Dual control of dopamine in Drosophila myeloid‐like progenitor cell proliferation and regulation of lymph gland growth

Abstract

In Drosophila, definitive haematopoiesis takes place in a specialized organ termed “lymph gland”. It harbours multi‐potent stem‐like blood progenitor cells whose development controls overall growth of this haematopoietic tissue and formation of mature blood cells. With respect to its development, neurotransmitters have emerged as potent regulators of blood‐progenitor cell development and function. In this study, we extend our understanding of neurotransmitters and show that progenitors are self‐sufficient with regard to synthesizing dopamine, a well‐established neurotransmitter. These cells also have modules for dopamine sensing through the receptor and transporter. We found that modulating expression of these components in progenitor cells affected lymph gland growth, which suggested growth‐promoting function of dopamine in blood‐progenitor cells. Cell‐cycle analysis of developing lymph glands revealed an unexpected requirement for intracellular dopamine in moderating the progression of early progenitor cells from S to G2 phase of the cell cycle, while activation of dopamine receptor signalling later in development regulated their progression from G2 and entry into mitosis. The dual capacity in which dopamine operated, first intracellularly to coordinate S/G2 transition and later extracellularly in G2/M transition, was critical for the growth of the lymph gland. Overall, the data presented highlight a novel non‐canonical use of dopamine in the myeloid system that reveals an uncharacterized function of intracellular dopamine in cell‐cycle phasing with outcomes on haematopoietic growth and immunity as well.

Peeling Back the Layers of Lymph Gland Structure and Regulation

“…Blocking dopamine sensing in mammalian HSCs reduces their number and interferes with their function [ 110 ]. This is similar to how the inhibition of dopamine signalling in Drosophila hemocyte progenitors hinders their proliferation, differentiation and their response to immune challenges [ 63 ].…”

“…Surprisingly, unlike GABA, dopamine is produced by both the MZ and the PSC and is sensed by MZ cells. Disrupting dopamine synthesis in the progenitors blocks their cell cycle progression and results in smaller lymph glands with bigger MZ, while blocking dopamine sensing in these cells affects only lymph gland size [ 63 ].…”

Engineering, applications, and future perspectives of GPCR‐based genetically encoded fluorescent indicators for neuromodulators

“…Rodents are by far the most common species on which these indicators have been used (86% in mice and 7% in rats). These indicators have been applied in fruit flies mainly as adult, but one study looked at larvae (Kapoor et al., 2022). In total, they correspond to 4% of the publications.…”

Kinetics of blood cell differentiation during hematopoiesis revealed by quantitative long-term live imaging

“…The copyright holder for this preprint this version posted October 7, 2022. ; https://doi.org/10. 1101/2022 More recent data has supported the view that rather than being a homogenous population, progenitors in the MZ are heterogeneous (Blanco-Obregon et al, 2020, Cho et al, 2020, Baldeosingh et al, 2018. Single cell transcriptomic analysis of the LG revealed a surprising level of heterogeneity of the developing blood cells and uncovered novel blood cell types including adipohemocytes, stem-cell like blood progenitors, and intermediate progenitors (Cho et al, 2020).…”

“…During early larval stages, blood progenitors undergo expansion and are typically found to be in S phase of the cell cycle (Dey et al, 2016). However, once progenitor expansion is completed in the late larval stages, they for the most part stay in the G2 phase through the action of dopamine (Sharma et al, 2019, Kapoor et al, 2022), although some intermediate progenitors remain in S phase (Sharma et al, 2019). Upon infection, there is a strong and rapid induction of mature blood cell production, which depends on the type of immune challenge and involves large scale differentiation of lamellocytes, crystal cells, or plasmatocytes (Banerjee et al, 2019, Khadilkar et al, 2017, Letourneau et al, 2016).…”