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Division of Metabolism, Endocrinology, and Metabolism (G.D.H.), Departments of Internal Medicine and Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan 48109-0678; Departments of Internal Medicine and Pharmacology (K.L.P.), University of Texas Southwestern Medical Center, Dallas, Texas 75390; and Banting and Best Department of Medical Research (B.P.S.), University of Toronto, Toronto, Ontario, Canada M5G 1L6
Address all correspondence to: Gary D. Hammer, Division of Metabolism, Endocrinology, and Metabolism, Departments of Internal Medicine and Molecular and Integrative Physiology, University of Michigan, 1150 West Medical Center Drive, Ann Arbor, Michigan 48109-0678. E-mail: ghammer{at}med.umich.edu.
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 Top Abstract Embryology and Differentiation...Transcription Factors that...Gene Interactions in Adrenal...Genetic Defects of...Intrauterine Growth Retardation,...Summary and PerspectivesReferences |
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Embryology and Differentiation of the Adrenal Gland |
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TopAbstractEmbryology and Differentiation...Transcription Factors that...Gene Interactions in Adrenal...Genetic Defects of...Intrauterine Growth Retardation,...Summary and PerspectivesReferences |
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; reviewed in Ref. 1). The adrenal cortex arises from a common adrenogonadal precursor lineage in the intermediate mesoderm that also gives rise to the steroid-secreting cells of the gonads (2). In human embryos, these adrenogonadal progenitors first appear in the fourth week of gestation as a thickening of the coelomic epithelium between the urogenital ridge and the dorsal mesentery (3). Cells destined to generate the adrenal cortex migrate to the cranial pole of the mesonephros, forming the adrenal primordium by the eighth week of gestation. This rudimentary adrenal gland contains an inner cluster of large, eosinophilic cells, termed the fetal zone, that express the steroidogenic enzyme 17
-hydroxylase (CYP17). Shortly thereafter, a second group of cells develops to form a densely packed, outer zone of cells that lack CYP17 expression, the definitive zone (1). The large mass of the fetal zone and its expression of the cholesterol side-chain cleavage enzyme (CYP11A) and CYP17, but not 3ß-hydroxysteroid dehydrogenase, dictate that the fetal adrenal produces primarily dehydroepiandrosterone and its sulfated derivative; these compounds serve as precursors for placental-derived estradiol, which is critical for sustaining pregnancy (1).
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After birth, significant remodeling of the adrenal gland occurs; the medullary islands coalesce to form a rudimentary medulla, the fetal zone regresses by the third postnatal month, and the definitive zone of the human adrenal cortex forms discrete functional compartments (the outer zona glomerulosa, the middle zona fasciculata, and the inner zona reticularis) (1). The zona glomerulosa, derived from the definitive zone, acquires steroidogenic capacity in the third trimester and produces aldosterone under control of the renin-angiotensin system. It has been proposed that the other two zones may arise from a transitional region of the fetal adrenal cortex that has characteristics intermediate between the fetal and definitive zones, but definitive lineage analyses are lacking. Regardless of their origins, the zona fasciculata secretes glucocorticoids under the regulation of ACTH by 15 wk of gestation, whereas the zona reticularis in humans secretes dehydroepiandrosterone and its sulfated derivative in response to the hormone. The levels of these adrenal androgens decline as the fetal zone regresses and then rise during childhood coincident with adrenarche.
The origin of the adrenocortical zones and the regulation of their proliferation are incompletely understood (reviewed in Ref. 5). After unilateral adrenalectomy, increased proliferation occurs predominantly just under the capsule. Such studies have been incorporated into cell migration models of adrenocortical zonation, one of which proposes that a precursor population differentiates first into zona glomerulosa cells and then changes its phenotype as it migrates centripetally into the zona fasciculata and then the zona reticularis. Analyses of the expression pattern of a steroid 21-hydroxylase (CYP21)-ß-galactosidase transgene have been interpreted to support this cell migration model (6). A second model predicts a population of undifferentiated stem cells that reside between the zona glomerulosa and zona fasciculata and that are characterized by the absence both the inner zone-specific isozyme of steroid 11ß-hydroxylase (CYP11B1) and the outer zone isozyme aldosterone synthase (CYP11B2) (7). According to this model, these putative stem cells represent a common precursor population that can contribute to either outer or inner cortical zones.
