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Department of Physiology, Biomedical Sciences Graduate Program, University of California, San Francisco, San Francisco, California 94143-0444
Address all correspondence and requests for reprints to: Holly A. Ingraham, Department of Physiology, Box 0444, University of California, San Francisco, San Francisco, California 94143-0444. E-mail: hollyi{at}itsa.ucsf.edu.
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ABSTRACT |
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Normal adrenal development is apparent at embryonic day (E) 9.0 when a population of cells derived from the coelomic epithelium of the intermediate mesoderm begin to express SF-1; these cells form the adrenogonadal primordium (9). Later at E11.0, cells in the adrenogonadal primordium differentiate and give rise to both the adrenal cortex and gonad. Further development at E13.0 involves the migration and infiltration of neural crest cells into the developing adrenal cortex; these cells give rise to the adrenal medulla and become completely enveloped by the cortex by E15.5 (10). Although SF-1 expression is restricted to adrenocortical cells, loss of both SF-1 alleles results in massive apoptosis in the adrenal cortex, and consequently, agenesis of both the adrenal cortex and medulla (1). Whereas human and mouse genetics have established a role for SF-1 in adrenal development, the defective developmental processes contributing to decreased adrenal growth in SF-1 +/- mice have not been explored.
In the adult adrenal, extensive in vitro studies have suggested that SF-1 functions to coordinately regulate basal expression of steroidogenic genes such as steroidogenic acute regulatory protein (StAR), scavenger receptor-B1 (SR-B1), melanocortin 2 receptor (MC2R), and the steroid hydroxylases. In addition, SF-1 is proposed to mediate ACTH-stimulated up-regulation of these steroidogenic genes via the cAMP-protein kinase A pathway (11). The mechanism linking SF-1 with cAMP- and protein kinase A-mediated increases in steroidogenic gene expression has yet to be determined. Several groups have proposed that posttranslational modifications of SF-1 in response to extracellular signaling modulate its activity (12, 13, 14, 15). Despite an abundance of in vitro evidence supporting SF-1’s central role in regulating steroidogenic gene expression, recent findings showed a paradoxical increase in SF-1 target gene expression in SF-1 +/- adrenals that express low levels of SF-1 (8, 16). These results are at odds with SF-1’s dose-dependent activity during adrenal development and raise questions as to whether SF-1 is critical for activating steroidogenic gene expression or whether functionally redundant pathways are induced in SF-1 heterozygous mice.
In this study, we investigated the mechanisms that underlie SF-1 haploinsufficiency beginning at the earliest stage of adrenal development. Specifically, we asked what mechanisms might account for reduced adrenal size in SF-1 heterozygotes, including: 1) an increase in apoptosis, 2) a decrease in cell proliferation, 3) a defect in homing of medullary precursors to the developing adrenal cortex, and/or 4) a decrease in allocation of cells in the adrenogonadal primordium to the adrenal. Moreover, we asked how a reduction in SF-1 gene dosage affected the steroidogenic capacity of adult SF-1 +/- adrenocortical cells. Our findings demonstrate that SF-1 gene dosage is most critical at the onset of adrenal development within the adrenogonadal primordium. We propose that compensatory pathways deployed later in adrenal development and in the adult allow SF-1 heterozygous adrenals to function at high, albeit insufficient, levels in the adult mouse.
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RESULTS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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) (8). Earlier in development, at E13.5, we noted a more dramatic difference in SF-1 +/+ and +/- adrenal size (Fig. 1B). Quantification of adrenal size throughout development revealed a 12-fold decrease in size at the earliest stages of development, whereas at late time points, heterozygous adrenals were only 2-fold smaller than wild-type adrenals (Fig. 1C).
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, A and B, and data not shown). We next asked whether a proliferation defect could account for decreased adrenal size in SF-1 +/- embryos and predicted that bromo-deoxyuridine (BrdU) labeling and histone-3 phosphorylation (indices of S phase and mitosis, respectively) would be decreased in SF-1 +/- embryos (17, 18, 19, 20). Unexpectedly, although no apparent difference in BrdU labeling was observed between +/+ and +/- embryos at E12.5, a significant increase in BrdU-positive cells was detected in SF-1 +/- adrenals by E13.5 (Fig. 3, A and B). Two additional stages in development (E15.5 and E17.5) also showed a significant increase in BrdU labeling and histone-3 phosphorylation in +/- adrenals when compared with +/+ adrenals (Fig. 3, C and D).
