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CRH-ACTH-POMC-ADRENAL |
Division of Endocrinology (B.J., J.L.J.), Metabolism and Molecular Medicine, Northwestern University Medical School, Chicago, Illinois 60611; and Internal Medicine and Physiology (P.S.B., D.L.B., F.B., S.S., G.D.H.), University of Michigan, Ann Arbor, Michigan 48109-0678
Address all correspondence and requests for reprints to: Gary D. Hammer, M.D., Ph.D., Assistant Professor, Internal Medicine and Physiology, University of Michigan 5560A MSRB II, 1150 West Medical Center Drive, Ann Arbor, Michigan 48109-0678. E-mail: ghammer{at}umich.edu
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Introduction |
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Molecular studies have suggested that Dax-1 may function either cooperatively or antagonistically with SF-1. Indeed, SF-1 consensus sites have been characterized in the Dax-1 promoter and transfected SF-1 apparently competes with the transcriptional repressor chicken ovalbumin upstream promoter for binding to the Dax-1 promoter, ultimately activating Dax-1 gene expression (14). However, Dax-1 gene expression is still maintained (albeit at low levels) in the adrenal primordia of SF-1 null mice (12). Additionally, in vitro studies have shown that the Dax-1 protein physically interacts with the SF-1 protein, can recruit the corepressor NCoR to the SF-1 complex, and results in repression of SF-1 dependent transcription (13, 16, 17, 18). The relative importance of these two different mechanisms (activation of Dax-1 gene expression by SF-1 vs. Dax-1 antagonism of SF-1-mediated transcription) in the regulation of adrenal organogenesis and steroidogenesis remains unknown. It is interesting that all of the Dax-1 mutations resulting in congenital adrenal hypoplasia fail to interact with NCoR and fail to repress SF-1-mediated transcription on synthetic promoters (16, 18). However, Dax-1-/Y mice have recently been shown to have baseline corticosterone levels identical to wild-type mice (19). This is different from many human Dax-1 mutations that result in significant cortisol deficiency due to hypoplasia/aplasia of the adrenal definitive zone, which gives rise to the zonated cortex of the adult. However, there is significant heterogeneity in the manifestations of adrenal insufficiency in these patients. While most patients are diagnosed in infancy with adrenal hypoplasia/aplasia, others present with adrenal insufficiency as late as adolescence. Additionally, a single female patient with a homozygous mutation in the Dax-1 gene has been described with no apparent adrenal insufficiency despite hypogonadotropic hypogonadism (20). Therefore, the lack of aplasia in Dax-1-/Y mice does not infer a lack of conserved Dax-1 function between mouse and human. This heterogeneity suggests multiple pleiotropic roles of Dax-1 in the developmental and steroidogenic programs of the gonad and adrenal cortex. The lack of a profound developmental defect in the definitive zone of Dax-1-/Y mice allowed us to study the role of Dax-1 in adrenal steroidogenesis without confounding aplasia that would preclude analysis of adrenal function in vivo. Therefore, to further explore how Dax-1 interacts with SF-1 in the adrenal cortex in vivo, we evaluated adrenal function in Dax-1-/Y mice in the genetic setting of SF-1+/- haplo-insufficiency under basal conditions and various stress paradigms. If Dax-1 is a repressor of SF-1 action, then breeding SF-1+/- haplo-insufficient mice to Dax-1-/Y null mice may ameliorate the effects of SF-1 deficiency. Using compound SF-1+/- haplo-insufficient: Dax-1-/Y null mice, we explored the in vivo role of Dax-1 in SF-1-mediated transcription. Our results support a model in which Dax-1 attenuates SF-1 mediated growth and steroidogenesis in the adrenal cortex, in vivo.
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Materials and Methods |
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), grouped as Dax-1-/Y, wild-type, compound SF-1+/-: Dax-1-/Y, and SF-1+/- mice and maintained in individual cages under standard conditions of temperature (22 C) and lighting (12-h light, 12-h dark). Basal blood samples were taken at 0900 h by retro-orbital bleeding within 1 min following initial mouse handling, preceding any stress induced ACTH release resulting from the procedure.