Cholesterol is the obligate precursor for the biosynthesis of all steroid hormones, and the pathways in all three zones share many components (8). Among these are the steroidogenic acute regulatory protein, which facilitates cholesterol transfer to the inner mitochondrial membrane, cholesterol side-chain cleavage enzyme (CYP11A), the type 2 isozyme of 3ß-hydroxysteroid dehydrogenase, and CYP21. Despite these shared components, the activities of certain key enzymes that catalyze terminal reactions in the steroid biosynthetic pathway permits the zones to produce different steroid products. CYP11B2 is expressed exclusively in the outer zona glomerulosa and carries out three successive reactions that convert corticosterone to aldosterone. The closely related isozyme, CYP11B1, is expressed in the inner zones and hydroxylates 11-deoxycortisol to produce cortisol, the predominant glucocorticoid in human beings. In humans, the inner zones of the human adrenal cortex also express CYP17, which is required for the biosynthesis of cortisol and adrenal androgens but is not used in aldosterone synthesis.
Knockout mice have provided unique insights into adrenal development, and we therefore discuss briefly distinctive features of the mouse adrenal cortex (Fig. 1
). Although the pattern of development differs somewhat from that in humans and other primates, the same genes likely regulate the basic developmental program in all mammalian species. Prenatal development occurs within a compressed period of approximately 3 wk, and mouse adrenals at birth are considerably less developed than their human counterparts. Similar to the developing human adrenal, the mouse adrenal gland possesses a transient zone between the cortex proper and the medulla, termed the X zone in mice. The X zone is first evident at approximately 10–14 d after birth and enlarges until 3 wk of age. In males, it degenerates by apoptosis at puberty, regressing completely by 38 d of age. In females, the X zone regresses via apoptosis during the first pregnancy. Studies suggest that X zone regression may be mediated by activin (9). Although many studies have sought to define a function of the X zone, its steroid products and functional roles remain poorly characterized. Unlike the human fetal zone, Cyp17 is expressed only transiently in the fetal mouse adrenal cortex, and adrenal androgens therefore are not produced.
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Transcription Factors that Mediate Key Events in Adrenal Development |
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Wilms’ tumor (WT) 1: a tumor suppressor gene that regulates adrenal development
WT1 is a zinc-finger protein that was isolated by positional cloning of a tumor suppressor gene involved in Wilms’ tumors, familial embryonic kidney tumors derived from the metanephric blastema (10, 11, 12). WT1 mutations are associated with congenital abnormalities of urogenital development (reviewed in Ref. 13), suggesting a developmental role for WT1. Consistent with this, WT1 is expressed very early during development of the urogenital ridge, and specific expression patterns occur in the developing kidneys, gonads, and adrenals (reviewed in Ref. 14).
WT1 is expressed during the earliest developmental stages of the adrenogonadal progenitors and thereafter is silenced in the adrenal primordium (but not in the genital ridge or kidney). Transgenic and gene knockout studies of wt1 first revealed its essential role in adrenal development. In addition to the renal and gonadal abnormalities predicted from studies of human beings (15), the wt1 knockout mice also lacked adrenal glands. Rescue experiments with a yeast artificial chromosome transgene containing human WT1 demonstrated a direct role for WT1 in adrenal development (16); this transgene prevented early embryonic death due to defects in the diaphragm and heart, revealing hypoplastic adrenal glands that minimally expressed CYP11A in the region in which adrenal glands normally develop.
Analyses of mice with isoform-specific disruption of wt1 have shown different roles for two alternatively spliced transcripts that encode proteins differing by the amino acids Lys-Thr-Ser and therefore designated the – and + KTS isoforms (17). Specific disruption of the –KTS isoform caused gonadal agenesis in both sexes, probably due to impaired steroidogenic factor (SF)-1 transcription. In contrast, selective inactivation of the +KTS isoform did not impair ovary development but rather impaired testis differentiation and male sex differentiation. These studies, which stand in contrast to the adrenal agenesis seen in mice lacking all Wt1 transcripts, argue that the two wt1 isoforms can complement each other in adrenal, but not gonadal, development.
