A ZNRF3-dependent Wnt/ß-catenin signaling gradient is required for adrenal homeostasis.

Spatiotemporal control of Wnt signaling is essential for the development and homeostasis of many tissues. The transmembrane E3 ubiquitin ligases ZNRF3 (zinc and ring finger 3) and RNF43 (ring finger protein 43) antagonize Wnt signaling by promoting degradation of frizzled receptors. ZNRF3 and RNF43 are frequently inactivated in human cancer, but the molecular and therapeutic implications remain unclear. Here, we demonstrate that adrenocortical-specific loss of ZNRF3, but not RNF43, results in adrenal hyperplasia that depends on Porcupine-mediated Wnt ligand secretion. Furthermore, we discovered a Wnt/ß-catenin signaling gradient in the adrenal cortex that is disrupted upon loss of ZNRF3. Unlike ß-catenin gain-of-function models, which induce high Wnt/ß-catenin activation and expansion of the peripheral cortex, ZNRF3 loss triggers activation of moderate-level Wnt/ß-catenin signaling that drives proliferative expansion of only the histologically and functionally distinct inner cortex. Genetically reducing ß-catenin dosage significantly reverses the ZNRF3-deficient phenotype. Thus, homeostatic maintenance of the adrenal cortex is dependent on varying levels of Wnt/ß-catenin activation, which is regulated by ZNRF3.

Regulation of Proliferative Processes in Rat Adrenal Cortex by Transcriptional Factor PRH under Conditions of Developmental Exposure to Endocrine Disruptor DDT.

The effects of endocrine disrupters of transcriptional control of morphogenesis are poorly studied. Changes in the expression of transcriptional factor PRH and proliferation of adrenal cortical cells were analyzed in pubertal and postpubertal rats exposed prenatally and postnatally to low doses of endocrine disrupter DDT. In rats exposed to DDT, the expression of PRH and proliferation of adrenal cortical cells differed from those in control rats. Association between these parameters was weakened in the zona glomerulosa and zona reticularis and was absent in the zona fasciculata. These findings suggest that exposure to DDT in pre- and postnatal periods impairs the regulation of proliferative processes by transcriptional factor PRH in all zones of rat adrenal cortex, which can be a mechanism of the disruptive action of DDT.

Aging-related impairment of urine-concentrating mechanisms correlates with dysregulation of adrenocortical angiotensin type 1 receptors in male Fischer rats.

To investigate age-associated impairments in fluid homeostasis, 4-mo (young) and 32-mo (old) Fischer 344/BN male rats were studied before and after a dietary sodium load. Transferring young rats from a low-sodium (LS) to a high-sodium (HS) diet increased water intake and urine volume by 1.9- and 3.0-fold, respectively, while urine osmolality and plasma aldosterone decreased by 33 and 98%. Concomitantly, adrenocortical angiotensin type 1 receptor (AT1R) density decreased by 35%, and AT1bR mRNA decreased by 39%; no changes were observed in AT1aR mRNA. In contrast, the increase in water intake (1.4-fold) was lower in the old rats, and there was no effect of the HS diet on urine volume or urine osmolality. AT1R densities were 29% less in the old rats before transferring to the HS diet, and AT1R densities were not reduced as rapidly in response to a HS diet compared with the young animals. After 6 days on the HS diet, plasma potassium was lowered by 26% in the old rats, whereas no change was detected in the young rats. Furthermore, while plasma aldosterone was substantially decreased after 2 days on the HS diet in both young and old rats, plasma aldosterone was significantly lower in the old compared with the young animals after 2 wk on the LS diet. These findings suggest that aging attenuates the responsiveness of the adrenocortical AT1R to a sodium load through impaired regulation of AT1bR mRNA, and that this dysregulation contributes to the defects in water and electrolyte homeostasis observed in aging.

Insulin and IGF1 receptors are essential for XX and XY gonadal differentiation and adrenal development in mice.