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ACTH stimulation test.
ACTH (Peninsula Laboratories, Inc., Belmont, CA) was reconstituted in saline and injected ip at a dose of 10 µg/g bodyweight at 0900 h. Blood was collected as described above after 60 min. Each group consisted of 10–13 animals.
Food deprivation stress.
Mice were deprived of food with free access to water for 48 h, then decapitated. This was followed by collection of trunk blood within 60 sec of initial handling, and subsequent adrenal dissection. Each group consisted of six animals.
Northern blot analysis
For the mRNA expression of SF-1 and Dax-1, membranes containing 10 µg of total RNA from adrenal tissues were hybridized with specific cRNA probes. The SF-1 and Dax-1 probes were generated using a 245-bp AccI/EcoRI fragment from the 3' UTR of SF-1, and a 788-bp BamHI fragment from the 5' region of Dax-1, respectively. Both were subcloned into PBKS II (-) vector. The RNAs were extracted from adrenals using Rneasy mini kit (QIAGEN Inc., Chatsworth, CA). For hybridization using cRNA probes, membranes were prehybridized for 3 h at 65 C in the Ultra Hyb solution (Ambion Inc., Austin, TX). This was followed by hybridization under the same conditions for 12 h but with 1 x 106 cpm/ml of 32P-labeled SF-1 and Dax-1 cRNA probes with a specific activity of 1 x 109 cpm/µg. After hybridization, the membranes were washed twice in 2x sodium chloride/sodium citrate (SSC), 0.1% SDS at 65 C, followed by two washes under high stringency conditions (0.1x SSC, 0.1% SDS at 65 C) before exposure to Bio-Max film (Eastman Kodak Co., Rochester, NY) with intensifying screens (Amersham Pharmacia Biotech, Buckinghamshire, UK). To monitor the loading of RNA samples from different tissues, membranes were stripped and rehybridized with a 32P-labled-mouse ß-actin cDNA probe. The cDNA probe was generated by Ready-To-Go labeling kit (Amersham Pharmacia Biotech). For hybridization using cDNA probes, membranes were hybridized at 42 C and washed to a stringency of 0.1x SSC, 1% SDS at 42 C.
Western blotting
Protein extracts were prepared from adrenal glands of respective groups. Four adrenals from each group were homogenized in lysis buffer [50 mM HEPES (pH 7.6), 250 mM NaCl, 0.5 mM EDTA, 0.5% Igepal, and protease inhibitors cocktail (Roche Molecular Biochemicals, Indianapolis, IN)]. The homogenate was allowed to rotate at 4 C for 1 h and the protein contents of the high-speed supernatant samples were estimated by using the Bio-Rad (Hercules, CA) assay reagent.
Equal amounts of protein samples from solubilized fractions of adrenal tissue of each genotype (6 µg) were separated by 10% SDS-PAGE minigel and transferred to polyvinylidendifluoride membrane for Western blotting as described earlier (21). After blocking nonspecific sites, membranes were incubated overnight at 4 C in Western buffer (TBS containing 5% (wt/vol) skim milk powder and 0.05% Tween-20) with primary antibodies to SF-1 (1:2500, K. Morahashi), Dax-1 (1:5000, P. Sassone-Corsi), p450scc (1:2500, W. Miller), steroidogenic acute regulatory protein (StAR) (1:2500, D. B. Hales), p450c21 (1:5000, W. Miller), or ACTH receptor (1:100, Santa Cruz Biotechnology, Inc., Santa Cruz, CA). The washed blots were then incubated with suitable secondary IgG conjugated to horseradish peroxidase (Sigma) (1:7000). Antibody binding to the membrane was visualized using the ECL plus (Amersham Pharmacia Biotech) chemiluminescent detection system. All blots were repeated with antibody to ß-actin (1:5000, Sigma). A range of exposure times for each immunoblot assured that signal intensity was proportional to protein concentration.
