Loss of LGR4/GPR48 causes severe neonatal salt wasting due to disrupted WNT signaling altering adrenal zonation

Lucas, Cécily; Sauter, Kay‐Sara; Steigert, Michael; Mallet, Delphine; Wilmouth, James; Olabe, Julie; Plotton, Ingrid; Morel, Yves; Aeberli, Daniel; Wagner, Franca; Pandey, Amit V.; Val, Pierre; Roucher‐Boulez, Florence; Flueck, Christa E.

doi:10.1172/jci164915

Cited by 6 publications

(2 citation statements)

References 36 publications

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“…ACC 5 was identified as the least abundant ACC specific cell type and is characterised by high scores for WNT , TGF -beta and NOTCH signalling pathways and top marker genes MIK67 , LGR4, JAG1, SOX4, NFE2L3 and NR3C1 . Among these top marker genes, expression of the RSPO3 receptor LGR4 was also recently detected in the developing adrenal cortex [27] and its mutation is known to drive aberrant adrenocortical zonation [60]. RSPO3 itself is a WNT signalling coactivator that is proposed to play a key role in maintaining the adrenocortical stem cell niche near the adrenal capsule [20,21,24,25,27,28].…”

Section: Discussionmentioning

confidence: 99%

Cellular landscape of adrenocortical carcinoma at single-nuclei resolution

Tourigny,

Altieri,

Secener

et al. 2023

Preprint

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Adrenocortical carcinoma (ACC) is a rare yet devastating tumour of the adrenal gland with a molecular pathology that remain incompletely understood. To gain novel insights into the cellular landscape of ACC, we generated single-nuclei RNA sequencing (snRNA-seq) data sets from twelve ACC tumour samples and analysed these alongside a previously published snRNA-seq data set from normal adrenal glands (NAGs). We find the ACC tumour microenvironment to be relatively devoid of immune cells compared to NAG tissues, consistent with known high tumour purity values for ACC as an immunologically ``cold'' tumour. Our analysis identifies three separate groups of ACC samples that are characterised by different relative compositions of adrenocortical cell types, including two populations (ACC 1 and ACC 2) that are specifically enriched in the most aggressive tumours and display hallmarks of the epithelial to mesenchymal transition (EMT) and dysregulated steroidogenesis, respectively. In addition to cell types associated with hypoxic and metabolic signatures (ACC 3 and ACC 4) prevalent among less-aggressive tumours, we also identified and validated a population of mitotically active adrenocortical cells (ACC M) strongly overexpressing genes POLQ and DIAPH3 that possibly supports the expansion of malignant cell lineages. The smallest identified ACC specific cell type, ACC 5, displays characteristics of increased proliferation and growth factor signalling, and is therefore a potential progenitor-like or cell-of-origin candidate for the different lineages involved in adrenocortical carcinogenesis. Intriguingly, linage tracing suggests the fate adopted by malignant adrenocortical cells upon differentiation appears to be at least partly associated with the copy number or allelic balance state of the imprinted DLK1/MEG3 genomic locus, which we verified by assessing DNA methylation status among samples from the three groups of tumours defined by their different cell type compositions. Our results therefore provide new insights into the cellular heterogeneity of ACC, indicating that genetic perturbations to a hierarchical cellular differentiation mechanism underlying healthy adrenocortical renewal and zonation may explain the molecular basis for disease pathogenesis.

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Section: Discussionmentioning

confidence: 99%

Cellular landscape of adrenocortical carcinoma at single-nuclei resolution

Tourigny,

Altieri,

Secener

et al. 2023

Preprint

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“… 105 ). Systematic pathway analysis of genes differentially regulated in ZG compared with ZF also indicated negative regulation of steroid and lipid synthesis, and of Wnt signalling 64 , 113 . These findings suggest that suppression of aldosterone secretion in adult ZG is, in part, an active process rather than a consequence of ANGII withdrawal due to excess of salt in the modern diet.…”

Section: Cacna1dmentioning

confidence: 93%

Primary aldosteronism: molecular medicine meets public health

Azizan,

Drake,

Brown

2023

Nat Rev Nephrol

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Primary aldosteronism is the most common single cause of hypertension and is potentially curable when only one adrenal gland is the culprit. The importance of primary aldosteronism to public health derives from its high prevalence but huge under-diagnosis (estimated to be <1% of all affected individuals), despite the consequences of poor blood pressure control by conventional therapy and enhanced cardiovascular risk. This state of affairs is attributable to the fact that the tools used for diagnosis or treatment are still those that originated in the 1970–1990s. Conversely, molecular discoveries have transformed our understanding of adrenal physiology and pathology. Many molecules and processes associated with constant adrenocortical renewal and interzonal metamorphosis also feature in aldosterone-producing adenomas and aldosterone-producing micronodules. The adrenal gland has one of the most significant rates of non-silent somatic mutations, with frequent selection of those driving autonomous aldosterone production, and distinct clinical presentations and outcomes for most genotypes. The disappearance of aldosterone synthesis and cells from most of the adult human zona glomerulosa is the likely driver of the mutational success that causes aldosterone-producing adenomas, but insights into the pathways that lead to constitutive aldosterone production and cell survival may open up opportunities for novel therapies.

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