Mouse sex determination provides an attractive model to study how regulatory genetic networks and signaling pathways control cell specification and cell fate decisions. This study characterizes in detail the essential role played by the insulin receptor (INSR) and the IGF type I receptor (IGF1R) in adrenogenital development and primary sex determination. Constitutive ablation of insulin/IGF signaling pathway led to reduced proliferation rate of somatic progenitor cells in both XX and XY gonads prior to sex determination together with the downregulation of hundreds of genes associated with the adrenal, testicular, and ovarian genetic programs. These findings indicate that prior to sex determination somatic progenitors in Insr;Igf1r mutant gonads are not lineage primed and thus incapable of upregulating/repressing the male and female genetic programs required for cell fate restriction. In consequence, embryos lacking functional insulin/IGF signaling exhibit (i) complete agenesis of the adrenal cortex, (ii) embryonic XY gonadal sex reversal, with a delay of Sry upregulation and the subsequent failure of the testicular genetic program, and (iii) a delay in ovarian differentiation so that Insr;Igf1r mutant gonads, irrespective of genetic sex, remained in an extended undifferentiated state, before the ovarian differentiation program ultimately is initiated at around E16.5.

3ßHSD and CYB5A double positive adrenocortical cells during adrenal development/aging.

Androstenedione is a common precursor of sex steroids produced and secreted in the human adrenal gland and produced by 3ß-hydroxysteroid dehydrogenase (3ßHSD), 17ß-hydroxylase/17,20-lyase (CYP17) and cytochrome b5 (CYB5A). 3ßHSD is expressed in the zona glomerulosa (ZG) and fasciculata (ZF), CYP17 in the ZF and zona reticularis (ZR) and CYB5A in the ZR, respectively. We previously demonstrated the presence of cortical parenchymal cells co-expressing 3ßHSD and CYB5A with hybrid features of both ZF and ZR in human adrenal cortex and hypothesized that these cells may play an important role in androstenedione production in human adrenal gland. Age-related morphologic development of these hybrid cells has, however, not been studied. Therefore, in this study, 48 human adrenal specimens from various age groups were retrieved. Double-immunohistochemical analyses were used in order to study the correlation between this hybrid cell type and age. In both male and female adrenal cortex, the means of total adrenocortical area, the area positive for CYB5A and its ratio reached highest peak in the 21-40-year-old (y.o.) group. The greatest overlap between 3ßHSD and CYB5A in both total and relative area was present in the 13-20 y.o. group. For all the markers mentioned above, statistically significant differences were detected among the different age groups examined (p < 0.05). These findings indicated that both area and ratio of 3ßHSD and CYB5A double positive cells, which could represent the hybrid cells of ZF and ZR, are correlated with human adrenal development and could subsequently influence age-related serum androstenedione levels.

Functional zonation of the rat adrenal cortex: the development and maintenance.

The adrenal cortex of mammals consists of three concentric zones, i.e., the zona glomerulosa (zG), the zona fasciculata (zF), and the zona reticularis (zR), which secrete mineralocorticoids, glucocorticoids, and adrenal androgens, respectively. In 1994, we identified immunohistochemically a new zone between zG and zF of the rat adrenal gland. The zone appeared to be devoid of any significant endocrine functions specific to adrenocortical zones, therefore, we designated the zone as "undifferentiated cell zone (zU)". Further, BrdU (5-bromo-2'-deoxyuridine)-incorporating cells (cells in S-phase) were concentrated at the outer region and the inner region of zU, and these cells proliferated and migrated bidirectionally: toward zG centrifugally and toward zF centripetally. We proposed that cells in and around zU are stem/progenitor cells of the rat adrenal cortex, maintaining functional zonation of the adrenal cortex. The view is consistent with observations reported recently that Sonic hedgehog (Shh), an important factor in embryonic development and adult stem cell maintenance, exists in zU of the rat adrenal gland and the Shh-containing cells seem to migrate bidirectionally.

Shh signaling regulates adrenocortical development and identifies progenitors of steroidogenic lineages.

The adrenal cortex is a critical steroidogenic endocrine tissue, generated at least in part from the coelomic epithelium of the urogenital ridge. Neither the intercellular signals that regulate cortical development and maintenance nor the lineage relationships within the adrenal are well defined. We have explored adrenal Shh activity and found that Shh is expressed in relatively undifferentiated steroidogenic cells, which signal to the overlying capsule and subjacent nonsteroidogenic mesenchyme cells that we also find are progenitors of steroidogenic lineages. Shh-expressing cells also generate all steroidogenic cell types, but not nonsteroidogenic ones. Shh mutant adrenals have a thin capsule and small cortex. Our findings both support a novel dual lineage, Shh-independent and Shh-dependent, model of adrenocortical development, and identify distinct populations of adrenocortical progenitor and candidate stem cells.

