Relish plays a dynamic role in the niche to modulate Drosophila blood progenitor homeostasis in development and infection
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Evaluation Summary:
Mandal and colleagues identified novel functions of the Imd pathway transcription factor Relish in the hematopoietic niche development. The authors found that Relish is required for the maintenance of hematopoietic progenitors downstream of hormonal control. This is the first study showing critical roles of Relish in blood development, and therefore, this study will draw broad attention and contribute to understanding of insect hematopoiesis and immunity.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)
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Abstract
Immune challenges demand the gearing up of basal hematopoiesis to combat infection. Little is known about how during development, this switch is achieved to take care of the insult. Here, we show that the hematopoietic niche of the larval lymph gland of Drosophila senses immune challenge and reacts to it quickly through the nuclear factor-κB (NF-κB), Relish, a component of the immune deficiency (Imd) pathway. During development, Relish is triggered by ecdysone signaling in the hematopoietic niche to maintain the blood progenitors. Loss of Relish causes an alteration in the cytoskeletal architecture of the niche cells in a Jun Kinase-dependent manner, resulting in the trapping of Hh implicated in progenitor maintenance. Notably, during infection, downregulation of Relish in the niche tilts the maintenance program toward precocious differentiation, thereby bolstering the cellular arm of the immune response.
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Reviewer #2 (Public Review):
In this manuscript, the authors investigate the role of Relish in the Drosophila lymph gland (LG). They establish that relish is expressed in PSC cells and that reducing its expression in these cells (by expressing relish RNAi with a PSC-gal4 driver) leads to an enlarged PSC, increased plasmatocyte differentiation, no effect on crystal cell numbers, and fewer progenitors in the medullary zone (MZ). In the PSC, Relish controls Wingless levels that in turn control PSC cell proliferation and thus PSC size. This study also establishes that the knock down of relish in the PSC leads to increased levels of several actin binding proteins, reduced filopodia formation in PSC cells and a decrease in Hh (HhExt) release from the PSC. In addition, relish knock-down in the PSC leads to the activation of the JNK pathway in …
Reviewer #2 (Public Review):
In this manuscript, the authors investigate the role of Relish in the Drosophila lymph gland (LG). They establish that relish is expressed in PSC cells and that reducing its expression in these cells (by expressing relish RNAi with a PSC-gal4 driver) leads to an enlarged PSC, increased plasmatocyte differentiation, no effect on crystal cell numbers, and fewer progenitors in the medullary zone (MZ). In the PSC, Relish controls Wingless levels that in turn control PSC cell proliferation and thus PSC size. This study also establishes that the knock down of relish in the PSC leads to increased levels of several actin binding proteins, reduced filopodia formation in PSC cells and a decrease in Hh (HhExt) release from the PSC. In addition, relish knock-down in the PSC leads to the activation of the JNK pathway in the PSC. Epistasis experiments establish that JNK acts downstream of Relish to control filopodia formation and HhExt. Under normal conditions, Relish levels in the PSC are under the control of ecdysone. Finally, in response to an E.coli infection, a decrease in Relish levels in the PSC is observed together with increased plasmatocyte differentiation.
This is an important study describing a yet unknown regulation of Drosophila LG hematopoiesis.
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Reviewer #1 (Public Review):
Mandal and colleagues identified novel functions of Relish in the hematopoietic niche development and its coordinative role in innate immunity. The authors found that Relish is expressed in the PSC, which is essential for various developmental functions, including the maintenance of hematopoietic progenitors, the number of PSC cells, expression of Wg, and the PSC actin cytoskeletal structure. Furthermore, Relish acts as an inhibitor of JNK signaling and functions downstream of the ecdysone pathway in the PSC. The authors moved on to find the developmental and physiological relevance of this phenomenon and discovered that Relish is downregulated upon bacterial infections to accommodate immune responses. These findings show that Relish plays a critical role in hematopoiesis as a downstream of hormonal control …
Reviewer #1 (Public Review):
Mandal and colleagues identified novel functions of Relish in the hematopoietic niche development and its coordinative role in innate immunity. The authors found that Relish is expressed in the PSC, which is essential for various developmental functions, including the maintenance of hematopoietic progenitors, the number of PSC cells, expression of Wg, and the PSC actin cytoskeletal structure. Furthermore, Relish acts as an inhibitor of JNK signaling and functions downstream of the ecdysone pathway in the PSC. The authors moved on to find the developmental and physiological relevance of this phenomenon and discovered that Relish is downregulated upon bacterial infections to accommodate immune responses. These findings show that Relish plays a critical role in hematopoiesis as a downstream of hormonal control and in switching between the developmental and physiological mode of the PSC.
Conclusions are well-supported by data, and experiments were carefully performed and analyzed. Given that most of the studies on Relish describe its function in innate immunity and that it is the first study showing critical roles of Relish in blood development, this study will draw broad attention and contribute to understanding insect hematopoiesis and immunity.
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Evaluation Summary:
Mandal and colleagues identified novel functions of the Imd pathway transcription factor Relish in the hematopoietic niche development. The authors found that Relish is required for the maintenance of hematopoietic progenitors downstream of hormonal control. This is the first study showing critical roles of Relish in blood development, and therefore, this study will draw broad attention and contribute to understanding of insect hematopoiesis and immunity.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)
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