Role of glucocorticoids in the chromaffin‐neuron developmental decision

Anderson, David J.; Michelsohn, Arie M.

doi:10.1016/0736-5748(89)90007-5

Cited by 52 publications

(23 citation statements)

References 26 publications

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“…It is tempting to speculate that hypermethylation of these TSGs in SDHB-related tumors could prevent induction of apoptosis by severe mitochondrial dysfunction caused by SDHx deficiency. Differential methylation of PNMT was of particular interest due to its role as a marker of chromaffin cell differentiation and in steroid-induced catecholamine biosynthesis (28). Our results verified PNMT hypermethylation previously reported in SDHBrelated PPGLs (2).…”

Section: Discussionsupporting

confidence: 80%

DNA Methylation Profiling in Pheochromocytoma and Paraganglioma Reveals Diagnostic and Prognostic Markers

Cubas

Korpershoek

Inglada-Pérez

et al. 2015

Clinical Cancer Research

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Purpose: Pheochromocytoma and paraganglioma (PPGL) are rare neuroendocrine tumors, associated with highly variable postoperative evolution. The scarcity of reliable PPGL prognostic markers continues to complicate patient management. In this study, we explored genome-wide DNA methylation patterns in the context of PPGL malignancy to identify novel prognostic markers.Experimental Design: We retrospectively investigated DNA methylation patterns in PPGL with and without metastases using high-throughput DNA methylation profiling data (Illumina 27K) from two large, well-characterized discovery (n ¼ 123; 24 metastatic) and primary validation (n ¼ 154; 24 metastatic) series. Additional validation of candidate CpGs was performed by bisulfite pyrosequencing in a second independent set of 33 paraffin-embedded PPGLs (19 metastatic).Results: Of the initial 86 candidate CpGs, we successfully replicated 52 (47 genes), associated with metastatic PPGL. Of these, 48 CpGs showed significant associations with time to progression even after correcting for SDHB genotype, suggesting their value as prognostic markers independent of genetic background. Hypermethylation of RDBP (negative elongation factor complex member E) in metastatic tumors was further validated by bisulfite pyrosequencing [Db metastatic-benign ¼ 0.29, P ¼ 0.003; HR, 1.4; 95% confidence interval (CI), 1.1-2.0; P ¼ 0.018] and may alter transcriptional networks involving (RERG, GPX3, and PDZK1) apoptosis, invasion, and maintenance of DNA integrity.Conclusions: This is the first large-scale study of DNA methylation in metastatic PPGL that identifies and validates prognostic markers, which could be used for stratifying patients according to risk of developing metastasis. Of the three CpGs selected for further validation, one (RDBP) was clearly confirmed and could be used for stratifying patients according to the risk of developing metastases. Clin Cancer Res; 21(13); 3020-30. Ó2015 AACR.

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Section: Discussionsupporting

confidence: 80%

DNA Methylation Profiling in Pheochromocytoma and Paraganglioma Reveals Diagnostic and Prognostic Markers

Cubas

Korpershoek

Inglada-Pérez

et al. 2015

Clinical Cancer Research

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“…Glucocorticoids provided by the adrenal cortex were believed to have a dual function in promoting the differentiation of chromaffin cells from SA progenitors: first, by promoting the downregulation of neuronal genes and, second, by inducing the adrenaline synthesizing enzyme, PNMT (Bohn et al 1981;Anderson and Axel 1986;Anderson and Michelsohn 1989). However, our analysis of glucocorticoid receptor (GR)-deficient mice does not support this hypothesis, since chromaffin cells mostly develop normally in the absence of GR signalling (Finotto et al 1999).…”