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

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 highlight the advances made, using transgenic mouse models, to delineate the molecular mechanisms regulating these processes.

Adrenal medulla development and medullary-cortical interactions.

The mammalian adrenal gland is composed of two distinct tissue types in a bidirectional connection, the catecholamine-producing medulla derived from the neural crest and the mesoderm-derived cortex producing steroids. The medulla mainly consists of chromaffin cells derived from multipotent nerve-associated descendants of Schwann cell precursors. Already during adrenal organogenesis, close interactions between cortex and medulla are necessary for proper differentiation and morphogenesis of the gland. Moreover, communication between the cortex and the medulla ensures a regular function of the adult adrenal. In tumor development, interfaces between the two parts are also common. Here, we summarize the development of the mammalian adrenal medulla and the current understanding of the cortical-medullary interactions under development and in health and disease.

ff1b, the SF1 ortholog, is important for pancreatic islet cell development in zebrafish.

The adrenal cortex and pancreatic islets have endocrine functions, producing steroid-based hormones and insulin, respectively. Cells of the adrenal cortex originate in the mesoderm while the cells of pancreatic islets originate in the endoderm. The zebrafish is a powerful model for understanding organ development due to its ease of genetic and molecular manipulation, transparent embryos, and large number of progeny for statistically powerful experiments. Like humans, the zebrafish pancreas has both exocrine and endocrine functions; unlike humans, there is only one endocrine islet cell group, instead of multiple islets. Using an eGFP-transgenic line of zebrafish, we have observed that the steroidogenic factor 1 (SF1) ortholog, ff1b, which is critical for adrenal cortex development and function in the zebrafish, is also implicated in zebrafish pancreatic islet development. We show that interruption of ff1b expression using an ff1b-morpholino (MO) disrupts development of insulin expressing cells. We conclude that ff1b-MO alters pancreatic islet development in zebrafish, demonstrating the utility of the zebrafish as a model for studying pancreatic development. This work is consistent with previous studies in mouse and human that have suggested SF1 participates in the vascular and ductal development of the pancreas, and disruption of SF1 function leads to abnormal development of the pancreatic islets due to poor vascularization.

Embryonic Development and Adult Regeneration of the Adrenal Gland.

The adrenal gland plays a pivotal role in an organism's health span by controlling the endocrine system. Decades of research on the adrenal gland have provided multiscale insights into the development and maintenance of this essential organ. A particularly interesting finding is that founder stem/progenitor cells participate in adrenocortical development and enable the adult adrenal cortex to regenerate itself in response to hormonal stress and injury. Since major advances have been made in understanding the dynamics of the developmental process and the remarkable regenerative capacity of the adrenal gland, understanding the mechanisms underlying adrenal development, maintenance, and regeneration will be of interest to basic and clinical researchers. Here, we introduce the developmental processes of the adrenal gland and discuss current knowledge regarding stem/progenitor cells that regulate adrenal cortex remodeling and regeneration. This review will provide insights into the fascinating ongoing research on the development and regeneration of the adrenal cortex.

Triphenyltin chloride reduces the development of rat adrenal cortex during puberty.

Triphenyltin has been classified as an endocrine disruptor. However, whether triphenyltin interferes with the adrenal glands during puberty remains unknown. Here, we reported the effects of triphenyltin on the adrenal glands in rats. Male Sprague Dawley rats (age of 35 days) were orally administered with 0, 0.5, 1, or 2 mg/kg/day triphenyltin for 18 days. Triphenyltin significantly lowered corticosterone levels at 1 and 2 mg/kg and adrenocorticotropic hormone at 2 mg/kg. The RNA-Seq analysis detected multiple differentially expressed genes. Four down-regulated genes were transcription factor genes (Nr4a1, Nr4a2, Nr4a3, and Ppard), which might be associated with the suppression of the adrenal cortex function. RNA-seq and qPCR showed that triphenyltin dose-dependently down-regulated the expression of the genes for cholesterol transport and biosynthesis, including Scarb1, Ldlr, Hmgcs1, Hmgcr, and Hsd17b7. Further Western blotting revealed that it lowered NR4A1, PPRAD, LDLR, and HMGCS1 protein levels. We treated H295R adrenal cells with 1-100 nM triphenyltin for 72 h. Triphenyltin induced significant higher ROS production at 100 nM and did not induce apoptosis at 10 and 100 nM. In conclusion, triphenyltin inhibits production of corticosterone via blocking the expression of cholesterol uptake transporters and cholesterol biosynthesis.