Histology
Adrenal glands from both wild-type and mutant animals were rapidly dissected and placed in Bouin’s fixative overnight. Tissues were dehydrated, embedded in paraffin, and 7-µm sections were cut and stained with hematoxylin and eosin using standard protocols.
Plasma hormone measurements
Plasma corticosterone and ACTH levels were determined by RIA using a 125I RIA kit according to the manufacturer’s protocols (ICN Diagnostics, Costa Mesa, CA). Samples were run in duplicate and concentrations were expressed as either ng/ml (corticosterone) or pg/ml (ACTH).
Statistical analysis
All results are expressed as mean ± SEM. Statistical comparisons were analyzed by ANOVA and Fisher’s protective least significant difference test posthoc ANOVA. Statistical significance is defined as P 
0.05.
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Results |
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), the adrenal weights in SF-1+/- mice were reduced by 40% (2.58 ± 0.10 mg) compared with wild-type mice (3.92 ± 0.14 mg) (Fig. 1B). Adrenal histology in SF-1+/- mice revealed normal zonation but significant cellular hypertrophy (cells/0.01 mm2:wild-type; 127.7 +/- 2.3 vs. SF-1+/-; 80.7 +/- 6.5) in a hypoplastic zona fasciculata (Fig. 2). In accordance with the known trophic effects of ACTH on adrenal growth, it is likely that these alterations in adrenal morphology are due to chronically elevated ACTH levels in SF-1+/- mice, as described previously (22). The X-zone regressed normally in SF-1+/- mice; however, the medulla was central of the DBA/2J:129S1/SvImJ cross-strain, unlike the previously published eccentric medulla in SF-1+/- mice of the cross-strain C57BL/6 x FVB (22). As reported in our initial report, the adrenal weight of Dax-1-/Y mice (4.0 ± 0.14 mg) was similar to wild-type mice despite a retained X-zone (19). Additionally, the zona fasciculata was histologically unaltered and had no change in cell number compared with wild-type mice (133.0 +/- 5.8 cells/0.01 mm2). Our analyses preclude the detection of potential subtle changes in the cortex or medulla that might account for the lack of the predicted increased weight due to the retained fetal X-zone. Nonetheless, the adrenal weights of compound SF-1+/-: Dax-1-/Y mice were significantly increased (3.55 ± 0.18 mg) compared with SF-1+/- mice and were not significantly different from the adrenal weights of WT mice. Histological analysis showed that the zona faciculata in the adrenal of compound SF-1+/-:Dax-1-/Y mice was less hypoplastic with less cellular hypertrophy (140.0 ± 4.0 cells/0.01 mm2) than SF-1+/- mice (Fig. 2). These findings suggest that Dax-1 deficiency partially reverses the decreased adrenal weight and gross histological appearance of the definitive zone in SF-1+/- mice under standard light microscopy.
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). As expected, SF-1 expression was lower in SF-1+/- and compound SF-1+/-: Dax-1-/Y mice when compared with wild-type mice as determined by Northern and Western analysis. The decrease in SF-1 protein was not as profound in the compound SF-1+/-: Dax-1-/Y mice, raising the possibility that in the absence of Dax-1, SF-1 protein is more stable. However, no changes in SF-1 mRNA or protein levels were observed in Dax-1-/Y mice, suggesting that Dax-1 does not transcriptionally or translationally regulate SF-1 in the adult adrenal cortex. Additionally, the Dax-1 mRNA and protein levels were identical in wild-type and SF-1+/- mice (Fig. 4). Although this result does not preclude a role for SF-1-dependent transcription of the Dax-1 gene in the developing cortex or gonads, it suggests that SF-1 haplo-insufficiency does not adversely affect Dax-1 expression in the adult adrenal cortex.
