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The Journal of Clinical Endocrinology & Metabolism Vol. 89, No. 1 8-12
Copyright © 2004 by The Endocrine Society

Special Feature

Expression of GCMB by Intrathymic Parathyroid Hormone-Secreting Adenomas Indicates Their Parathyroid Cell Origin

Alexander Maret, Isabelle Bourdeau, Changlin Ding, Shrihari S. Kadkol, William H. Westra and Michael A. Levine

Division of Pediatric Endocrinology, Department of Pediatrics (A.M., C.D., M.A.L.), Illysa Center for Molecular and Cellular Endocrinology (A.M., C.D., M.A.L.), and Department of Pathology (S.S.K., W.H.W.), The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287; Unit of Genetics and Endocrinology, Developmental Endocrinology Branch, National Institutes of Health (I.B., M.A.L.), Bethesda, Maryland 20892; and The Children’s Hospital at The Cleveland Clinic (M.A.L.), Cleveland, Ohio 44195

Address all correspondence and requests for reprints to: Dr. Michael A. Levine, Division of Pediatrics, The Children’s Hospital at The Cleveland Clinic, 9500 Euclid Avenue, Mailstop A120, Cleveland, Ohio 44195. E-mail: levinem{at}ccf.org.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
GCMA and GCMB are related transcription factors that are critically important for embryological development of the placenta and parathyroid glands, respectively. Mice in which parathyroid glands have been surgically removed or fail to develop due to genetic loss of GCMB show continued production of PTH from a subset of thymic cells that express GCMA. In this study we examined whether human thymus produces PTH and/or GCMA and whether intrathymic PTH-secreting adenomas express GCMA or GCMB to determine the embryological origin of the secretory cells. By contrast to mouse thymus, analysis of 22 samples of human thymus tissue by RT-PCR and/or immunohistochemistry failed to demonstrate the expression of either PTH or GCMA. RT-PCR analysis of 16 intrathymic adenomas from patients with surgically cured primary hyperparathyroidism showed that these tumors expressed PTH and GCMB and not GCMA. We conclude that the normal human thymus does not express GCMA or PTH, and therefore, in contrast to the mouse, the human thymus is not a source of PTH production. Finally, intrathymic PTH-secreting adenomas express the parathyroid-specific GCMB gene, which suggests that these tumors were derived from parathyroid cells that migrated errantly during embryogenesis.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
THE THYMUS AND the parathyroid glands in mice develop from a common primordium of the third pharyngeal pouch (1). The expression of the transcription factors Gcm2 and Foxn1 divides the primordium into parathyroid- and thymus-specific domains even before the morphological separation of the two organs (2). Insight into the mechanisms controlling the initial formation of the common primordium and subsequent development of the thymus and parathyroids has been gained by generation of knockout mice in which genes encoding embryonic transcription factors (i.e. Hoxa3, Eya1, Pax1, Pax9, and Foxn1) have been disrupted. Mice that lack either Hoxa3 or Eya1 have the most severe defects, as they fail to initiate formation of the thymus/parathyroid primordium (3, 4). The closely related paired box transcription factors Pax1 and Pax9 are also required for normal development of thymus and parathyroid, as loss of these factors results in an early failure of organogenesis with hypoplasia of both thymus and parathyroids (1, 5). Foxn1, the gene mutated in the classical nude mouse strain, is not required for initiation of thymus organogenesis, but is critical for subsequent differentiation of thymic epithelial cells (6, 7).

Recent work to elucidate the developmental biology of the parathyroid glands has disclosed novel roles for the related transcription factors encoded by the human GCMA and GCMB (the murine orthologs are termed Gcm1 and Gcm2, respectively) genes. These proteins are mammalian orthologs of the Drosophila transcription factor glial cells missing (gcm), so-called because disruption of gcm causes presumptive glial cells to convert into neural cells (8). Neither GCMA nor GCMB is expressed in the mammalian nervous system, however. GCMA is primarily expressed in the placenta and has been shown to be critical for the function of syncytiotrophoblasts (9). By contrast, GCMB (Gcm2) expression is restricted to parathyroid cells, and transgenic mice (10) and humans (11) that genetically lack gcmb fail to develop parathyroid glands, implying that GCMB is a master control gene for parathyroid development. Remarkably, although transgenic mice with homozygous disruption of the Gcm2 gene (Gcm2-/-) lack parathyroid glands, they continue to have detectable serum PTH (10). This observation led to the identification of a subset of cells in the mouse thymus that coexpress the genes encoding PTH, the calcium-sensing receptor and gcm1, and which can therefore serve as an auxiliary source of PTH (10).