Targeted disruption of Sonic Hedgehog in the mouse adrenal leads to adrenocortical hypoplasia.

Development of the mammalian adrenal gland is regulated by a diverse network of growth and transcription factors. Disruptions in these pathways often result in adrenal insufficiency because of adrenal hypoplasia. Several lines of evidence have suggested that the Hedgehog signaling pathway, which controls many aspects of tissue and organ patterning, may play a direct role in adrenal morphogenesis as well. Therefore, we examined the role of Sonic Hedgehog (Shh), a member of the Hedgehog family, in mouse adrenal development. We show that Shh and its downstream effectors Gli1, Gli2, and Gli3 are expressed in the adrenal cortex throughout development, and that Shh is required for normal adrenal organogenesis. Conditional inactivation of Shh in the adrenal cortex using a Cre-loxP system resulted in severe hypoplasia and disorganization of the cortex. In mice carrying the targeted mutation (Shh(fl/fl;SF-1/Cre+)), adrenal mass was significantly reduced and the cortex failed to encapsulate the adrenal medulla. Taken together, these results establish a direct role for Shh signaling in normal adrenal development.

Prolonged zidovudine administration induces a moderate increase in the growth and steroidogenic capacity of the rat adrenal cortex.

Zidovudine (AZT) is an antiretroviral drug widely used in the treatment of human immunodeficiency virus (HIV)-infected patients, whose prolonged administration was found to cause toxic lesions in cardiomyocytes in humans and experimental animals. Alterations in adrenocortical secretion were frequently observed in HIV patients, but it is not clear whether medication is involved in the production of these complications. Hence, we studied in vivo and in vitro, the effects of AZT on the rat adrenal cortex. The prolonged AZT administration (100 mg/kg per day for 4 months) did not cause overt qualitative morphological alterations of adrenocortical cells, which, however, underwent a net hypertrophy. Hypertrophy is associated with increases in the volume and surface area per cell of the mitochondrial compartment and smooth endoplasmic reticulum (where the enzymes of steroid synthesis are located), and a marked decrease in the volume of the lipid-droplet compartment (where cholesterol and its esters, the precursors of steroid hormones, are stored). AZT chronic treatment induced rises in the plasma concentrations of aldosterone and corticosterone, and in the basal and ACTH-stimulated in vitro secretion of these hormones from adrenal slices. The 24-h exposure to AZT (10(-5) M) did not significantly affect either secretory activity or proliferation and apoptotic rates of cultured rat adrenocortical cells. Taken together, these findings suggest that AZT chronic treatment enhances the growth and steroidogenic capacity of rat adrenal cortex, probably by activating the central branch of the hypothalamic-pituitary-adrenal axis. The toxic activity of AZT is thought to depend on increased production of ROS. On these grounds, it is likely that the lack of toxic effect of AZT on adrenocortical cells is due to their very elevated content in vitamin C, which prevents the deleterious effect of the AZT-induced increase in intracellular ROS production.

Neuromedin U enhances proliferation of ACTH-stimulated adrenocortical cells in the rat.

Neuromedin U (NMU) is a brain-gut peptide involved in the regulation of the hypothalamic-pituitary-adrenal axis and adrenocortical cell proliferation. In this study, we investigated the effects of NMU8 (three subcutaneous injections of 6.0 nmol/100 g, 24, 16 and 8 h before autopsy) on the adrenal glands of rats treated for 2 or 4 days with a low (2 microg/100 g body weight/24 h) or a high (8 microg) dose of adrenocorticotropic hormone (ACTH). As revealed by RT-PCR, ACTH treatment did not prevent expression of NMUR1 in rat adrenal cortex. At day 4 of ACTH administration, the weight of adrenals was lower than at day 2. NMU8 administration prevented ACTH-induced increases of adrenal weight at day 2 of the experiment. ACTH plasma concentrations were increased in all ACTH-administered rats. NMU8 administration increased ACTH plasma concentration at day 2 of the lower ACTH dose-treated group while it reduced the ACTH plasma level at day 4 in the higher ACTH dose-administered rats. In all groups of ACTH-treated rats, NMU8 changed neither aldosterone nor corticosterone plasma concentrations. In the zona glomerulosa (ZG), NMU8 increased metaphase index at days 2 and 4 in the lower ACTH dose-treated group and had no statistically significant effect in rats treated with the higher ACTH dose. In the zona fasciculata (ZF), NMU8 administration increased metaphase index at day 2 in the lower ACTH dose-treated group but reduced metaphase index at day 4 in the higher dose ACTH-administered rats. NMU8 reduced the number of cells per unit area both in ZG and ZF at day 2 in the higher ACTH dose-treated rats. In the remaining groups NMU8 did not produce statistically significant changes in the number of cells per unit area. Thus, our findings demonstrate that exogenous NMU may stimulate proliferation primarily of the cortical ZG cells in rats administered with ACTH, although at high doses of exogenous corticotropin an opposite effect occurred.