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). To amplify any potential effect of Dax-1 deficiency on adrenal steroidogenesis, mice were subjected to restraint stress for 30 min followed by measurement of plasma corticosterone and ACTH. Following restraint stress, the Dax-1-/Y mice had higher plasma corticosterone levels (364.69 ± 24.96 ng/ml) compared with SF-1+/- mice (256.50 ± 18.48 ng/ml) but were not significantly different from WT (328.20 ± 33.03 ng/ml) or SF-1+/-: Dax-1-/Y mice (272.1521.64 ng/ml) (Fig. 5A). The corresponding ACTH levels reveal an inverse relationship to corticosterone levels (Fig. 5B), with Dax-1-/Y mice having statistically lower ACTH levels (965.08 ± 197.92 pg/ml) than SF-1+/- mice (1968.58 ± 305.13 pg/ml). The inverse relationship between ACTH and corticosterone suggests a primary defect in the adrenal cortex rather than a hypothalamic/pituitary defect. ACTH/corticosterone ratios were calculated to further illustrate the adrenal responsiveness of the adrenal glands. A higher ACTH/corticosterone ratio indicates a lower adrenal responsiveness defined by a higher ACTH level needed to achieve a given corticosterone response. Dax-1-/Y mice exhibited a statistically significant decrease of 45% in ACTH/corticosterone ratio (2.64 ± 0.56) vs. wild-type mice (4.73 ± 0.64). SF-1+/- mice (7.77 ± 1.07) had a statistically significant increase of 64% in ACTH/corticosterone ratio compared with wild-type mice. Compound SF-1+/-: Dax-1-/Y mice exhibited intermediate adrenal responsiveness (ACTH/corticosterone: 5.87 ± 0.52) when compared with wild-type and SF-1+/- mice, suggesting a primary inhibitory role of Dax-1 in SF-1-mediated stress responsiveness (Fig. 6A).
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). These results provide further evidence for a specific increase in adrenal responsiveness in the adrenal cortex of Dax-1-/Y mice.
Protein levels of SF-1-responsive genes are increased in the absence of Dax-1
To explore specific effects of Dax-1 deficiency on the expression of steroidogenic enzymes, we examined the effects of chronic stress on the protein expression of SF-1-dependent genes in the four groups of mice (Fig. 7). We determined the expression of proteins coded for by SF-1 target genes critical for corticosterone production [StAR, P450scc (side chain cleavage enzyme), P450c21 (21-hydroxylase) and the ACTH receptor] following 48-h food deprivation. StAR is a phosphoprotein that rapidly increases the transport of cholesterol from the outer to the inner mitochondrial membrane (23), thus increasing the availability of substrate for P450scc, which initiates the synthesis of steroid hormones. Although StAR is a known target gene of SF-1, StAR protein levels were higher both in SF-1+/- and SF-1+/-: Dax-1-/Y mice representing a SF-1-independent compensatory increase in StAR expression. No significant changes were observed in the Dax-1-/Y mice.
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The ACTH receptor is also a SF-1-responsive gene. To explore whether the increased adrenal responsiveness to ACTH observed in the Dax-1-/Y and compound SF-1+/-:Dax-1-/Y mice could in part be accounted for by an increase in adrenal ACTH receptor expression, we determined the expression level of this SF-1 responsive gene following chronic stress, where a marked increase in ACTH receptor was evident in Dax-1-/Y mice and a modest increase in SF-1+/-: Dax-1-/Y mice (Fig. 7) compared with WT mice. Together, these results indicate that in addition to increased expression of p450c21, elevated ACTH receptor levels may be partly responsible for the heightened adrenal responsiveness in the absence of Dax-1.
