wdb基因调控果蝇血细胞发育的功能及机制研究

血液系统发育是人及动物发育过程中的重要一环并在不同物种间表现了保守的调控机制。目前已知，蛋白磷酸酶2A（PP2A）通过调控细胞凋亡而与多种血液疾病密切相关，但其在血细胞分化及谱系形成方面的功能并不完全清楚。PP2A以三聚体形式行使功能，包括结构亚基、调节亚基和催化亚基，其中调节亚基控制PP2A的底物特异性。申请人在前期研究中发现，编码果蝇PP2A调节亚基的wdb基因抑制晶细胞（果蝇主要血细胞之一）的终端分化并在果蝇翅膀发育中调控Notch和Hedgehog信号活性。本项目拟在此基础上，利用发育生物学和分子生物学等手段，深入研究wdb基因在果蝇造血系统发育各阶段对各类血细胞形成、分化的影响，并进一步检验该基因是否通过特定信号通路调控血细胞发育，以探讨包含Wdb亚基的PP2A在造血系统发育过程中的新功能及新机制。该研究将有助于了解蛋白磷酸酶与相关血液疾病的关系，为临床研究提供理论支撑。

Hematopoiesis is an important part of human and animal development. Among different species, similar and conserved regulatory mechanisms are repeatedly employed during hematopoiesis. Misregulation of hematopoiesis results in blood diseases. As known, protein phosphatase 2A (PP2A) is closely related with many types of blood diseases through regulating blood cell apoptosis. However, it remains elusive whether PP2A plays any other roles during hematopoiesis, especially the blood cell differentiation and pattern formation. PP2A functions as hetero-trimeric holoenzyme, including scaffolding subunit, regulatory subunit and catalytic subunit. Among these three subunits, regulatory subunit confers the specificity of PP2A substrate and cellular localization of PP2A holoenzyme. In the preliminary work, the applicant found that over-expressing wdb, encoding the regulatory subunit of Drosophila PP2A, dramatically inhibited the formation of crystal cell, one of three main blood cell types in Drosophila. Besides this, the applicant’s preliminary data suggested that wdb is involved to modulate Notch and Hedgehog signaling activity during Drosophila wing development. Here, we will utilize Drosophila lymph gland system, conduct genetic, molecular and developmental experiments, to study the role of wdb for different blood cell development, differentiation, and pattern formation during hematopoiesis. Furthermore, given that Notch signaling is thought to guide the formation of crystal cell and Hedgehog signaling is required to maintain the prohemocytes, the undifferentiated hemocytes, we will reveal whether this function of wdb acts through Notch or Hedgehog signaling pathway. All above, we aim to discuss the new function and new regulatory mechanism of wdb-containing PP2A during hematopoiesis, which will benefit the understanding of the relationship between protein phosphatase and blood diseases, and provide the theoretic support for the related clinic study.