Trajectories of maternal depressive symptoms over her child's life span: relation to adrenocortical, cardiovascular, and emotional functioning in children.

Maternal depression has a number of adverse effects on children. In the present study, maternal depressive symptoms were assessed (using the Center for Epidemiological Studies Depression Scale) when their child was 3 months, 6 months, 1 year, 2 years, 4.25 years, 6 years, 7 years, 8 years, and 10 years of age. At 9.5 years of age, children's (94 females, 82 males) depressive symptoms as well as cardiovascular and cortisol levels during baseline and two psychologically stressful tasks were measured. Using multilevel modeling, maternal depressive symptom trajectories were considered in relation to their child's adrenocortical and cardiovascular responses to acute stress. Our goal was to determine maternal depressive symptom trajectories for children with elevated cardiovascular and cortisol reactivity to acute stress and elevated depressive symptoms. In general, those mothers with chronically elevated depressive symptoms over their child's life span had children with lower initial cortisol, higher cardiac output and stroke volume in response to acute stress, lower vascular resistance during acute stress tasks, and significantly more depressive symptoms at 9.5 years of age. These results are discussed in the context of established associations among hypothalamic-pituitary-adrenal axis dysregulation, depression, and cardiovascular disease.

Developmental and functional biology of the primate fetal adrenal cortex.

The unique characteristics of the primate (particularly human) fetal adrenal were first realized in the early 1900s when its morphology was examined in detail and compared with that of other species. The unusual architecture of the human fetal adrenal cortex, with its unique and disproportionately enlarged fetal zone, its compact definitive zone, and its dramatic remodeling soon after birth captured the interest of developmental anatomists. Many detailed anatomical studies describing the morphology of the developing human fetal adrenal were reported between 1920 and 1960, and these morphological descriptions have not changed significantly. More recently, it has become clear that fetal adrenal cortical growth involves cellular hypertrophy, hyperplasia, apoptosis, and migration and is best described by the migration theory, i.e. cells proliferate in the periphery, migrate centripetally, differentiate during their migration to form the functional cortical zones, and then likely undergo apoptosis in the center of the cortex. Consistent with this model, cells of intermediate phenotype, arranged in columnar cords typical of migration, have been identified between the definitive and fetal zones. This cortical area has been referred to as the transitional zone and, based on the expression of steroidogenic enzymes, we consider it to be a functionally distinct cortical zone. Elegant experiments during the 1950s and 1960s demonstrated the central role of the primate fetal adrenal cortex in establishing the estrogenic milieu of pregnancy. Those findings were among the first indications of the function and physiological role of the human fetal adrenal cortex and led Diczfalusy and co-workers to propose the concept of the feto-placental unit, in which DHEA-S produced by the fetal adrenal cortex is used by the placenta for estrogen synthesis. Tissue and cell culture techniques, together with improved steroid assays, revealed that the fetal zone is the primary source of DHEA-S, and that its steroidogenic activity is regulated by ACTH. In recent years, function of the human and rhesus monkey fetal adrenal cortical zones has been reexamined by assessing the localization and ontogeny of steroidogenic enzyme expression. The primate fetal adrenal cortex is composed of three functionally distinct zones: 1) the fetal zone, which throughout gestation does not express 3 beta HSD but does express P450scc and P450c17 required for DHEA-S synthesis; 2) the transitional zone, which early in gestation is functionally identical to the fetal zone but late in gestation (after 25-30 weeks) expresses 3 beta HSD, P450scc, and P450c17, and therefore is the likely site of glucocorticoid synthesis, and 3) the definitive zone, which lacks P450c17 throughout gestation but late in gestation (after 22-24 weeks) expresses 3 beta HSD and P450scc, and therefore is the likely site of mineralocorticoid synthesis. Indirect evidence, based on effects of P450c21 deficiency and maternal estriol concentrations, indicate that the fetal adrenal cortex produces cortisol and DHEA-S early in gestation (6-12 weeks). However, controversy exists as to whether cortisol is produced de novo or derived from the metabolism of progesterone, as data regarding the expression of 3 beta HSD in the fetal adrenal cortex early in gestation are conflicting. During the 1960s, Liggins and colleagues demonstrated that in the sheep, cortisol secreted by the fetal adrenal cortex late in gestation regulates maturation of the fetus and initiates the cascade of events leading to parturition. Those pioneering discoveries provided insight into the mechanism underlying the timing of parturition and therefore were of particular interest to obstetricians and perinatologists confronted with the problems of preterm labor. However, although cortisol emanating from the fetal adrenal cortex promotes fetal maturation in primates as it does in sheep, its role in the regulation of primate parturition, unlike that in sheep