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Discussion |
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Our initial report defining the phenotype of the Dax-1-/Y mice described baseline corticosterone in Dax-1 -/Y mice as unchanged from wild-type mice (19), suggesting that Dax-1 does not functionally cooperate with SF-1 to increase steroidogenesis. While the data presented here confirm this finding, ACTH levels at baseline and following restraint stress were actually lower in the Dax-1-/Y mice compared with wild-type mice, suggesting a heightened adrenal responsiveness to ACTH in Dax-1-/Y mice, where less ACTH is required to achieve a given corticosterone response. To take into account the dynamic changes in ACTH and corticosterone during stress, we calculated adrenal responsiveness as an ACTH/corticosterone ratio. In this context, Dax-1-/Y mice exhibited a statistically significant 2-fold increase in ACTH/corticosterone compared with wild-type mice following restraint stress. Additionally, following an ACTH stimulation test with a fixed dose of ACTH, the Dax-1-/Y group exhibited the highest corticosterone level of all groups of mice, confirming an intrinsic increase in adrenal responsiveness in the adrenal cortex of Dax-1-/Y mice. It is not surprising that the largest differences in hormonal profiles are seen when comparing SF-1+/- mice and Dax-1-/Y mice, in that these groups are most different regarding the gene dosage ratio of SF-1 and Dax-1. Our results are consistent with the removal of the transcriptional activation function of one SF-1 allele in the SF-1+/- mice and removal of the transcriptional repression function of Dax-1 in the Dax-1-/Y mice.
To specifically examine whether Dax-1’s repression function is dependent upon SF-1’s activation function in vivo, we crossed Dax-1-/Y mice with SF-1+/- mice and compared steroidogenic responses in compound SF-1+/-: Dax-1-/Y mice and SF-1+/- mice. In the various experimental paradigms, corticosterone, ACTH, and calculated ACTH/corticosterone ratios in compound SF-1+/-: Dax-1-/Y mice were intermediate to levels in wild-type and SF-1+/- mice following restraint stress, indicating a partial reversal of the decreased steroidogenic response observed in SF-1+/- mice. Four possible explanations can account for the inability of Dax-1 deficiency in SF-1+/-: Dax-1-/Y mice to completely reverse the defects in SF-1+/- mice. 1) SF-1 haplo-insufficiency down-regulates transcription of the Dax-1 gene. 2) Dax-1 does not function as a repressor of steroidogenesis or functions as a transcriptional repressor independent of SF-1. 3) The presence of the retained X-zone in the SF-1+/-: Dax-1-/Y mice underestimates steroidogenesis in the definitive zone compared with wild-type mice. 4) SF-1 activation is prerequisite for Dax-1 repression, which is maximal under physiologic activation of steroidogenesis during stress.
First, if SF-1 stimulates transcription of the Dax-1 gene in the adult adrenal, Dax-1 levels would be expected to be decreased in SF-1+/- mice. However, we did not see changes in baseline Dax-1 levels in the SF-1+/- mice when compared with wild-type adult mice. This result does not preclude a role for SF-1-mediated transcription of the Dax-1 gene in adrenal development (12), where the coordinate roles of Dax-1 and SF-1 are not clearly understood (1). Second, Dax-1 may not repress steroidogenesis in vivo or Dax-1 transcriptional repression may be mediated through an SF-1-independent mechanism in vivo as has been proposed for the inhibition of StAR transcription by Dax-1 binding to hairpin loops in the StAR promoter (25). However, in vitro studies document that Dax-1 mediates transcriptional repression of various SF-1 target genes through binding to SF-1 (16, 18). Most importantly, Dax-1 mutations that result in adrenal insufficiency due to congenital adrenal hypoplasia fail to physically interact with SF-1 and do not repress SF-1-mediated transcription (17). Third, the retention of the X zone in SF-1+/-: Dax-1-/Y mice might underestimate the steroidogenesis of the definitive zone compared with wild-type mice. It is for this reason that corticosterone was measured in blood to reflect adrenal steroid output and hence definitive zone function. The fetal X-zone, while playing an important role in fetal life, does not play a role in steroid production in the adult (27, 28). Because the adrenal glands in the Dax-1-/Y and SF-1+/-: Dax-1-/Y mice have a retained fetal X-zone, the increased expression observed would only be magnified if calculated as expression level per definitive zone. As such, the results presented in this report and discussed below reflect the most conservative estimates regarding intrinsic changes in adrenal responsiveness of the adrenal cortical cells in the presence and/or absence of SF-1 and Dax-1.