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). However, by E15.0, no tissue corresponding to an adrenal medulla was found in SF-1 -/- embryos. In the presence of one functional SF-1 allele, growth of the adrenal medulla was diminished and no appreciable infiltration of ß-gal (+) cells into the adrenal was observed at E15.0 or E16.5 compared with wild type (Fig. 4B and data not shown).
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). At E10.0, SF-1/GATA-4 double-positive cells were observed in the coelomic epithelium of the intermediate mesoderm, whereas SF-1 single-positive cells were observed dorsal and somewhat rostral to the SF-1/GATA-4 double-positive population (Fig. 5B). We found that the total area of the adrenogonadal primordium did not differ between +/+ and +/- embryos (data not shown). However, the percentage of SF-1 single-positive cells in the adrenogonadal primordium was decreased significantly in SF-1 +/- embryos, suggesting that SF-1 gene dosage is most critical at the onset of adrenal development (Fig. 5C).
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). Morphological inspection of cultured +/+ and +/- adrenocortical cells revealed no major differences (Fig. 6B). Further analysis of SF-1 +/- adrenocortical primary cells revealed reduced expression of SF-1, whereas expression of two rate-limiting proteins in steroidogenesis StAR and side chain cleavage (SCC), was increased (Fig. 6C); these results are identical with those obtained from whole +/- adrenals (8, 16). Collectively, these data suggest that factors distinct from SF-1 drive increased expression of steroidogenic genes, and thus, would account for the increased cellular function observed in SF-1 +/- adrenocortical cells.
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, A and B, and data in legend) (26). Dexamethasone treatment resulted in a marked reduction in the levels of StAR, SCC, and SR-B1, with equivalent, low levels observed in wild-type and heterozygous adrenals (Fig. 7, C and D). By contrast, SF-1 levels were unaltered after hormone treatment in either genotype. Finally, dexamethasone treatment also suppressed corticosterone secretion and led to high, equivalent levels of CD4+CD8+ thymocyte programmed cell death in both genotypes (data not shown) (8). These results demonstrate that ACTH maintains high expression levels of SF-1 target genes in SF-1 +/- adrenals.
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and data in legend). Other potential mechanisms may include altered expression of transcription factors that positively regulate steroidogenic genes or negatively regulate SF-1 in heterozygous adrenals. One such factor is the orphan nuclear receptor liver receptor homolog-1 (LRH-1). LRH-1 shares high identity with SF-1 and thus could potentially regulate SF-1 target genes (27, 28, 29). However, no appreciable levels of LRH-1 transcripts were detected in either +/+ or +/- adrenals using Northern and RT-PCR analyses (data not shown).
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, B and C). Up-regulation of NGFI-B expression was confirmed by Western blot analysis, with elevated NGFI-B protein levels (2.3-fold on average) observed in SF-1 +/- adrenals compared with +/+ adrenals. It should be noted that the broadly migrating NGFI-B signal consists of multiple bands due to hyperphosphorylation, as previously reported (Fig. 8D) (34). Finally, we excluded that diminished levels of a putative repressor of SF-1, Dax1, might account for the up-regulation of SF-1 target genes. Instead, we find equivalent levels of Dax1 protein in wild-type and heterozygous adrenals, with or without dexamethasone treatment (Fig. 8E). |
DISCUSSION |
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SF-1 gene dosage is most critical during the earliest stages of adrenal development as evidenced by the severe reduction of adrenocortical precursors in SF-1 +/- embryos at E12.0. Whereas our immunocytochemical analysis of GATA-4 and SF-1-positive cells at E10.0 revealed that the total size of the adrenogonadal primordium does not differ in +/+ and +/- embryos, our findings indicated that fewer cells are dedicated to the adrenal (SF-1 positive, GATA-4 negative) in SF-1 heterozygotes at this stage of development. Our data suggest that SF-1 is important for expansion of adrenal progenitors in the adrenogonadal primordium. Separation of adrenal and gonadal precursors may also rely on SF-1. At this step, SF-1 could act in concert with the signaling molecule Wnt4, which was recently shown to repress migration of adrenal precursors into the developing gonad (35). Delineating SF-1’s role in the earliest steps of adrenal development will require identification of SF-1’s embryonic target genes.
A consequence of impaired adrenocortical development in SF-1 +/- and -/- embryos is disrupted adrenomedullary development. We found that the initial migration of neural crest cells to the adrenal cortex (or its approximate location) occurs normally regardless of SF-1 dosage, showing that neural crest cells do not rely on signals from adrenocortical cells for proper homing. However, at later stages of development, medullary cells are lost in SF-1 -/- embryos and the medulla fails to infiltrate the small SF-1 +/- adrenal cortex. Our data show that normal growth and survival of the adrenal medulla depends on SF-1 function in the adrenal cortex. It will be of interest to determine whether the requirement for SF-1 is indirect or direct. For instance, normal medullary growth may simply require sufficient adrenocortical mass. Alternatively, SF-1 might directly regulate genes that serve as paracrine growth factors for medullary cells. This occurs in skin, where target-derived growth factors support expansion and correct localization of neural crest-derived melanocyte precursors (36).
