Nitric oxide regulates growth coordination during regeneration

Mechanisms that coordinate the growth of different tissues during development are essential for producing adult animals with proper organ proportion. Here we describe a pathway through which tissues communicate with each other to coordinate growth. DuringDrosophila melanogasterlarval development, damage to imaginal discs activates a regeneration checkpoint that produces both a delay in developmental timing and slows the growth of undamaged tissues, coordinating regeneration of the damaged tissue with developmental progression and overall growth. Both developmental delay and growth control are mediated by secretion of the insulin/relaxin family peptide Dilp8 from regenerating tissues. Here we demonstrate that Dilp8-dependent growth coordination between regenerating and undamaged tissues, but not developmental delay, requires the activity of nitric oxide synthase (NOS) in the prothoracic gland. NOS limits the growth of undamaged tissues by reducing ecdysone biosynthesis, a requirement for imaginal disc growth during both the regenerative checkpoint and normal development. Therefore, NOS activity in the prothoracic gland translates information about the growth status of individual tissues into coordinated tissue growth through the regulation of endocrine signals.

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The relaxin receptor Lgr3 mediates growth coordination and developmental delay during Drosophila melanogaster imaginal disc regeneration

10.1101/032508 ◽

2015 ◽

Author(s):

Jacob S. Jaszczak ◽

Jacob B. Wolpe ◽

Rajan Bhandari ◽

Rebecca G. Jaszczak ◽

Adrian Halme

Keyword(s):

Drosophila Melanogaster ◽

Developmental Delay ◽

Imaginal Disc ◽

Imaginal Discs ◽

Prothoracic Gland ◽

Disc Regeneration ◽

Relaxin Family ◽

Dependent Growth ◽

Oxide Synthase ◽

Relaxin Receptor

Damage to Drosophila melanogaster imaginal discs activates a regeneration checkpoint that 1) extends larval development and 2) coordinates the regeneration of the damaged disc with the growth of undamaged discs. These two systemic responses to damage are both mediated by Dilp8, a member of the insulin/IGF/relaxin family of peptide hormones, which is released by regenerating imaginal discs. Growth coordination between regenerating and undamaged imaginal discs is dependent on Dilp8 activation of NOS in the prothoracic gland (PG), which slows the growth of undamaged discs by limiting ecdysone synthesis. Here we demonstrate that the Drosophila relaxin receptor homologue Lgr3, a leucine-rich repeat-containing G-protein coupled receptor, is required for Dilp8-dependent growth coordination and developmental delay during the regeneration checkpoint. Lgr3 regulates these responses to damage via distinct mechanisms in different tissues. Using tissue-specific RNAi disruption of Lgr3 expression, we show that Lgr3 functions in the PG upstream of nitric oxide synthase (NOS), and is necessary for NOS activation and growth coordination during the regeneration checkpoint. When Lgr3 is depleted from neurons, imaginal disc damage no longer produces either developmental delay or growth inhibition. To reconcile these discrete tissue requirements for Lgr3 during regenerative growth coordination, we demonstrate that Lgr3 activity in the both the CNS and PG is necessary for NOS activation in the PG following damage. Together, these results identify new roles for a relaxin receptor in mediating damage signaling to regulate growth and developmental timing.

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Serotonergic neuron ribosomes regulate the neuroendocrine control of Drosophila development.

10.1101/2021.06.10.447971 ◽

2021 ◽

Author(s):

Lisa P Deliu ◽

Deeshpaul Jadir ◽

Abhishek Ghosh ◽

Savraj S Grewal

Keyword(s):

Developmental Delay ◽

Ribosomal Proteins ◽

Growth Control ◽

Prothoracic Gland ◽

Neuroendocrine Control ◽

Ribosomal Function ◽

A Cell ◽

Animal Growth ◽

Main Regulator ◽

Mechanism Of Growth

The regulation of ribosome function is a conserved mechanism of growth control. While studies in single cell systems have defined how ribosomes contribute to cell growth, the mechanisms that link ribosome function to organismal growth are less clear. Here we explore this issue using Drosophila Minutes, a class of heterozygous mutants for ribosomal proteins (Rps). These animals exhibit a delay in larval development caused by decreased production of the steroid hormone ecdysone, the main regulator of larval maturation. We found that this developmental delay is not caused by decreases in either global ribosome numbers or translation rates. Instead, we show that they are due in part to loss of Rp function specifically in a subset of serotonin (5-HT) neurons that innervate the prothoracic gland to control ecdysone production. We found that these 5-HT neurons have defective secretion in Minute animals, and that overexpression of synaptic vesicle proteins in 5-HTergic cells can partially reverse the Minute developmental delay. These results identify a cell-specific role for ribosomal function in the neuroendocrine control of animal growth and development.

