Reimels Theresa A, Pfleger Cathie M
Department of Oncological Sciences, The Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA The Graduate School of Biomedical Sciences, The Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Department of Oncological Sciences, The Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA The Graduate School of Biomedical Sciences, The Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
J Cell Sci. 2015 Dec 15;128(24):4512-25. doi: 10.1242/jcs.174433. Epub 2015 Nov 13.
Hematopoietic homeostasis requires the maintenance of a reservoir of undifferentiated blood cell progenitors and the ability to replace or expand differentiated blood cell lineages when necessary. Multiple signaling pathways function in these processes, but how their spatiotemporal control is established and their activity is coordinated in the context of the entire hematopoietic network are still poorly understood. We report here that loss of the gene Rabex-5 in Drosophila causes several hematopoietic abnormalities, including blood cell (hemocyte) overproliferation, increased size of the hematopoietic organ (the lymph gland), lamellocyte differentiation and melanotic mass formation. Hemocyte-specific Rabex-5 knockdown was sufficient to increase hemocyte populations, increase lymph gland size and induce melanotic masses. Rabex-5 negatively regulates Ras, and we show that Ras activity is responsible for specific Rabex-5 hematopoietic phenotypes. Surprisingly, Ras-independent Notch protein accumulation and transcriptional activity in the lymph gland underlie multiple distinct hematopoietic phenotypes of Rabex-5 loss. Thus, Rabex-5 plays an important role in Drosophila hematopoiesis and might serve as an axis coordinating Ras and Notch signaling in the lymph gland.
造血稳态需要维持未分化血细胞祖细胞库，并在必要时具备替换或扩增分化血细胞谱系的能力。多种信号通路在这些过程中发挥作用，但它们的时空控制是如何建立的，以及它们的活性在整个造血网络中是如何协调的，目前仍知之甚少。我们在此报告，果蝇中Rabex - 5基因的缺失会导致多种造血异常，包括血细胞（血淋巴细胞）过度增殖、造血器官（淋巴腺）尺寸增大、片状细胞分化和黑色素瘤形成。血细胞特异性敲低Rabex - 5足以增加血细胞数量、增大淋巴腺尺寸并诱导黑色素瘤形成。Rabex - 5负向调节Ras，并且我们表明Ras活性是Rabex - 5特定造血表型的原因。令人惊讶的是，淋巴腺中不依赖Ras的Notch蛋白积累和转录活性是Rabex - 5缺失导致的多种不同造血表型的基础。因此，Rabex - 5在果蝇造血过程中发挥重要作用，并且可能作为协调淋巴腺中Ras和Notch信号的一个轴。