Mechanistic insight into the role of WT1 in differentiation of the adrenogonadal precursors, and presumably for adrenal development, emerged from additional studies of the wt1 knockout (KO) mice (18). In situ hybridization studies showed that expression of the orphan nuclear receptor SF-1 was markedly decreased in wt1 KO mice. Furthermore, the –KTS isoform of wt1 activated the SF-1 promoter via specific promoter elements in cotransfection experiments. Finally, expression of a reporter plasmid with ß-galactosidase driven by the proximal 5'-flanking region of SF-1 was markedly decreased in wt1 KO mice. Collectively, these findings support a hierarchical model in which WT1 contributes to gonadal (and perhaps adrenal) development by inducing the expression of SF-1 in the early adrenogonadal precursor lineage. Studies in the gonads also suggest that WT1 and SF-1 interact synergistically via protein-protein interactions to regulate key genes in the sex differentiation cascade such as anti-Mullerian hormone (19). Similar interactions are unlikely to contribute to adrenal function, however, because WT1 is silenced before the onset of expression of the target genes that comprise the differentiated adrenocortical phenotype.
SF-1
SF-1 (officially designated NR5A1) is an orphan member of the nuclear receptor family that was first identified because it regulated the activities of the proximal promoter regions of several cytochrome P450 steroid hydroxylases in steroidogenic cell lines. Subsequently many laboratories showed that SF-1 acts at multiple levels of the hypothalamic-pituitary-steroidogenic organ axis to regulate the expression of a diverse array of genes that mediate steroidogenesis and reproduction (reviewed in Refs. 20 and 21).
SF-1 is expressed from the earliest stages of human adrenal development, first in the common adrenogonadal precursors and then in both the fetal and definitive zones of the adrenal cortex (3). KO mice lacking SF-1 dramatically illustrated its importance in adrenal development. Although the adrenal primordium formed in the absence of SF-1, subsequent events were interrupted by programmed cell death, leading to adrenal agenesis and postnatal death from adrenal insufficiency (22, 23). These observations suggest that SF-1 regulates the expression of genes that determine cell proliferation and apoptosis. Consistent with this model, heterozygous mice with one disrupted allele had decreased adrenocortical volume and impaired corticosterone synthesis (24, 25). The effect on adrenocortical size was most pronounced in utero, after which there was compensatory growth, perhaps related to enhanced expression of the orphan nuclear receptor NGFI-B/nur77 (26).
SF-1 KO mice also lacked gonads and had marked structural abnormalities of the ventromedial nucleus of the hypothalamus (27, 28), impaired pituitary gonadotropin expression (28, 29), and abnormal splenic parenchyma (30), revealing essential roles in multiple tissues, especially those related to reproduction.
Human subjects with SF-1 mutations have established a global importance of SF-1 in human endocrine development and function. The first subject presented with adrenal insufficiency and 46, XY sex reversal associated with bilateral gonadal dysgenesis (31). Intriguingly, this patient had one normal SF-1 allele, whereas the other allele contained a de novo missense mutation in the first zinc finger domain (G35E) that abolished DNA binding. The mutated protein did not affect activity of wild-type SF-1 in cotransfection experiments, and it therefore was proposed that the phenotype reflected haploinsufficiency of SF-1 rather than a dominant-negative effect. The second subject, who also apparently had one normal SF-1 allele and one allele with a missense mutation (R255L), had a 46, XX karyotype with apparently normal ovaries on magnetic resonance imaging scan in association with adrenal insufficiency (32). A third human subject had impaired adrenal function and 46, XY sex reversal due to a homozygous mutation in an accessory DNA binding domain (R92Q) that diminished but did not abolish function (33). Most recently individuals with gonadal dysgenesis but normal adrenocortical function have been described by two groups, due in one case to an 8-bp deletion in the ligand binding region that truncates the protein (34) and in the second case to an early nonsense mutation, C16X (35); these latter mutations expand considerably the spectrum of clinical disorders caused by SF-1 mutations.
Dosage-sensitive sex reversal, adrenal hypoplasia congenita, X-linked (DAX)-1 and adrenal hypoplasia congenita (AHC)
DAX-1 (officially designated NR0B1) is another orphan nuclear receptor whose roles in adrenal development were first revealed by patients with DAX-1 mutations leading to the X-linked disorder AHC. Patients with AHC generally present in infancy with manifestations of primary adrenal insufficiency (e.g. salt wasting, hypoglycemia). Histologically, their adrenal glands are hypoplastic, with an absence or near absence of the adult zones and a poorly organized fetal zone with enlarged (cytomegalic), eosinophilic cells (36).