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Nitric Oxide Is Protective in Listeric Meningoencephalitis of Rats

Infection and Immunity ◽

10.1128/iai.69.6.4086-4093.2001 ◽

2001 ◽

Vol 69 (6) ◽

pp. 4086-4093 ◽

Cited By ~ 21

Author(s):

K. A. Remer ◽

T. W. Jungi ◽

R. Fatzer ◽

M. G. Täuber ◽

S. L. Leib

Keyword(s):

Nitric Oxide ◽

Growth Control ◽

Brain Infection ◽

Infant Rat ◽

Inos Inhibitor ◽

Order Of Magnitude ◽

Oxide Synthase ◽

And Control ◽

Dose Dependent ◽

The Brain

ABSTRACT The bacterium Listeria monocytogenes causes meningoencephalitis in humans. In rodents, listeriosis is associated with granulomatous lesions in the liver and the spleen, but not with meningoencephalitis. Here, infant rats were infected intracisternally to generate experimental listeric meningoencephalitis. Dose-dependent effects of intracisternal inoculation with L. monocytogeneson survival and activity were noted; 104 L. monocytogenes organisms induced a self-limiting brain infection. Bacteria invaded the basal meninges, chorioid plexus and ependyme, spread to subependymal tissue and hippocampus, and disappeared by day 7. This was paralleled by recruitment and subsequent disappearance of macrophages expressing inducible nitric oxide synthase (iNOS) and nitrotyrosine accumulation, an indication of nitric oxide (NO⋅) production. Treatment with the spin-trapping agent α-phenyl-tert-butyl nitrone (PBN) dramatically increased mortality and led to bacterial numbers in the brain 2 orders of magnitude higher than in control animals. Treatment with the selective iNOS inhibitorl-N 6-(1-iminoethyl)-lysine (L-NIL) increased mortality to a similar extent and led to 1 order of magnitude higher bacterial counts in the brain, compared with controls. The numbers of bacteria that spread to the spleen and liver did not significantly differ among L-NIL-treated, PBN-treated, and control animals. Thus, the infant rat brain is able to mobilize powerful antilisterial mechanisms, and both reactive oxygen and NO⋅ contribute to Listeria growth control.

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Ecdysone regulates the Drosophila imaginal disc epithelial barrier, determining the length of regeneration checkpoint delay

Development ◽

10.1242/dev.195057 ◽

2021 ◽

Vol 148 (6) ◽

Author(s):

Danielle DaCrema ◽

Rajan Bhandari ◽

Faith Karanja ◽

Ryunosuke Yano ◽

Adrian Halme

Keyword(s):

Imaginal Disc ◽

Steroid Hormone ◽

Prothoracic Gland ◽

Epithelial Barrier ◽

Septate Junctions ◽

Barrier Permeability ◽

The Third ◽

Developmental Progression ◽

Relaxin Family ◽

The Brain

ABSTRACT Regeneration of Drosophila imaginal discs, larval precursors to adult tissues, activates a regeneration checkpoint that coordinates regenerative growth with developmental progression. This regeneration checkpoint results from the release of the relaxin-family peptide Dilp8 from regenerating imaginal tissues. Secreted Dilp8 protein is detected within the imaginal disc lumen, in which it is separated from its receptor target Lgr3, which is expressed in the brain and prothoracic gland, by the disc epithelial barrier. Here, we demonstrate that following damage the imaginal disc epithelial barrier limits Dilp8 signaling and the duration of regeneration checkpoint delay. We also find that the barrier becomes increasingly impermeable to the transepithelial diffusion of labeled dextran during the second half of the third instar. This change in barrier permeability is driven by the steroid hormone ecdysone and correlates with changes in localization of Coracle, a component of the septate junctions that is required for the late-larval impermeable epithelial barrier. Based on these observations, we propose that the imaginal disc epithelial barrier regulates the duration of the regenerative checkpoint, providing a mechanism by which tissue function can signal the completion of regeneration.

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Ecdysone regulates the Drosophila imaginal disc epithelial barrier, determining the duration of regeneration checkpoint delay

10.1101/2020.07.16.207704 ◽

2020 ◽

Author(s):

Danielle DaCrema ◽

Rajan Bhandari ◽

Faith Karanja ◽

Ryunosuke Yano ◽

Adrian Halme

Keyword(s):

