Molecular Mechanisms of Drosophila Hematopoiesis

Abstract

As a model organism, the fruit fly (Drosophila melanogaster) has assumed a leading position in modern biological research. The Drosophila genetic system has a number of advantages making it a key model in investigating the molecular mechanisms of metazoan developmental processes. Over the past two decades, significant progress has been made in understanding the molecular mechanisms regulating Drosophila hematopoiesis. This review discusses the major advances in investigating the molecular mechanisms involved in maintaining the population of multipotent progenitor cells and their differentiation into mature hemocytes in the hematopoietic organ of the Drosophila larva. The use of the Drosophila hematopoietic organ as a model system for hematopoiesis has allowed to characterize the complex interactions between signaling pathways and transcription factors in regulating the maintenance and differentiation of progenitor cells through the signals from the hematopoietic niche, autocrine and paracrine signals, and the signals emanated by differentiated cells.

Keywords: Drosophila melanogaster; differentiation; hematopoiesis; hematopoietic niche; hematopoietic organ; hematopoietic stem cells; hemocytes; multipotency; signaling pathways; transcription factors.

Fig. 1

(A) Drosophila hematopoietic organ (lymph gland of the third larval instar) structure. The HO consists of paired anterior and posterior lobes, attached and interacting with DV and pericardial cells. The anterior lobes of HO are a model system for studying Drosophila hematopoiesis. They consist of cell populations or cellular zones of the PSC (hematopoietic niche); the medullary zone (MZ) involving preprohemocyte (PPH) and prohemocyte (PH) populations; the cortical zone (CZ), consisting of differentiated hemocytes such as plasmatocytes (PLs), crystal cells (CCs), and lamellocytes (LMs); and intermediate prohemocytes (IPHs) of the intermediate zone (IZ). (B) Genesis of hematopoietic organ. At the early embryonic stage, cardiogenic mesoderm cells or hemangioblasts (HAB) give rise to hematopoietic lineage (HL) and cardiovascular precursor cells, cardioblasts (CB). At subsequent embryonic stages, three pairs of thoracic segments (T1–3) of cardiogenic mesoderm produce the HO’s anterior pairs. Two anterior segments (T1–2) fuse and give rise to PPHs and all the hemocytes of the HO anterior lobe, while the third posterior segment produces PSC cells (highlighted in green). At the first instar larva, the anterior lobes contain PPH, PH, and PSC cells. At the second instar larva, PHs begin to differentiate into IPHs, which differentiate into plasmatocytes and CCs, forming the HO’s CZ (these hemocyte lineages are highlighted in colors, as shown on panel B’). At the third larval stage, IPH differentiation into terminally differentiated hemocytes continues, accompanied by CZ growth. At this stage, MZ PHs are maintained in a mitotically quiescent state. (B`) Hematopoiesis occurring in the HO. Hematopoietic progenitor cells and differentiated hemocyte lineages are indicated, and the abbreviations of the subtypes of the hemocyte lineages detected by scRNAseq are shown in parentheses

Fig. 2

Schematic representation of the participation and interaction of the main signaling pathways and TFs in the regulation of HO hematopoiesis in the fruit fly. PSC-cell (in green) maintenance and proliferation are positively and negatively controlled by the respective Wg/Fz2/Myc and Dpp/TGFβ signalling pathways. PPH (in grey) maintenance and proliferation are positively controlled by the Dpp, Notch, and Pvf2/Pvr signals. PH (in blue) maintenance (PH, blue) is positively controlled by the Hh/PKA/Ci signals from the hematopoietic niche, autocrine signals Wnt/Fz/Fz2 and Ca²⁺ and negatively controlled by the Adgf-A signal originating from differentiated CZ hemocytes (in orange). PSC cells positively control Adgf-A expression through activation of Pvr and STAT in differentiated CZ hemocytes, being a link in the equilibrium signals between PSC cells and the mature hemocytes that control PH maintenance. IPHs are marked in yellow. PL differentiation and proliferation is positively regulated by FGF/Htl/Ras and ROS/JNK/FoxO: those of CC, by Ser/Notch; and those of LM, by Spi/EGFR, Jak/Stat, and ROS/JNK/FoxO (see details in the text)