Protein phosphatase 2A regulates blood cell proliferation and differentiation in Drosophila larval lymph glands

• Published in: The FEBS journal 2024-10, Vol.291 (20), p.4558-4580
• Main Authors: Zhang, Fang, Luo, Wang, Liu, Sumin, Zhao, Long, Su, Ying
• Format: Article
• Language: English
• Subjects: Blood cells; Cell differentiation; Cell proliferation; Differentiation; Down-regulation; Drosophila; Drosophila melanogaster; Fruit flies; Functionals; Hedgehog protein; Hematopoiesis; Hematopoietic stem cells; Hematopoietic system; Hemocytes; Hemopoiesis; Inactivation; Insects; Leukemia; Lymph; Lymph gland; Phenotypes; Phosphatase; Phosphoprotein phosphatase; PP2A; Progenitor cells; Protein phosphatase; Proteins; Smo; Vascular endothelial growth factor; Vertebrates
• ISSN: 1742-464X; 1742-4658; 1742-4658
• DOI: 10.1111/febs.17247

Protein phosphatase 2A (PP2A), one of the most abundant protein phosphatases, has divergent functions in multiple types of cells. Its inactivation has been closely associated with leukemia diseases. However, the physiological function of PP2A for hematopoiesis has been poorly understood in organisms. Drosophila hematopoiesis parallels the vertebrate counterpart in developmental and functional features but involves a much simpler hematopoietic system. Here, utilizing the Drosophila major larval hematopoietic organ lymph gland, we studied the function of PP2A for hematopoiesis in vivo. By knocking down the expression of Pp2A‐29B that encodes the scaffold subunit of the PP2A holoenzyme complex, we found that PP2A silencing in the differentiating hemocytes resulted in their excessive proliferation. Furthermore, this PP2A inhibition downregulated the expression of Smoothened (Smo), a crucial component in the Hedgehog pathway, and smo overexpression was able to rescue the phenotypes of PP2A depletion, indicating that Smo functions as a downstream effector of PP2A to restrict the hemocyte proliferation. PDGF/VEGF‐receptor (Pvr) overexpression also restored the Smo expression and lymph gland morphology of PP2A silencing, suggesting a PP2A‐Pvr‐Smo axis to regulate lymph gland growth and hemocyte proliferation. Moreover, inhibiting PP2A activity in the blood progenitor cells promoted their differentiation, but which was independent with Smo. Together, our data suggested that PP2A plays a dual role in the Drosophila lymph gland by preserving the progenitor population and restraining the hemocyte proliferation, to properly regulate the hematopoietic process. The hematopoietic organ of Drosophila melanogaster, the lymph gland, is composed of the primary and posterior lobes. Protein phosphatase 2A PP2A depletion in the cortical zone (CZ) of primary lobes, leads to excessive hemocyte proliferation blurring the physical separation between lobes. This can be rescued by the Protein smoothened (Smo). Depletion of PP2A in the progenitor cells of the medullary zone promotes their differentiation. In this context, Smo can rescue lymph gland size, but not the differentiation of progenitor cells.