How can the early growth defects in SF-1 +/- adrenals be reconciled with their impressive increase in cell proliferation later in development? Perhaps decreased adrenal mass is somehow sensed at E13.5 and leads to increased adrenal growth factor levels that drive cell proliferation in SF-1 heterozygotes. This strategy would parallel the compensatory response to SF-1 haploinsufficiency in the adult adrenal in which elevated ACTH levels lead to increased steroidogenic capacity per cell. Another anterior pituitary hormone, pro-
-MSH, stimulates adrenal cell proliferation after undergoing local proteolysis (carried out by adrenal secretory protease) that produces a shorter form with mitogenic activity (26, 37, 38). This signaling pathway is thought to account for the compensatory adrenal growth response after removal of one adrenal. The lack of this growth response in SF-1 +/- mice might suggest that SF-1 participates in pro--MSH signaling (39). It will be of interest to determine the interplay between SF-1, ACTH, and/or pro--MSH signaling pathways during early adrenal development.
Ultimately, increased cell proliferation in SF-1 +/- adrenals cannot compensate for the early deficits in adrenal development. SF-1 +/- adrenals do not secrete enough corticosterone to support normal physiological responses to stress, but elevated ACTH levels in +/- mice stimulate steroidogenic gene expression and raise steroidogenic capacity per cell, ensuring relatively normal basal corticosterone secretion (1, 8). Are heterozygous levels of SF-1 sufficient to maintain SF-1 target gene expression at supernormal levels in +/- adrenals or are other mechanisms such as posttranslational modification, ligand availability, or up-regulation of other transcription factors employed? Although it is known that phosphorylation of SF-1 on Ser 203 promotes SF-1 transcriptional activity, we did not detect significant differences in the ratio of phosphorylated to total SF-1 in +/+ and +/- adrenals. Increased ligand availability is also an unlikely mechanism because neither an exogenous nor an endogenous obligatory ligand has been identified for SF-1, consistent with the fact that SF-1 is constitutively active in a variety of steroidogenic and nonsteroidogenic cell lines (40). Furthermore, biophysical and structural evidence suggests that members of nuclear receptor subfamily V (SF-1 and LRH-1) adopt an active conformation in the apparent absence of ligand (15, 41).
Increased or decreased activity of other transcription factors may underlie the paradoxical increases in SF-1 target gene expression in SF-1 +/- adrenals. For example, the orphan nuclear receptor Dax1 represses SF-1 activity in vitro (42, 43, 44). However, loss of Dax1 does not lead to further increases in SF-1 target gene expression in SF-1 +/- adrenals (16). Indeed, we found that Dax1 levels were similar in SF-1 +/+ and +/- adrenals, regardless of circulating ACTH levels. Our data show that NGFI-B levels are significantly elevated in SF-1 +/- adrenals, supporting a compensatory role for NGFI-B in the regulation of steroidogenic gene expression. However, the normal adrenal responses to stress in NGFI-B null mice suggest that NGFI-B does not normally regulate steroidogenic genes, including 21-hydroxylase (32). Taken together, these data indicate that NGFI-B does not serve as the primary regulator of steroidogenic genes but may assume a more important role when SF-1 dosage is reduced.
Although our data confirm and extend the essential role of SF-1 in early embryonic adrenal development, they also lead us to question SF-1’s precise role in late adrenal development and in the adult adrenal gland. The increase in steroidogenic capacity in SF-1 +/- adrenocortical cells is particularly unexpected given the central role that SF-1 has been thought to play in coordination of adrenal steroidogenesis. Our study strongly suggests that alternative molecular mechanisms exist to increase expression of many SF-1 target genes and illustrates the differential requirement for transcription factor function in development and the adult. Future experiments aimed at generating a temporal-specific SF-1 deletion in the adult will be essential for dissecting SF-1’s well-established role in adrenal development from its less-defined role in regulating adult adrenal steroidogenesis.