Data presented in this report suggest that SF-1 activation is prerequisite to observe the repressive effects of Dax-1. As has been shown in numerous in vitro studies and in both mice and patients with SF-1 haplo-insufficiency, SF-1 gene dosage is clearly important for both adrenal growth and steroidogenesis. It is plausible that the effects of SF-1 haplo-insufficiency on adrenal growth preclude a complete reversal of steroidogenic responses in the compound SF-1+/-: Dax-1-/Y mice when evaluating hormonal responses in vivo. We therefore evaluated the adrenal levels of key components of the steroidogenic response, including the SF-1 target genes, p450c21, and the ACTH receptor. Similar to previous reports in SF-1+/- mice, no change in P450scc is evident in any of the four groups at baseline or following prolonged fasting stress. A recent report finds that SF-1 response elements in the p450scc promoter are essential for transcriptional activation of the p450scc gene in transgenic mice (29). These results suggest that this critical first step in steroidogenesis, while SF-1 dependent, is not influenced by changes in SF-1 and/or Dax-1 levels in vivo. While StAR has been demonstrated to be an essential SF-1 target gene (30) that regulates the transfer of cholesterol to the inner mitochondrial membrane (23), the surprising increase in StAR in the SF-1+/- and compound SF-1+/-: Dax-1-/Y mice indicates a probable compensatory SF-1-independent regulation of StAR transcription as previously described (22).
Consistent with a lower adrenal responsiveness to ACTH in SF-1+/- mice following restraint, a decrease in P450c21 was observed in SF-1+/- mice following chronic stress, whereas an increase in P450c21 was detected in Dax-1-/Y mice compared with wild-type mice. In compound SF-1+/-:Dax-1-/Y mice, despite the lack of complete reversal of the decreased adrenal responsiveness seen in SF-1+/- mice, the absence of Dax-1 in these mice results in a modest increase in P450c21 and ACTH receptor compared with SF-1+/- mice. However, these levels were lower than those observed in Dax-1-/Y mice that had a marked increase in p450c21 and ACTH receptor levels compared with SF-1+/- mice. This data points to an incomplete steroidogenic rescue of the SF-1 haplo-insufficiency phenotype by Dax-1 deficiency in vivo. We propose that, without threshold induction of SF-1 target genes in SF-1+/- mice, the inhibitory effects of Dax-1 are not completely manifest. In the absence of one SF-1 allele, the decrease in steroidogenesis is mediated primarily by the SF-1 haplo-insufficient state and not by a relative increase in Dax-1. Therefore, only a modest reversal of the steroidogenic defect in SF-1+/- mice is observed in the compound SF-1+/-: Dax-1-/Y mice. It is when steroidogenesis is maximally stimulated by ACTH in the presence of sufficient SF-1 levels that the effect of Dax-1 is most evident as supported by the increased adrenal responsiveness following restraint in the Dax-1-/Y mice compared with wild-type mice.
For the first time, these data support a primary role for Dax-1 as an inhibitor of steroidogenic responses to stress in vivo. These findings suggest that Dax-1 primarily serves a counter-regulatory function to modulate SF-1-mediated steroidogenesis during stress, possibly to avoid hyperresponsiveness to ACTH and subsequent prolonged steroid excess. Further developmental studies in these compound mice are exploring the role of Dax-1 in SF-1-dependent adrenal development and will address whether Dax-1 cooperates with or antagonizes SF-1 during adrenal development. An elucidation of the mechanisms by which Dax-1 itself is regulated transcriptionally and posttranslationally will be essential for our understanding of this integrated response to stress in the adrenal cortex.
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Acknowledgments |
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Footnotes |
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Abbreviations: Dax-1, Dosage-sensitive sex reversal adrenal hypoplasia congenita, critical region on the X chromosome gene-1; SF-1, steroidogenic factor-1; SSC, sodium chloride/sodium citrate; StaR, steroidogenic acute regulatory protein.
Received June 27, 2001.
Accepted for publication October 23, 2001.
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