PKA signaling drives reticularis differentiation and sexually dimorphic adrenal cortex renewal

Dumontet, Typhanie; Sahut‐Barnola, Isabelle; Septier, Amandine; Montanier, Nathanaëlle; Plotton, Ingrid; Roucher‐Boulez, Florence; Ducros, Véronique; Lefrançois-Martinez, Anne Marie; Pointud, Jean Christophe; Zubair, Mohamad; Morohashi, Ken Ichirou; Breault, David T.; Val, Pierre; Martinez, Antoine

doi:10.1172/jci.insight.98394

Cited by 86 publications

(89 citation statements)

References 70 publications

(76 reference statements)

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“…Although PKA-mediated transcriptional activation is well documented, data on mechanisms relaying its repressive effects are scarce, even though they are quite prominent. Indeed, our transcriptome analyses of mice with adrenal Prkar1a gene inactivation with various Cre drivers (13,14) showed similar numbers of down-and up-regulated genes following constitutive PKA activation. The only negative molecular mechanism identified to date in the adrenal gland mobilizes the oscillating salt-inducible kinase (SIK)-cAMP responsive element binding protein (CREB)-regulated transcription coactivator cascade, in which SIK represses the activity of CREB in a transient PKA-dependent manner (50)(51)(52).…”

Section: Discussionmentioning

confidence: 77%

“…We have previously established that WNT and PKA signaling pathways exert complementary and antagonistic actions to maintain adrenal cortex zonation: WNT signaling is essential for zG identity, whereas PKA signaling drives identity of the inner cortex (zF and zR) (13,14). Therefore, we hypothesized that relative hyper-SUMOylation of the outer cortex could rely on WNT/ b-catenin signaling.…”

Section: Wnt/b-catenin Signaling Favors Sumoylation In the Adrenal Comentioning

confidence: 99%

“…In the adrenal cortex, ACTH/PKA signaling is required for differentiation, maintenance, and function of the zF (12,13). Active SUMOylation processes can be assessed in tissue sections by monitoring changes in the intensity of nuclear SUMO signal (47,48).…”

Section: Regionalization Of Sumoylation In the Adrenal Cortex Is Depementioning

confidence: 99%

“…We have shown that the adrenal inactivation of Prkar1a in developing mice is sufficient to induce ACTH-independent Cushing syndrome and formation of apoptosis-resistant hyperplasia in the inner zF (21,22). Moreover, by tracing the lineage of Prkar1a mutant cells in the adult gland, we have established that PKA signaling is a driving force for sexually dimorphic cortex replenishment and for the conversion of zF into zR identity (13).…”

mentioning

confidence: 91%

“…Hormonal signals that control adrenal function also participate in the zonation of the cortex. The R-spondin/wingless-related integration site (WNT)/b-catenin signaling pathway contributes to the acquisition of zG identity (10,11), whereas ACTH/ cAMP/PKA signaling is essential for zF and zR differentiation (12,13). Maintaining adequate zonation during the unidirectional renewal of the cortex is ensured at least by the antagonistic interactions between these 2 signaling pathways and through epigenetic programming of newly recruited cells (14)(15)(16).…”

mentioning

confidence: 99%

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Hormonal and spatial control of SUMOylation in the human and mouse adrenal cortex

et al. 2019

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SUMOylation is a highly conserved and dynamic post‐translational mechanism primarily affecting nuclear programs for adapting organisms to stressful challenges. Alteration of SUMOylation cycles leads to severe developmental and homeostatic defects and malignancy, but signals coordinating SUMOylation are still unidentified. The adrenal cortex is a zonated endocrine gland that controls body homeostasis and stress response. Here, we show that in human and in mouse adrenals, SUMOylation follows a decreasing centripetal gradient that mirrors cortical differentiation flow and delimits highly and weakly SUMOylated steroidogenic compartments, overlapping glomerulosa, and fasciculata zones. Activation of PKA signaling by acute hormonal treatment, mouse genetic engineering, or in Carney complex results in repression of small ubiquitin‐like modifier (SUMO) conjugation in the inner cortex by coordinating expression of SUMO pathway inducers and repressors. Conversely, genetic activation of canonical wingless‐related integration site signaling maintains high SUMOylation potential in the outer neoplastic cortex. Thus, SUMOylation is tightly regulated by signaling pathways that orchestrate adrenal zonation and diseases.—Dumontet, T., Sahut‐Barnola, I., Dufour, D., Lefrançois‐Martinez, A.‐M., Berthon, A., Montanier, N., Ragazzon, B., Djari, C., Pointud, J.‐C., Roucher‐Boulez, F., Batisse‐Lignier, M., Tauveron, I., Bertherat, J., Val, P., Martinez, A. Hormonal and spatial control of SUMOylation in the human and mouse adrenal cortex. FASEB J. 33, 10218–10230 (2019). http://www.fasebj.org

