Rab5蛋白调控果蝇造血作用的分子机制

Hematopoiesis is a complex biological process that is playing an important role in the normal life. Therefore, intensive research about proliferation and differentiation of hematopoietic progenitor cells and the mechanism for maintaining progenitor cells homeostasis is important for reveal hematopoietic dysfunction. Recently, we found that down-regulation of Rab5 in Drosophila was associated with increased number of plasmatocytes and lamellocytes; formation of melanotic nodules in larvae and adults; enlarged lymph gland and mature blood cells of CZ; and decreased progenitor MZ compared with control. Based on our previous results, in present study, we try to demonstrate the regulatory mechanism of Rab5 for proliferation and differentiation of progenitor cells, formation of melanotic nodule. We also try to elucidate the signaling pathway that contributes to maintenance of lymph gland homeostasis and the relationship between cell proliferation/differentiation and autophagy regulated by Rab5. A variety of transgenic flies and blood cell-specific antibodies were used in the study via the combination of molecular biology, cell biology and immunology methods. These results may lay a foundation for define a new class of Rab5 genes that functioned in proliferation and differentiation of hemocytes, and for further studies about Rab family genes that are involved in hematopoiesis.

造血或血细胞生成是一个复杂的生物学过程，同时是维持机体正常生命活动的重要部分。因此，深入研究造血祖细胞的增殖和分化、维持祖细胞稳态的调控机制，对揭示造血功能紊乱具有重要意义。最近我们发现，果蝇Rab5低表达时能够引起游离浆细胞数量增加、薄层细胞异常分化、幼虫和成虫都能产生黑色素瘤、淋巴腺变大、成熟血细胞CZ区变大、祖细胞MZ区变小等现象。本项目在前期研究结果的基础上，利用实验室已有的多种转基因果蝇和血细胞特异性抗体，结合分子生物学、细胞生物学和免疫学等方法，揭示Rab5对血细胞增殖和分化的调节机制、明确产生黑色素瘤的原因、阐明维持淋巴腺稳态的信号途径、探索Rab5调节细胞增殖/分化与自噬的关系。此研究为进一步揭示参与血细胞增殖和分化的新的功能基因Rab5的调控机制，以及Rab家族基因在造血作用中的功能提供理论基础。

造血或血细胞生成是一个复杂的生物学过程，同时是维持机体正常生命活动的重要部分。因此，深入研究造血祖细胞的增殖和分化、维持祖细胞稳态的调控机制，对揭示造血功能紊乱具有重要意义。我们发现标记内体的蛋白Rab5 在膜运输中起关键作用，并明确了其参与果蝇的造血过程。在血细胞或皮质区 (CZ) 中抑制 Rab5 可明显诱导循环血细胞数量增加、淋巴腺中的细胞过度增殖、并产生薄层细胞，由此破坏造血祖细胞稳态。另外，明确了薄层细胞的形成涉及 JNK、Toll 和 Ras/EGFR 信号通路。值得注意的是，我们首次证明了薄层细胞的形成也与 JNK 依赖性自噬有关。综上所述，我们明确了Rab5调控造血干细胞稳态，是新的造血调节因子，我们的研究结果可以为理解维持造血稳态的机制以及白血病等血液疾病研究提供理论基础。