The gene responsible for AHC gene mapped at Xp22 and was positionally cloned and designated DAX1 (37, 38). DAX-1 encodes an atypical nuclear hormone receptor that contains the conserved ligand-binding domain but lacks the typical zinc finger DNA-binding motif. Additional complexity is suggested by the finding that alternative splicing may generate a second DAX-1 isoform (39). DAX1 contains three copies of a novel 67- to 69-amino acid repeat that alternatively has been reported to bind DNA (40) or polyadenylated RNA (41). To date, missense mutations that impair DAX-1 function have mapped exclusively to the C-terminal ligand-binding domain rather than to the novel repeats. Many of these human mutations abolish the ability of DAX-1 to repress SF-1-mediated transcription, suggesting that a functional antagonism between these two orphan receptors may be important for adrenal development (42, 43). Other studies, however, suggest that DAX-1 also can inhibit the function of other nuclear receptors (44, 45), adding complexity to a full understanding of its potential roles in endocrine development.
The cloning of DAX-1 and the ability to identify additional members with DAX-1 mutations among families of AHC patients have revealed expanded functions of DAX-1 (46). For example, AHC patients at the time of normal puberty exhibit features of hypogonadotrophic hypogonadism due to a compound hypothalamic-pituitary defect, whereas female carriers of DAX-1 mutations sometimes present with delayed puberty. Like SF-1, DAX-1 is expressed not only in the adrenal primordium from its earliest stages of development but also in developing gonads, pituitary gonadotropes, and the ventromedial hypothalamic nucleus (47, 48). These concordant expression patterns very likely reflect that fact that that SF-1 positively regulates the expression of DAX-1 at these sites (49, 50, 51).
DAX-1 appears to play a more modest role in the mouse adrenal cortex. In Dax-1 KO mice (52), spermatogenesis was impaired despite apparently normal levels of gonadotropins, suggesting a distinct role for DAX1 in sperm development. Subsequent analyses have suggested that Dax-1 is also essential for testis differentiation and testis cord formation (53, 54). Surprisingly, these Dax1 KO mice did not exhibit manifestations of adrenal insufficiency, and the integrity of the adrenal cortex was largely intact (52). There were, however, some effects on the adrenal cortex. However, the X-zone in males failed to regress at the time of normal puberty, and Cyp11a expression in the zona fasciculata was decreased relative to wild-type controls. Moreover, the Dax-1 deficiency partially restored adrenocortical function in mice heterozygous mice for the SF-1 KO allele (55), suggesting that tonic inhibition of SF-1 by Dax-1 is an important part of normal adrenocortical function.
PBX1
A relatively recent addition to the list of transcription factors that regulate adrenocortical development is the homeobox protein PBX1. PBX1 is a three-amino acid loop extension homeodomain protein that is expressed in a number of cells of mesodermal origin and interacts with other transcription factors to regulate gene expression. Pbx1 was first implicated in adrenal function as a protein that regulated expression of CYP17 (56). Both Pbx1 and its binding partner Meis2 were expressed in mouse Y1 adrenocortical tumor cells and bound to the CRS-1 cAMP-responsive element in the 5'-flanking region of bovine CYP17. The recognition of its contributions to adrenal development came from analyses of Pbx1 KO mice. These Pbx1 KO mice, which die in utero due to defects in multiple organs, completely lacked adrenal glands and had impaired testes development associated with decreased proliferation in the urogenital ridges (57). In a manner reminiscent to that described above for WT1, SF-1 expression was markedly decreased in Pbx1 KO mice. These findings are consistent with a role for Pbx1 near the apex of a hierarchical transcriptional network that determines adrenal development.
cAMP response element binding protein-binding protein/p300-interacting transactivator with ED (glutamic-asparatic acid)-rich tail (CITED2)
Studies of transcriptional regulation have delineated complex interactions among the core transcriptional apparatus, sequence-specific transcription factors, and transcriptional coactivators and corepressors that help establish the proper context for transcription. Recent studies support an important developmental role for the coactivator Cited2, which was originally isolated by virtue of its ability to interact with the transcription factor activator protein-2. In addition to other defects in the heart and brain, KO mice lacking Cited2 were found to have adrenal agenesis (58). Although the transcription factors influenced by Cited2 remain unknown, this finding suggests that Cited2 coregulates genes that are essential for adrenal development.