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Section: Discussionmentioning

confidence: 77%

Section: Wnt/b-catenin Signaling Favors Sumoylation In the Adrenal Comentioning

confidence: 99%

Section: Regionalization Of Sumoylation In the Adrenal Cortex Is Depementioning

confidence: 99%

mentioning

confidence: 91%

mentioning

confidence: 99%

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Hormonal and spatial control of SUMOylation in the human and mouse adrenal cortex

et al. 2019

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Prolactin as an adrenocorticotropic hormone: Prolactin signalling is a conserved key regulator of sexually dimorphic adrenal gland function in health and disease

Lalli

Figueiredo²

2022

BioEssays

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A large number of previous reports described an effect of the pituitary hormone prolactin (PRL) on steroid hormone production by the adrenal cortex. However, those studies remained anecdotal and were never converted into a conceptual and mechanistic framework, let alone being translated into clinical care. In the light of our recently published landmark study where we described PRL signalling as a pivotal regulator of the sexually dimorphic adrenal phenotype in mouse and of adrenal androgen production in humans, we present here the overarching hypothesis that PRL signalling increases the activity of Steroidogenic Factor-1 (SF-1/NR5A1), a transcription factor that has an essential role in adrenal gland development and function, to regulate adrenal cortex growth and hormonal production in physiological and pathological conditions. PRL can then be considered as a bona fide adrenocorticotropic hormone synergizing with ACTH in the endocrine control of adrenal cortex function.

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Single‐nucleus and spatial transcriptome reveal adrenal homeostasis in normal and tumoural adrenal glands

Altieri,

Secener,

Sai

et al. 2024

Clinical & Translational Med

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The human adrenal gland is a complex endocrine tissue. Studies on adrenal renewal have been limited to animal models or human foetuses. Enhancing our understanding of adult human adrenal homeostasis is crucial for gaining insights into the pathogenesis of adrenal diseases, such as adrenocortical tumours.Here, we present a comprehensive cellular genomics analysis of the adult human normal adrenal gland, combining single‐nuclei RNA sequencing and spatial transcriptome data to reconstruct adrenal gland homeostasis. As expected, we identified primary cells of the various zones of the adrenal cortex and medulla, but we also uncovered additional cell types. They constitute the adrenal microenvironment, including immune cells, mostly composed of a large population of M2 macrophages, and new cell populations, including different subpopulations of vascular‐endothelial cells and cortical‐neuroendocrine cells. Utilizing spatial transcriptome and pseudotime trajectory analysis, we support evidence of the centripetal dynamics of adrenocortical cell maintenance and the essential role played by Wnt/β‐catenin, sonic hedgehog, and fibroblast growth factor pathways in the adult adrenocortical homeostasis. Furthermore, we compared single‐nuclei transcriptional profiles obtained from six healthy adrenal glands and twelve adrenocortical adenomas. This analysis unveiled a notable heterogeneity in cell populations within the adenoma samples. In addition, we identified six distinct adenoma‐specific clusters, each with varying distributions based on steroid profiles and tumour mutational status.Overall, our results provide novel insights into adrenal homeostasis and molecular mechanisms potentially underlying early adrenocortical tumorigenesis and/or autonomous steroid secretion. Our cell atlas represents a powerful resource to investigate other adrenal‐related pathologies.

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PKA signaling drives reticularis differentiation and sexually dimorphic adrenal cortex renewal

Cited by 86 publications

References 70 publications

Hormonal and spatial control of SUMOylation in the human and mouse adrenal cortex

Hormonal and spatial control of SUMOylation in the human and mouse adrenal cortex

Prolactin as an adrenocorticotropic hormone: Prolactin signalling is a conserved key regulator of sexually dimorphic adrenal gland function in health and disease

Single‐nucleus and spatial transcriptome reveal adrenal homeostasis in normal and tumoural adrenal glands

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