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MATERIALS AND METHODS |
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Measurements of Cellular Proliferation and Cell Death
For BrdU labeling, timed-pregnant mice received an ip injection of BrdU (50 mg/kg, Sigma). After a 1-h pulse, whole embryos or fetal adrenals were collected, fixed overnight in 4% paraformaldehyde, cryoprotected in 30% sucrose, and frozen in OCT compound (Tissue Tek Sakura, Torrance, CA). Cryostat sections (10 µm) were treated with 2 N HCl at 37 C for 20 min to denature DNA, blocked in 10% normal goat serum, incubated overnight at 4 C with rat anti-BrdU antisera (1:10, Harlan Sera-Lab) and either rabbit anti-SF-1 (1:1000) or rabbit antiphosphorylated histone 3 (phospho-His3, 1:1000, Upstate Biotechnologies, Waltham, MA), washed, and incubated for 2 h at room temperature with goat antirabbit Alexa 488 and goat antirat Alexa 546 secondary antibodies (1:200 each, Molecular Probes, Eugene, OR). Images were collected with a confocal microscope, and adrenal cross-section area and the number of BrdU-positive (+) and phospho-His3 (+) cells per section were measured with the NIH Image program. The number of digitally counted BrdU (+) and phospho-His3 (+) cells was confirmed by visual assessment to ensure appropriate parameter settings. Apoptosis was detected using an in-house terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end-labeling (TUNEL) assay as described previously (45). For each section, the number of TUNEL (+) cells was divided by the area of SF-1 immunoreactivity. For SF-1 -/- embryos, the average number of TUNEL (+) cells per section was divided by the average area of SF-1 immunoreactivity in SF-1 +/- genital ridges.
For measurement of adrenogonadal primordia size, embryos were staged by counting somites. Embryos were fixed as described above. Cryostat sections (10 µm) were blocked for 30 min in 10% normal donkey serum, and incubated overnight at 4 C with rabbit anti-SF-1 (1:200) and goat anti-GATA-4 (1:500, Santa Cruz Biotechnology, Inc., Santa Cruz, CA). The next day, sections were washed, incubated for 2 h at room temperature with donkey antirabbit Alexa 488 (1:200, Molecular Probes) and donkey antigoat Cy3 (1:200, Jackson ImmunoResearch, West Grove, PA). Images were collected with a confocal microscope and the total areas of all SF-1 (+) cells and SF-1 (+), GATA-4 (-) cells were measured with NIH Image.
Histological Analysis
Detection of ß-gal in DßH-nLacZtransgenic embryos was performed as described previously (21). Adrenal sections (10 µm) were stained with toluidine blue O. Cellular hypertrophy was assessed by counting Hoechst-stained nuclei per 0.01 mm2 in four sections per +/+ and +/- adrenal (n = 4 adrenals per group).
Western and Northern Analysis
Western analyses were carried out as described previously (8). For Western analysis, each lane represents a separate individual, n = 3–6 per genotype. Additional antibodies used in this study were: rabbit anti-SR-B1 (1:20,000, Novus Biologicals, Littleton, CO), mouse anti-NGFI-B [1:10,000, a kind gift of Dr. J. Milbrandt (Washington University, St. Louis, MO)], and goat antimouse horseradish peroxidase (1:10,000, Bio-Rad, Hercules, CA). For quantification of protein levels, scanning densitometry was performed on blots developed with chemiluminescence (ECL, Amersham Biosciences, Piscataway, NJ). These levels were confirmed by quantifying radioactive signals from Western blots performed with a radiolabeled goat antirabbit secondary antibody (NEN, Boston, MA). For Northern analyses, total RNA (20 µg) prepared from SF-1 +/+ and +/- adrenals was separated by formaldehyde-gel electrophoresis, transferred to nylon membranes, and hybridized overnight at 42 C with random-primed, labeled DNA probes for fragments of the mouse SF-1, mouse LRH, rat NGFI-B, and rat actin cDNAs. Membranes were washed at medium stringency (0.2x sodium chloride sodium citrate, 0.1% sodium dodecyl sulfate at 42 C) and exposed to X-OMAT film (Kodak, Rochester, NY). For Northern blot and EMSA (see EMSA) experiments, radioactive signals were quantified with ImageQuant Mac software (Amersham Biosciences after exposure to a phosphorimager screen (Storm, Amersham Biosciences).
