The glucocorticoid receptor is required for stress erythropoiesis

Bauer, Anna; Tronche, François; Wessely, Oliver; Kellendonk, Christoph; Reichardt, Holger M.; Steinlein, Peter; Schütz, Günther; Beug, Hartmut

doi:10.1101/gad.13.22.2996

Cited by 261 publications

(267 citation statements)

References 37 publications

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“…As GR null/null mice die at birth [24] we studied the pancreas of these mice at embryonic stage E18. The whole digestive tract from GR null/null mutants was smaller and had a pale colour, especially the spleen, compared with the GR +/+ littermates (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Nevertheless, several mechanisms can be proposed. First, these mutants show defective erythropoiesis [6,24], a defect which could contribute to the massive cell death. Second, another plausible cause, in line with the pale colour of the spleen and of all organs composing the digestive tract, could be impaired vascularisation.…”

Section: Discussionmentioning

confidence: 99%

“…However, such effects in early life could ultimately lead to metabolic diseases in adulthood. The analysis of mice in which the GR has been genetically modified, GR hypo/hypo (also designated GR −/− [6,23] and GR null/null [6,24,25]), has provided evidence for a role of the GR in the development or function of several tissues, including fetal lung, adrenal and erythroblasts, and this modification is associated with neonatal death. We have previously shown that undernutrition during the last week of gestation in the rat increases both maternal and fetal glucocorticoid levels, which further causes decreased fetal pancreatic beta cell mass [26,27].…”

Section: Introductionmentioning

confidence: 99%

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Glucocorticoid signalling affects pancreatic development through both direct and indirect effects

et al. 2006

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Aims/hypothesis Beta cell development is sensitive to glucocorticoid levels. Although direct effects of glucocorticoids on pancreatic precursors have been shown to control beta cell mass expansion, indirect effects of these hormones on pancreatic development remain unexplored. This issue was addressed in mice lacking the glucocorticoid receptor (GR) in the whole organism. Materials and Methods The pancreatic phenotype of GR null/null mice was studied at fetal ages (embryonic day [E]) E15.5 and E18 by immunohistochemistry and beta cell fraction measurements. To distinguish between direct and indirect effects, mutant E15.5 fetal pancreata were grafted under the kidney capsule of immunodeficient mice and analysed after 1 week. Results E18 GR null/null fetuses had smaller digestive tracts and tiny pancreata. Massive pancreatic disorganisation and apoptosis were observed despite the presence of all cell types. E15.5 GR null/null mutants were indistinguishable from wild-type regarding pancreatic size, tissue structure and organisation, beta cell fraction and production of exocrine transcription factor Ptf1a, neurogenin 3 and Pdx-1. Grafting E15.5 GR null/null pancreata into a GR-expressing environment rescued the increased apoptosis and mature islets were observed, suggesting that GR null/null pancreatic cell death can be attributed to indirect effects of glucocorticoids on this tissue. Heterozygous GR +/null mutants with reduced GR numbers showed no apoptosis but increased beta cell fraction at E18 and the adult age, strengthening the importance of an accurate GR dosage on beta cell mass expansion. Conclusions/interpretation Our results provide evidence for GR involvement in pancreatic tissue organisation and survival through indirect effects. GR does not appear necessary for early phases, but its accurate dosage is critical to modulate beta cell mass expansion at later fetal stages, presumably through direct effects.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Glucocorticoid signalling affects pancreatic development through both direct and indirect effects

et al. 2006

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“…These hormones act through nuclear receptors, and recent investigations indicate that mice deficient in glucocorticoid receptor expression exhibit a complete loss of stress erythropoiesis, that is, the capacity to respond with an increased erythropoietic production to stress conditions, such as erythrolysis or hypoxia. 4 Molecular mechanisms of control of erythropoiesis: role of transcription factors…”

