Resident progenitor and/or stem cell populations in the adult adrenal cortex enable cortical cells to undergo homeostatic renewal and regeneration after injury. Renewal occurs predominantly in the outer layers of the adrenal gland but newly formed cells undergo centripetal migration, differentiation and lineage conversion in the process of forming the different functional steroidogenic zones. Over the past 10 years, advances in the genetic characterization of adrenal diseases and studies of mouse models with altered adrenal phenotypes have helped to elucidate the molecular pathways that regulate adrenal tissue renewal, several of which are fine-tuned via complex paracrine and endocrine influences. Moreover, the adrenal gland is a sexually dimorphic organ, and testicular androgens have inhibitory effects on cell proliferation and progenitor cell recruitment in the adrenal cortex. This Review integrates these advances, including the emerging role of sex hormones, into existing knowledge on adrenocortical cell renewal. An in-depth understanding of these mechanisms is expected to contribute to the development of novel therapies for severe endocrine diseases, for which current treatments are unsatisfactory.

Adrenal cortex renewal in health and disease.

Fibrosis disrupts adipose tissue (AT) homeostasis and exacerbates metabolic dysfunction upon chronic caloric excess. The molecular mechanisms linking adipocyte plasticity to AT fibrosis are largely unknown. Here we show that the Hippo pathway is coupled with TGFβ signaling to orchestrate a cellular and/or functional shift of adipocytes from energy storage to extracellular matrix (ECM) remodeling in AT fibrosis. We found that Lats1/2-knockout adipocytes could dedifferentiate into DPP4+ progenitor cells and convert to DPP4- myofibroblasts upon TGFβ stimulation. On the other hand, Hippo pathway inhibition during obesity impaired adipocyte identity while promoted ECM remodeling activity of adipocytes. Macrophages recruited by CCL2 produced TGFβ to accelerate AT fibrosis. YAP and TAZ, the Hippo downstream effectors, enhanced SMAD2 stability to promote fibrotic responses. Importantly, inhibition of YAP/TAZ activity in obese mice markedly relieved AT fibrosis and improved metabolic homeostasis. Together, our findings identify the Hippo pathway as a molecular switch in the initiation and development of AT fibrosis, implying it as a therapeutic target. 

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The Hippo pathway links adipocyte plasticity to adipose tissue fibrosis

The adrenal cortex is an endocrine organ organized into concentric zones that are specialized to produce specific steroid hormones essential for life. The development and maintenance of the adrenal cortex are complex, as a fetal adrenal is first formed from a common primordium with the gonads, followed by its separation in a distinct primordium, the invasion of the adrenal primordium by neural crest-derived cells to form the medulla, and finally its encapsulation. The fetal cortex is then replaced by a definitive cortex, which will establish zonation and be maintained throughout life by regeneration relying on the proliferation, centripetal migration and differentiation of several stem/progenitor cell populations whose activities are sex-specific. Here, we will highlight the advances made, using transgenic mouse models, to delineate the molecular mechanisms regulating these processes.

Adrenal Cortex Development and Maintenance: Knowledge Acquired From Mouse Models.

Abstract Recent conditional knockout of core components of the Hippo signaling pathway in the adrenal gland of mice has demonstrated that this pathway must be tightly regulated to ensure proper development and maintenance of the adrenal cortex. We report herein that the most upstream kinases of the pathway, the mammalian STE20-like protein kinases 1 and 2 (MST1and MST2, respectively), are expressed in the mouse adrenal cortex with MST2 expression being restricted to the zona glomerulosa (zG). To further explore the role of Hippo signaling in adrenocortical cells, we conditionally deleted Mst1/2 in steroidogenic cells using an Nr5a1-cre strain (Mst1flox/flox; Mst2flox/flox; Nr5a1-cre). Our results show that the loss of MST1/2 leads to the premature and progressive accumulation of subcapsular GATA4+, WT1+ adrenal gonadal primordium (AGP)-like progenitor cells starting at 2 months of age without affecting aldosterone and corticosterone secretion. To help us understand this phenotype, microarray analyses were performed on adrenal glands from 2-month-old mutant and control mice. Gene expression analyses revealed that loss of Mst1/2 leads to the overexpression of known downstream target genes (Ajuba, Aqp1, Fn1, Ibsp, Igf1, Igfbp2, Mmp2, Thbs1) of the main effector of Hippo signaling, YAP; and underexpression of genes (Agtr1b, Ecgr4, Hsd3b6, Nr0b1, Tesc, Vsnl1) that are normally specifically expressed in the zG or overexpressed in the zG compared to the zona fasciculata (zF). Together, these results suggest that MST1/2 regulates Hippo signaling activity in the adrenal cortex and that these two kinases are also involved in the fine tuning of zG cell function or differentiation.

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Effect of Inactivation of Mst1 and Mst2 in the Mouse Adrenal Cortex

The cortex of the adrenal gland is organized into concentric zones that produce distinct steroid hormones essential for body homeostasis in mammals. Mechanisms leading to the development, zonation and maintenance of the adrenal cortex are complex and have been studied since the 1800s. However, the advent of genetic manipulation and transgenic mouse models over the past 30 years has revolutionized our understanding of these mechanisms. This review lists and details the distinct Cre recombinase mouse strains available to study the adrenal cortex, and the remarkable progress total and conditional knockout mouse models have enabled us to make in our understanding of the molecular mechanisms regulating the development and maintenance of the adrenal cortex.

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Transgenic Mouse Models to Study the Development and Maintenance of the Adrenal Cortex

It has recently been shown that the loss of the Hippo signaling effectors Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) in adrenocortical steroidogenic cells impairs the postnatal maintenance of the adrenal gland. To further explore the role of Hippo signaling in mouse adrenocortical cells, we conditionally deleted the key Hippo kinases large tumor suppressor homolog kinases 1 and -2 (Lats1 and Lats2, two kinases that antagonize YAP and TAZ transcriptional co-regulatory activity) in steroidogenic cells using an Nr5a1-cre strain (Lats1flox/flox;Lats2flox/flox;Nr5a1-cre). We report here that developing adrenocortical cells adopt characteristics of myofibroblasts in both male and female Lats1flox/flox;Lats2flox/flox;Nr5a1-cre mice, resulting in a loss of steroidogenic gene expression, adrenal failure and death by 2 to 3 weeks of age. A marked accumulation of YAP and TAZ in the nuclei of the myofibroblast-like cell population with an accompanying increase in the expression of their transcriptional target genes in the adrenal glands of Lats1flox/flox;Lats2flox/flox;Nr5a1-cre animals suggested that the myofibroblastic differentiation could be attributed in part to YAP and TAZ. Taken together, our results suggest that Hippo signaling is required to maintain proper adrenocortical cell differentiation and suppresses their differentiation into myofibroblast-like cells.

Marie Le Gad Le Roy

Papers

Targeted Disruption of Lats1 and Lats2 in Mice Impairs Adrenal Cortex Development and Alters Adrenocortical Cell Fate