Section: Introductioncontrasting

confidence: 57%

Development of adrenal chromaffin cells in Sf1 heterozygous mice

et al. 2006

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Adrenal medullary chromaffin cells are derivatives of the neural crest and are widely believed to share a common sympathoadrenal (SA) progenitor with sympathetic neurons. For decades, the adrenal cortical environment was assumed to be essential for channelling SA progenitors towards an endocrine chromaffin cell fate. Our recent analysis of steroidogenic factor 1(Sf1) -/- mice, which lack an adrenal cortex, has challenged this view: in Sf1 -/- mice chromaffin cells migrate to the correct "adrenal" location and undergo largely normal differentiation. In contrast to Sf1 homozygous mutants, heterozygous animals have an adrenal cortex, which, however, is smaller than in wildtype littermates. We show here that the Sf1 +/- adrenal cortical anlagen attract normal numbers of chromaffin progenitor cells into their vicinity by embryonic day 13.5 (E13.5). Two days later, however, only a few scattered cells with highly immature features have immigrated into the adrenal cortex, whereas the remainder form a coherent cell assembly ectopically located at the medial surface of the gland. These cells appear more mature than the scattered intracortical chromaffin progenitors and express the adrenaline synthesizing enzyme PNMT with a delay of 1 day in comparison with wildtype littermates. Nevertheless, chromaffin progenitor cells undergo a numerical reduction of approximately 30% by E17.5. Together, our data suggest that normal adrenocortical development is critical for the correct immigration of chromaffin progenitors into the cortical anlagen, for the timing of PNMT expression and for the regulation of chromaffin cell numbers.

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“…For decades, glucocorticoid hormones from the adrenal cortex were assumed to influence crucially the decision of SA progenitor cells to develop into chromaffin cells (Unsicker et al, 1978;Doupe et al, 1985;Anderson and Axel, 1986;Anderson and Michelsohn, 1989;Michelsohn and Anderson, 1992). In-vitro studies with mammalian SA progenitors had suggested that glucocorticoid signalling via the glucocorticoid receptor (GR) governs two essential steps in chromaffin cell development: (1) the suppression of neuronal traits; and (2) the induction of the adrenaline-synthesizing enzyme phenylethanolamine-N-methyltransferase (PNMT) in a majority of adrenal chromaffin cells (Wurtman and Axelrod, 1966;Bohn et al, 1981;Anderson and Axel, 1986;Michelsohn and Anderson, 1992;Anderson, 1993;Unsicker, 1993).…”

Section: Introductionmentioning

confidence: 99%

Lack of an adrenal cortex inSf1mutant mice is compatible with the generation and differentiation of chromaffin cells

et al. 2005

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The diversification of neural-crest-derived sympathoadrenal (SA) progenitor cells into sympathetic neurons and neuroendocrine adrenal chromaffin cells was thought to be largely understood. In-vitro studies with isolated SA progenitor cells had suggested that chromaffin cell differentiation depends crucially on glucocorticoids provided by adrenal cortical cells. However, analysis of mice lacking the glucocorticoid receptor gene had revealed that adrenal chromaffin cells develop mostly normally in these mice. Alternative cues from the adrenal cortex that may promote chromaffin cell determination and differentiation have not been identified. We therefore investigated whether the chromaffin cell phenotype can develop in the absence of an adrenal cortex, using mice deficient for the nuclear orphan receptor steroidogenic factor-1 (SF1), which lack adrenal cortical cells and gonads. We show that in Sf1–/– mice typical chromaffin cells assemble correctly in the suprarenal region adjacent to the suprarenal sympathetic ganglion. The cells display most features of chromaffin cells, including the typical large chromaffin granules. Sf1–/–chromaffin cells are numerically reduced by about 50% compared with the wild type at embryonic day (E) 13.5 and E17.5. This phenotype is not accounted for by reduced survival or cell proliferation beyond E12.5. However, already at E12.5 the `adrenal' region in Sf1–/– mice is occupied by fewer PHOX2B+ and TH+ SA cells as well as SOX10+ neural crest cells. Our results suggest that cortical cues are not essential for determining chromaffin cell fate, but may be required for proper migration of SA progenitors to and/or colonization of the adrenal anlage.

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Role of glucocorticoids in the chromaffin‐neuron developmental decision

Cited by 52 publications

References 26 publications

DNA Methylation Profiling in Pheochromocytoma and Paraganglioma Reveals Diagnostic and Prognostic Markers

DNA Methylation Profiling in Pheochromocytoma and Paraganglioma Reveals Diagnostic and Prognostic Markers

Development of adrenal chromaffin cells in Sf1 heterozygous mice

Lack of an adrenal cortex inSf1mutant mice is compatible with the generation and differentiation of chromaffin cells

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