Vanin-1 Inactivation Antagonizes the Development of Adrenocortical Neoplasia in Sf-1 Transgenic Mice

Laté, Perle Latré de; Wakil, Abeer El; Jarjat, Marielle; Krijger, Ronald R. de; Heckert, Leslie L.; Naquet, Philippe; Lalli, Enzo

doi:10.1210/en.2014-1088

Cited by 17 publications

(12 citation statements)

References 25 publications

(35 reference statements)

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“…This suggests that SF1 can influence cell fate determination. Intriguingly, genetic ablation of the SF1 target gene Vnn1 , encoding the gonadal-like marker Vanin-1, has been shown to reduce the severity of neoplastic lesions in the Sf1 transgenic mice ( 96 ). Similarly, mice in which the endogenous Sf1 gene of the mouse has been replaced with a mutant lacking a key SUMOylation site exhibit abnormal cell fate specification in steroidogenic tissues, including ectopic expression of gonadal markers ( 97 ).…”

Section: Transcription Factors Implicated In Renewal and Remodelingmentioning

confidence: 99%

Adrenocortical Zonation, Renewal, and Remodeling

et al. 2015

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The adrenal cortex is divided into concentric zones. In humans the major cortical zones are the zona glomerulosa, zona fasciculata, and zona reticularis. The adrenal cortex is a dynamic organ in which senescent cells are replaced by newly differentiated ones. This constant renewal facilitates organ remodeling in response to physiological demand for steroids. Cortical zones can reversibly expand, contract, or alter their biochemical profiles to accommodate needs. Pools of stem/progenitor cells in the adrenal capsule, subcapsular region, and juxtamedullary region can differentiate to repopulate or expand zones. Some of these pools appear to be activated only during specific developmental windows or in response to extreme physiological demand. Senescent cells can also be replenished through direct lineage conversion; for example, cells in the zona glomerulosa can transform into cells of the zona fasciculata. Adrenocortical cell differentiation, renewal, and function are regulated by a variety of endocrine/paracrine factors including adrenocorticotropin, angiotensin II, insulin-related growth hormones, luteinizing hormone, activin, and inhibin. Additionally, zonation and regeneration of the adrenal cortex are controlled by developmental signaling pathways, such as the sonic hedgehog, delta-like homolog 1, fibroblast growth factor, and WNT/β-catenin pathways. The mechanisms involved in adrenocortical remodeling are complex and redundant so as to fulfill the offsetting goals of organ homeostasis and stress adaptation.

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Section: Transcription Factors Implicated In Renewal and Remodelingmentioning

confidence: 99%

Adrenocortical Zonation, Renewal, and Remodeling

et al. 2015

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“…Here, feminisation occurred even in the presence of the male adrenal gland. On the other hand, Vnn1, a marker for steroidogenic Sertoli, Leydig and adrenocortical cells 28,29 and a protectant against oxidative stress 30 , was downregulated in the autografts (0.4-fold decrease) ( Fig. 7).…”

