulator and a putative stem cell niche, which adds to our understanding of how signals from the microenvironment regulate progenitor multipotency.
造血祖细胞在多能性和分化之间的选择受到内在因素和周围微环境外在信号的严格调控。黑腹果蝇的造血淋巴腺已成为研究体内调节造血祖细胞选择机制的有力工具。淋巴腺包含祖细胞，这些祖细胞与哺乳动物造血祖细胞具有共同的关键特征，如静止、多能性和对小生境的依赖性。淋巴腺呈区域排列，祖细胞位于髓质区，分化细胞位于皮质区，干细胞小生境或后部信号中心（PSC）位于髓质区（MZ）底部。这种排列便于研究微环境信号如何控制祖细胞的选择。果蝇GATA转录调节因子的Friend，即U形蛋白，是一种保守的造血调节因子。为了鉴定与U形蛋白相互作用以控制造血的其他新的内在和外在调节因子，我们对与u形蛋白发生遗传相互作用的因子进行了体内筛选。Smoothened是Hedgehog信号的下游效应器，是筛选中鉴定出的因子之一。在此，我们报告了表征Smoothened与U形蛋白之间关系的研究。我们表明PSC和Hedgehog信号是U形蛋白表达所必需的，并且U形蛋白是一种重要的内在祖细胞调节因子。这些观察结果确定了祖细胞调节机制与PSC外在信号之间的潜在联系。此外，我们表明Hedgehog信号和PSC都是维持祖细胞亚群所必需的。这导致了对PSC依赖性与PSC非依赖性祖细胞的划分，并提供了进一步的证据表明MZ祖细胞群体是异质的。总体而言，我们确定了一种保守的造血主调节因子与假定的干细胞小生境之间的联系，这加深了我们对微环境信号如何调节祖细胞多能性的理解。