Primary Cell Culture
Adrenals from female mice were dissected free of fat, minced, and washed in culture medium (M-199 with 4 mg/ml BSA plus penicillin and streptomycin). Cells were incubated in dispersal medium (M-199 containing 20 mg/ml BSA plus penicillin and streptomycin, 2.5 mg/ml type I collagenase (Invitrogen, Carlsbad, CA), and 10 µg/ml deoxyribonuclease I) for 30 min at 37 C with shaking and were dissociated by repeated pipetting every 10 min, filtered over 70-µm nylon mesh, washed twice by centrifugation, and resuspended in culture medium. Equivalent numbers of SF-1 +/+ and +/- cortical cells were incubated in 950 µl culture medium at 37 C with 5% CO2. After 1 h, H2O or 8-bromo-cAMP (Sigma) at final concentrations of 0.1, 0.5, and 1 mM were added in a volume of 50 µl. Cells were incubated for 90 min, pelleted by centrifugation, and the supernatant was removed for corticosterone measurements. Cells were lysed with 2% sodium dodecyl sulfate, 100 mM dithiothreitol (DTT), and 60 mM Tris-HCl (pH 6.8), and Western blot analyses was carried out as described above. Small aliquots of +/+ and +/- cells were plated on tissue culture slides coated with collagen and incubated overnight at 37 C, 5% CO2 in culture medium plus 10% fetal calf serum. The next day, cells were fixed with 4% paraformaldehyde and stained with oil red O.
EMSA
Nuclear extracts were prepared from adrenal glands collected under basal conditions at 1730 h. Adrenals were cleaned of fat, homogenized in cold PBS, and centrifuged at 4000 rpm for 5 min. Cells from eight to 12 adrenals were resuspended in 400 µl buffer A [10 mM HEPES (pH 7.9), 10 mM KCl, 0.1 mM EDTA, 0.1 mM EGTA, 1 mM DTT, and 0.5 mM phenylmethylsulfonyl fluoride] and incubated on ice for 15 min before the addition of 25 µl of 0.1% Nonidet P-40 in buffer A. Nuclei were vortexed for 10 sec and centrifuged at 11,000 rpm for 30 min. Nuclei were resuspended in 50 µl buffer C [20 mM HEPES (pH 7.9), 0.4 M NaCl, 1 mM EDTA, 1 mM EGTA, 1 mM DTT, and 1 mM phenylmethylsulfonyl fluoride], rotated at 4 C for 15 min and then centrifuged for 5 min at 11,000 rpm. The supernatant was subjected to EMSAs as follows: oligonucleotides encoding the SF-1 response element in the human glycoprotein hormone 
-subunitpromoter (forward: 5'-GCTGACCTTGTCGTCAC-3', reverse: 5'-GTGACGACAAGGTCAGC-3') were annealed and radiolabeled as described (14). In each binding reaction, 1–3 µg of adrenal nuclear protein extracts were mixed with the labeled probes in 20 µl volume of 20 mM Tris (pH 8.0), 60 mM KCl, 2 mM MgCl2, 1.2 mM DTT, 12% glycerol, 2.5 µg poly (deoxyinosine-deoxycytosine), 1% (wt/vol) BSA, incubated at room temperature for 5 min before the addition of 2 µl of probe (200,000 cpm) and incubation for 15 min at 30 C. Typically, 8 µl of the reaction mixture were resolved on a 5% native acrylamide gel, dried and visualized by autoradiography. For all antibody gel-shift experiments, 0.1–3.0 µl of anti-phospho-SF-1 antiserum was added to the reaction minus probe and incubated on ice for 60 min.
Statistical Analysis
Data are presented as means ± SEM. Unpaired two-tailed t tests and ANOVA were used to determine statistical significance.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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Abbreviations: BrdU, Bromo-deoxyuridine; 8Br-cAMP, 8-bromo-cAMP; DßH-nLacz, dopamine ß-hydroxylase-nuclear LacZ; DTT, dithiothreitol; E, embryonic day; LRH, liver receptor homolog; MC2R, melanocortin 2 receptor; NGFI-B, nerve growth factor-induced-B; SCC, side chain cleavage; Ser, serine; SF-1, steroidogenic factor-1; SR-B1, scavenger receptor-B1; StAR, steroidogenic acute regulatory protein; TUNEL, terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end-labeling.
Received for publication August 29, 2003. Accepted for publication January 8, 2004.
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REFERENCES |
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-subunit gene (GSU) in gonadotropes. Mol Endocrinol 17:2177–2188-melanotropin at the adrenal to stimulate growth. Cell 105:903–912[CrossRef][Medline]
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K.-H. Song, Y.-Y. Park, K. C. Park, C. Y. Hong, J. H. Park, M. Shong, K. Lee, and H.-S. Choi The Atypical Orphan Nuclear Receptor DAX-1 Interacts with Orphan Nuclear Receptor Nur77 and Represses Its Transactivation Mol. Endocrinol., August 1, 2004; 18(8): 1929 - 1940. [Abstract] [Full Text] [PDF]
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