Section: Apoptotic Mechanisms In the Control Of Erythropoiesis U Testamentioning

confidence: 99%

Apoptotic mechanisms in the control of erythropoiesis

2004

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Erythropoiesis is a complex multistep process encompassing the differentiation of hemopoietic stem cells to mature erythrocytes. The steps involved in this complex differentiation process are numerous and involve first the differentiation to early erythoid progenitors (burst-forming units-erythroid, BFU-E), then to late erythroid progenitors (colony-forming unitserythroid) and finally to morphologically recognizable erythroid precursors. A key event of late stages of erythropoiesis is nuclear condensation, followed by extrusion of the nucleus to produce enucleated reticulocytes and finally mature erythrocytes. During the differentiation process, the cells became progressively sensitive to erythropoietin that controls both the survival and proliferation of erythroid cells.A normal homeostasis of the erythropoietic system requires an appropriate balance between the rate of erythroid cell production and red blood cell destruction. Growing evidences outlined in the present review indicate that apoptotic mechanism play a relevant role in the control of erythropoiesis under physiologic and pathologic conditions. Withdrawal of erythropoietin or stimulation of death receptors such as Fas or TRAIL-Rs leads to activation of a subset of caspases-3, -7 and -8, which then cleave the transcription factors GATA-1 and TAL-1 and trigger apoptosis. In addition, there is evidence that a number of caspases are physiologically activated during erythroid differentiation and are functionally required for erythroid maturation. Several caspase substrates are cleaved in differentiating cells, including the protein acinus whose activation by cleavage is required for chromatin condensation.The studies on normal erythropoiesis have clearly indicated that immature erythroid precursors are sensitive to apoptotic triggering mediated by activation of the intrinsic and extrinsic apoptotic pathways. These apoptotic mechanisms are frequently exacerbated in some pathologic conditions, associated with the development of anemia (ie, thalassemias, multiple myeloma, myelodysplasia, aplastic anemia).The considerable progress in our understanding of the apoptotic mechanisms underlying normal and pathologic erythropoiesis may offer the way to improve the treatment of several pathologic conditions associated with the development of anemia.

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“…Thus, the lack of glucocorticoid receptor function abolishes stress induced (but not normal) erythropoiesis in vivo, as shown by transplantation studies using erythroid progenitor Page 17 of 39 A c c e p t e d M a n u s c r i p t cells derived from GR -/-fetal livers [128]. Stress erythropoiesis appears to require binding of the receptor to DNA, since stress induced proliferation is also severely impaired in mice carrying a receptor dimerisation mutant (GR dim/dim ).…”

Section: Cell Proliferation Defects In Glucocorticoid Receptor Mutantsmentioning

confidence: 99%

Glucocorticoids and circadian clock control of cell proliferation: At the interface between three dynamic systems

Dickmeis

Foulkes

2011

Molecular and Cellular Endocrinology

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The circadian clock, an endogenous timekeeper that regulates daily rhythms of physiology, also influences the dynamic release of glucocorticoids. The release of glucocorticoids is characteristically pulsatile and is further modulated in a circadian fashion. A circadian pacemaker in the brain regulates daily rhythms of hypothalamicpituitary-adrenal axis and autonomic nervous system activity that both influence glucocorticoid release from the adrenal gland. This systemic regulation interacts with rhythms in the adrenal gland itself that are driven by its own circadian clock. One function of glucocorticoids is the regulation of cell proliferation. Depending on the tissue, this can involve both negative and positive regulation of a variety of processes, including cell differentiation and cell death. Cell proliferation is also under circadian control, and recent evidence suggests that this regulation may involve glucocorticoid signalling. Here, we review the dynamic processes participating in the interplay between the circadian clock, glucocorticoids and cell proliferation, and we discuss the potential implications for therapy.

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The glucocorticoid receptor is required for stress erythropoiesis

Cited by 261 publications

References 37 publications

Glucocorticoid signalling affects pancreatic development through both direct and indirect effects

Glucocorticoid signalling affects pancreatic development through both direct and indirect effects

Apoptotic mechanisms in the control of erythropoiesis

Glucocorticoids and circadian clock control of cell proliferation: At the interface between three dynamic systems

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