WNT4
Wnt proteins are secreted glycoproteins that act via the frizzled receptor (FZD) family associated with the frizzled receptor coreceptor, low-density lipoprotein receptor-related protein-5 or -6 to initiate a canonical cascade of intracellular signals leading to ß-catenin accumulation in the nucleus and subsequent transcriptional activation of downstream target genes (59). In the absence of Wnt signaling, ß-catenin associates with a complex containing adenomatous polyposis coli, axin, and glycogen synthase kinase-3 leading to gly-cogen synthase kinase-3-mediated phosphorylation of ß-catenin and subsequent degradation by the proteosome. Whereas ß-catenin and the canonical WNT pathway have generally been viewed as acting via the T-cell transcription factor/Lef family of DNA binding proteins to facilitate transcription, recent evidence indicates that ß-catenin can directly bind and activate nuclear receptors, including SF-1 (60, 61).
WNTs have been shown to that play important roles in the development of a number of embryonic structures, including the adrenal cortex, kidney, pituitary, mammary gland, and female reproductive system. Wnt-4 is expressed at embryonic d 9.5 throughout the mesonephros and later is expressed in the adult mouse adrenal cortex. Disruption of Wnt-4 in mice causes a marked masculinization of XX females with absence of the female Mullerian duct and persistence of the male Wolffian duct-derivatives due to excess gonadal testosterone synthesis. Subsequent reports documented abnormal differentiation of the definitive zone in the adrenal gland in Wnt-4 KO mice (62) and ectopic expression of cells with a partial adrenal phenotype in XX gonads that is proposed to reflect abnormal cell migration of adrenal precursors into the structure (63).
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Gene Interactions in Adrenal Development |
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TopAbstractEmbryology and Differentiation...Transcription Factors that...Gene Interactions in Adrenal...Genetic Defects of...Intrauterine Growth Retardation,...Summary and PerspectivesReferences |
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Because WT1 is expressed only in the earliest adrenogonadal precursors, it has been difficult to demonstrate that direct interactions between SF-1 and WT1 are required for adrenocortical development. One report has suggested that WT1 is a direct upstream activator of SF-1 expression within the gonads. How these studies might apply to adrenocortical development is not yet known. As noted above, studies of gene expression in cell culture models also indicate that SF-1 and WT1 interact directly to activate the expression the gene encoding anti-Mullerian hormone (19). Similarly, it has been suggested that WT1, like SF-1, activates the expression of DAX-1 (66). Thus, it is plausible that SF-1 and WT1 interact at earliest stages of adrenogonadal development to permit the survival of cells that ultimately form the adrenal cortex.
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Genetic Defects of Adrenocortical Function Caused by Unknown Genes |
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TopAbstractEmbryology and Differentiation...Transcription Factors that...Gene Interactions in Adrenal...Genetic Defects of...Intrauterine Growth Retardation,...Summary and PerspectivesReferences |
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40% of mice died within 24 h of birth and all died by 10 wk of age). Mice presumptively homozygous for the acd mutation had low corticosterone and high ACTH levels, consistent with the model that they died from adrenocortical insufficiency. These findings led the authors to propose that mutations in the acd gene impair cellular proliferation in the adrenal cortex, with a secondary hypertrophy of cortical cells perhaps driven by the elevated ACTH levels. The locus responsible for adrenocortical dysplasia recently has been mapped to a relatively small region of mouse chromosome 8, suggesting that acd may soon be isolated by positional cloning (Hammer, G., unpublished observation). |
Intrauterine Growth Retardation, Metaphyseal Dysplasia, Adrenal Hypoplasia Congenita, Genital Anomalies (Image) |
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TopAbstractEmbryology and Differentiation...Transcription Factors that...Gene Interactions in Adrenal...Genetic Defects of...Intrauterine Growth Retardation,...Summary and PerspectivesReferences |
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Summary and Perspectives |
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TopAbstractEmbryology and Differentiation...Transcription Factors that...Gene Interactions in Adrenal...Genetic Defects of...Intrauterine Growth Retardation,...Summary and PerspectivesReferences |
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Footnotes |
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Abbreviations: acd, Adrenocortical dysplasia; AHC, adrenal hypoplasia congenita; CITED2, cAMP response element binding protein-binding protein/p300-interacting transactivator with ED (glutamic-asparatic acid)-rich tail; DAX, Dosage-sensitive sex reversal, adrenal hypoplasia congenita, X-linked; IMAGE, intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies; KO, knockout; SF, steroidogenic factor; WT, Wilms’ tumor.
Received October 21, 2004.
Accepted for publication November 15, 2004.
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TopAbstractEmbryology and Differentiation...Transcription Factors that...Gene Interactions in Adrenal...Genetic Defects of...Intrauterine Growth Retardation,...Summary and PerspectivesReferences |
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