Adrenal gland development and defects.

The network regulating human adrenal development is complex. Studies of patients with adrenal insufficiency due to gene mutations established a central role for transcription factors GLI3, SF1 and DAX1 in the initial steps of adrenal formation. Adrenal differentiation seems to depend on adrenocorticotropic hormone (ACTH) stimulation and signalling, including biosynthesis and action of POMC, PC1, TPIT, MC2R, MRAP and ALADIN, all of which cause adrenocortical hypoplasia when mutated in humans. Studies of knockout mice revealed many more factors involved in adrenal development; however, in contrast to rodents, in humans several of those factors had no adrenal phenotype when mutated (e.g. WT1, WNT4) or, alternatively, human mutations have not (yet) been identified. Tissue profiling of fetal and adult adrenals suggested 69 genes involved in adrenal development. Among them were genes coding for steroidogenic enzymes, transcription and growth factors, signalling molecules, regulators of cell cycle and angiogenesis, and extracellular matrix proteins; however, the exact role of most of them remains to be elucidated.

Effects of neuromedin-U on immature rat adrenocortical cells: in vitro and in vivo studies.

Neuromedin U (NMU) is a brain-gut peptide, that in the peripheral organs and tissues acts via a G protein-coupled receptor, called NMUR1. Reverse transcription-polymerase chain reaction showed the expression of NMUR1 mRNA in either cortex and medulla or dispersed zona glomerulosa and zona fasciculata-reticularis cells of the immature rat adrenals. Accordingly, immunocytochemistry demonstrated the presence of NMUR1-like immunoreactivity in the cortex and medulla of immature adrenals. NMU8 administration to immature rats was found to raise aldosterone, but not corticosterone, plasma concentration, without altering adrenal growth. Conversely, the exposure to NMU8 markedly enhanced the proliferative activity of immature rat inner adrenocortical cells in primary in vitro culture, without significantly affecting their corticosterone secretion. Collectively, our findings suggest that adrenals of immature rats may be a target for circulating NMU. However, the physiological significance and relevance of the adrenal effects of NMU remain to be ascertained.

The human adrenal cortex: growth control and disorders.

This review summarizes key knowledge regarding the development, growth, and growth disorders of the adrenal cortex from a molecular perspective. The adrenal gland consists of two distinct regions: the cortex and the medulla. During embryological development and transition to the adult adrenal gland, the adrenal cortex acquires three different structural and functional zones. Significant progress has been made in understanding the signaling and molecules involved during adrenal cortex zonation. Equally significant is the knowledge obtained regarding the action of peptide factors involved in the maintenance of zonation of the adrenal cortex, such as peptides derived from proopiomelanocortin processing, adrenocorticotropin and N-terminal proopiomelanocortin. Findings regarding the development, maintenance and growth of the adrenal cortex and the molecular factors involved has improved the scientific understanding of disorders that affect adrenal cortex growth. Hypoplasia, hyperplasia and adrenocortical tumors, including adult and pediatric adrenocortical adenomas and carcinomas, are described together with findings regarding molecular and pathway alterations. Comprehensive genomic analyses of adrenocortical tumors have shown gene expression profiles associated with malignancy as well as methylation alterations and the involvement of miRNAs. These findings provide a new perspective on the diagnosis, therapeutic possibilities and prognosis of adrenocortical disorders.