Gadd45 regulates fate decisions of myeloid-type blood progenitor cells in Drosophila

Abstract

Gadd45 is a highly conserved stress response protein that interacts with multiple cellular proteins, playing a crucial role in regulating the cell cycle and responding to various forms of stress. Altered expression of Gadd45 is linked to several solid tumors and hematopoietic malignancies. It is also identified as a gene crucial for cytokine-induced myeloid differentiation, although the precise molecular mechanisms underlying this process remain unclear. We utilized the Drosophila hematopoietic system to investigate the role of Gadd45 in the development of myeloid-type blood cells, employing in vivo genetics and cell biological methods. We show that the absence of Gadd45 reduces the number of crystal cells but does not significantly impact macrophage-like cell plasmatocyte differentiation. However, Gadd45 overexpression caused intermediate progenitors to differentiate into lamellocytes and plasmatocytes to transdifferentiate into lamellocytes, a response typically observed during larval stages in response to immune challenges and injury. Interestingly, Gadd45 overexpression initiated the lamellocyte differentiation program by activating a combination of Toll, JNK, and JAK/STAT signaling pathways. This closely resembles the process by which specialized macrophages are derived in mammals. Moreover, Gadd45 overexpression does not induce cell death but alters the cell cycle status of hematopoietic progenitor cells. This study enhances our understanding of how Gadd45 functions during myeloid cell development. Significance StatementO_LILoss of Gadd45 causes a reduction in crystal cells but does not significantly impact macrophage-like plasmatocyte differentiation. C_LIO_LIGadd45 overexpression causes myeloid-type progenitor cells to differentiate into lamellocyte, as well as plasmatocyte transdifferentiate to lamellocyte. Gadd45 triggers differentiation by activating a combination of Toll, JNK, and JAK/STAT signaling pathways. C_LIO_LIOverexpressing Gadd45 does not induce apoptosis but alters the cell cycle behavior of hematopoietic progenitor cells. C_LI