Section: Effect Of Acth On Adrenocortical Regeneration Foetal Adrenomentioning

confidence: 97%

GATA4/6 regulate DHH transcription in rat adrenocortical autografts

Yoshida

Takizawa

Matsuda

et al. 2020

Sci Rep

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Adrenal cortex autotransplantation with ACTH stimulation may be an alternative therapy for patients with bilateral adrenalectomy to avoid adrenal crisis, but its underlying mechanism has not been elucidated. Previously, we detected Dhh upregulation in rat adrenocortical autografts after transplantation. Here, we investigated potential regulators such as Gata4, Gata6, Sry and Sox9 which affect Dhh transcription in adrenocortical autografts with or without ACTH stimulation. In ACTHstimulated autografts, Gata4 and Gata6 were downregulated compared to control autografts. This response was linked to rDhh repression. A reporter assay using the upstream region of rDhh and a GATA binding motif revealed that rDhh promoters were significantly upregulated by co-transfection with Gata4 or Gata6 or both. Sry and Sox9 expression in autografts with or without ACTH stimulation were verified by PCR and RNAscope analyses. The ovarian differentiation factors Foxl2 and Rspo1 were also upregulated in the autografts. Gata4 and Gata6 were found to be significant factors in the regulation of rDhh expression and could be associated with adrenocortical autograft maintenance. Gonadal primordia with bipotential testicular and ovarian functions may also be present in these autografts.Pheochromocytomas arise from the adrenal medulla and are catecholamine-producing tumours. Hereditary pheochromocytoma can be treated with bilateral adrenalectomy and lifelong glucocorticoid replacement therapy 1 . Autotransplantation and allotransplantation of the adrenal cortex are potential alternatives that allow bilateral adrenalectomy patients to avoid adrenal crises 1,2 . However, adrenal autotransplantation has not been established in humans and its success rate is only 20-35% 3,4 . Possible reasons for this poor performance include ACTH suppression by negative feedback from excessive postoperative glucocorticoid replacement therapy. This response causes autograft regression. According to previous reports, adrenal autotransplantation has been highly successful in the management of Cushing's disease (ACTH hypersecretion from the pars distalis) 5-7 . Four patients who underwent bilateral adrenalectomy and ACTH replacement were able to withdraw from glucocorticoid replacement immediately after adrenal autotransplantation 8 . Dexamethasone-induced adrenal atrophy in mice was restored with daily ACTH stimulation 9 . ACTH stimulation after autotransplantation preserves autografts and may involve an unidentified pathway which promotes adrenal cortical regeneration and recovers endocrine function.In the search for factors affecting post-transplant adrenocortical autograft remodelling and regeneration, we found that Dhh was upregulated and Shh was downregulated in the regeneration step of rat adrenocortical autograft 8 . The HH signalling pathway may participate in adrenocortical autograft regeneration as well as adrenal cortex development. The regulation of Dhh transcription during gonadal development involves transcription factors such as Wt1, Gata4, Gata6, Sox9...

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“…Recently, it has been proposed that SF-1 overexpression induces alterations of redox mechanisms, which may contribute to adrenal tumorigenesis. Indeed, inactivation of SF1 target gene Vnn1 , encoding the Vanin-1 protein involved in the response to oxidative stress, was found to antagonize the development of adrenocortical neoplasia in SF-1 transgenic mice ( 123 ).…”

Section: Adrenocortical Carcinomas: the Lack Of Mouse Modelsmentioning

confidence: 99%

Mouse Models Recapitulating Human Adrenocortical Tumors: What Is Lacking?

et al. 2016

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Adrenal cortex tumors are divided into benign forms, such as primary hyperplasias and adrenocortical adenomas (ACAs), and malignant forms or adrenocortical carcinomas (ACCs). Primary hyperplasias are rare causes of adrenocorticotropin hormone-independent hypercortisolism. ACAs are the most common type of adrenal gland tumors and they are rarely “functional,” i.e., producing steroids. When functional, adenomas result in endocrine disorders, such as Cushing’s syndrome (hypercortisolism) or Conn’s syndrome (hyperaldosteronism). By contrast, ACCs are extremely rare but highly aggressive tumors that may also lead to hypersecreting syndromes. Genetic analyses of patients with sporadic or familial forms of adrenocortical tumors (ACTs) led to the identification of potentially causative genes, most of them being involved in protein kinase A (PKA), Wnt/β-catenin, and P53 signaling pathways. Development of mouse models is a crucial step to firmly establish the functional significance of candidate genes, to dissect mechanisms leading to tumors and endocrine disorders, and in fine to provide in vivo tools for therapeutic screens. In this article, we will provide an overview on the existing mouse models (xenografted and genetically engineered) of ACTs by focusing on the role of PKA and Wnt/β-catenin pathways in this context. We will discuss the advantages and limitations of models that have been developed heretofore and we will point out necessary improvements in the development of next generation mouse models of adrenal diseases.

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Vanin-1 Inactivation Antagonizes the Development of Adrenocortical Neoplasia in Sf-1 Transgenic Mice

Cited by 17 publications

References 25 publications

Adrenocortical Zonation, Renewal, and Remodeling

Adrenocortical Zonation, Renewal, and Remodeling

GATA4/6 regulate DHH transcription in rat adrenocortical autografts

Mouse Models Recapitulating Human Adrenocortical Tumors: What Is Lacking?

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