Imaginal Disc ◽

Larval Instar ◽

Prothoracic Gland ◽

Epithelial Barrier ◽

Developmental Progression ◽

Relaxin Family ◽

Larval Hemolymph ◽

Summary Statement ◽

The Brain ◽

Ecdysone Signaling

AbstractRegeneration of Drosophila imaginal discs, larval precursors to adult tissues, produces a systemic response, a regeneration checkpoint that coordinates regenerative growth with developmental progression. This regeneration checkpoint is coordinated by the release of the relaxin-family peptide Dilp8 from regenerating tissues. Secreted Dilp8 protein can be detected within the imaginal disc lumen. The disc epithelium separates from the lumen from the larval hemolymph and the targets for Dilp8 activity in the brain and prothoracic gland. Here we demonstrate that the imaginal disc epithelial barrier limits Dilp8 signaling and checkpoint delay. We also observe that the wing imaginal disc barrier becomes more restrictive during development, becoming impermeable only at end of the final larval instar. This change in barrier permeability is driven by the steroid hormone ecdysone and correlates with changes in localization of Coracle, a component of the septate junctions that is required for the late, impermeable epithelial barrier. Based on these observations, we propose that the imaginal disc epithelial barrier regulates the duration of the regenerative checkpoint, providing a mechanism by which tissue function can signal the completion of regeneration.Summary StatementEcdysone signaling directs the Drosophila third instar imaginal disc epithelial barrier to mature, becoming more restrictive. This mature barrier limits Dilp8 signaling and determines the duration of the regeneration checkpoint.

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Differentiated PDGFRα-Positive Cells: A Novel In-Vitro Model for Functional Studies of Neuronal Nitric Oxide Synthase

International Journal of Molecular Sciences ◽

10.3390/ijms22073514 ◽

2021 ◽

Vol 22 (7) ◽

pp. 3514

Author(s):

Bashair M. Mussa ◽

Amir Ali Khan ◽

Ankita Srivastava ◽

Sallam Hasan Abdallah

Keyword(s):

Nitric Oxide ◽

Survival Rate ◽

Growth Factor ◽

Nitric Oxide Synthase ◽

Connective Tissue ◽

Neuronal Nitric Oxide Synthase ◽

Tissue Growth ◽

No Donor ◽

Functional Studies ◽

Oxide Synthase

It is evident that depletion of interstitial cells and dysfunction of nitric oxide (NO) pathways are key players in development of several gastrointestinal (GI) motility disorders such as diabetic gastroparesis (DGP). One of the main limitations of DGP research is the lack of isolation methods that are specific to interstitial cells, and therefore conducting functional studies is not feasible. The present study aims (i) to differentiate telomerase transformed mesenchymal stromal cells (iMSCs) into platelet-derived growth factor receptor-α-positive cells (PDGFRα-positive cells) using connective tissue growth factor (CTGF) and L-ascorbic acids; (ii) to investigate the effects of NO donor and inhibitor on the survival rate of differentiated PDGFRα-positive cells; and (iii) to evaluate the impact of increased glucose concentrations, mimicking diabetic hyperglycemia, on the gene expression of neuronal nitric oxide synthase (nNOS). A fibroblastic differentiation-induction medium supplemented with connective tissue growth factor was used to differentiate iMSCs into PDGFRα-positive cells. The medium was changed every day for 21 days to maintain the biological activity of the growth factors. Gene and protein expression, scanning electron and confocal microscopy, and flow cytometry analysis of several markers were conducted to confirm the differentiation process. Methyl tetrazolium cell viability, nitrite measurement assays, and immunostaining were used to investigate the effects of NO on PDGFRα-positive cells. The present study, for the first time, demonstrated the differentiation of iMSCs into PDGFRα-positive cells. The outcomes of the functional studies showed that SNAP (NO donor) increased the survival rate of differentiated PDGFRα-positive cells whereas LNNA (NO inhibitor) attenuated these effects. Further experimentations revealed that hyperglycemia produced a significant increase in expression of nNOS in PDGFRα-positive cells. Differentiation of iMSCs into PDGFRα-positive cells is a novel model to conduct functional studies and to investigate the involvement of NO pathways. This will help in identifying new therapeutic targets for treatment of DGP.

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Localization of endothelial nitric oxide synthase in the normal and failing human atrial myocardium

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100166397 ◽

1996 ◽

Vol 54 ◽

pp. 786-787

Author(s):

Chi-Ming Wei ◽

Margarita Bracamonte ◽

Shi-Wen Jiang ◽

Richard C. Daly ◽

Christopher G.A. McGregor ◽

...

Keyword(s):

Nitric Oxide ◽

Heart Failure ◽

Nitric Oxide Synthase ◽

Endothelial Nitric Oxide Synthase ◽

Cardiac Tissues ◽

Mammalian Tissues ◽

End Stage Heart Failure ◽

End Stage ◽

Oxide Synthase ◽

Endothelial Nitric Oxide

Nitric oxide (NO) is a potent endothelium-derived relaxing factor which also may modulate cardiomyocyte inotropism and growth via increasing cGMP. While endothelial nitric oxide synthase (eNOS) isoforms have been detected in non-human mammalian tissues, expression and localization of eNOS in the normal and failing human myocardium are poorly defined. Therefore, the present study was designed to investigate eNOS in human cardiac tissues in the presence and absence of congestive heart failure (CHF).Normal and failing atrial tissue were obtained from six cardiac donors and six end-stage heart failure patients undergoing primary cardiac transplantation. ENOS protein expression and localization was investigated utilizing Western blot analysis and immunohistochemical staining with the polyclonal rabbit antibody to eNOS (Transduction Laboratories, Lexington, Kentucky).

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