The identification of the mouse thymus as a source of PTH led us to ask whether normal human thymus can also produce PTH. Moreover, we further sought to determine whether intrathymic adenomas that produce PTH originate from thymic epithelial cells or from ectopic parathyroid epithelial cells. We report here that human thymus does not express PTH or GCMA. Moreover, the intrathymic PTH-secreting adenomas that we analyzed expressed GCMB rather than GCMA, suggesting that these tumors arose from parathyroid cells that had migrated errantly within the thymus during embryological development.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Tissue specimens

After receiving approval from the Johns Hopkins Joint Commission on Clinical Investigation, we obtained paraffin-embedded tumor specimens from 16 patients with primary hyperparathyroidism who had undergone resection of a solitary intrathymic PTH-secreting adenoma between 1994 and 2000 at the Johns Hopkins Hospital. One eutopic parathyroid adenoma and 13 nonparathyroid endocrine tumors (7 pituitary adenomas, 3 adrenal adenomas, and 3 adrenal hyperplasias) were used as controls. In addition, we collected specimens of thymus tissue from various sources: 1) 6 fresh surgical samples of normal human thymus obtained from subjects, 20–60 yr of age; 2) 6 entire human thymi from autopsies of fetuses older than 22 wk gestation or neonates; 3) total RNA preparation that was derived from whole thymus organs of 3 individuals, aged 22–32 yr (636549, Clontech, Palo Alto, CA); 4) 7 paraffin-embedded thymus specimens from normal subjects, 0–21 yr of age (courtesy of Dr. B. Bodey, University of Southern California, Los Angeles, CA); 5) 2 specimens from transplanted thymus tissue from patients with DiGeorge syndrome (courtesy of Dr. M. L. Markert, Duke University Medical Center, Durham, NC); and 6) fresh mouse thymus. Total RNA from human placenta was obtained from Clontech (Palo Alto, CA).

RNA extraction

Fresh thymus or endocrine tumor tissue was either frozen immediately or stored in a RNA preservative (RNA later, Qiagen, Valencia, CA). To extract RNA, tissue specimens were resuspended in TRIzol-LS reagent (Invitrogen, Carlsbad, CA) and homogenized for 60 sec with a Plytron power homogenizer (Kinematica, Luzerne, Switzerland). Total RNA was isolated according to the manufacturer’s instructions and suspended in ribonuclease-free water. RNA concentration and purity were assessed spectrophorometrically.

Total RNA was extracted from paraffin-embedded tissue samples using the paraffin block RNA isolation kit from Ambion (Austin, TX) according to the manufacturer’s instructions. Isolated RNA was treated with ribonuclease-free DNase I (Ambion) for 30 min at 37 C, extracted with phenol-chloroform, and resuspended in 10 µl RNA storage solution (Ambion). The yield of RNA was estimated by RT-PCR of ribosomal 18S.

RT-PCR

Total RNA (1 µg) was denatured at 65 C for 5 min, and first strand cDNA was synthesized using oligo(deoxythymidine)12–18 as the primer (Invitrogen) and 50 U reverse transcriptase (Superscript II RT, Invitrogen) in a 20-µl reaction. The first strand cDNA was used as a template for PCR with exonic oligonucleotide primers for human GCMA, GCMB, PTH, GNAS1, and ß-actin and mouse Gcm1 and Pth. The primer sequences, product sizes, and PCR conditions are listed in Table 1Go. We performed hot-start PCR (12) in a final volume of 25 µl containing 1.5 mM MgCl2, 0.2 mM deoxy-NTPs, 0.5 µM of each primer, 2 µl of first strand cDNA, and 2.5 U Hotstar Taq DNA polymerase (Qiagen). Aliquots of PCR-amplified products were resolved by electrophoresis on a 1.5% agarose gel or a 6% polyacrylamide gel, stained with ethidium bromide, and photographed under UV transillumination.


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  		TABLE 1. Oligonucleotide sequences used in RT-PCR analysis

 
Direct sequence analysis and slot-blot analysis

PCR products of the expected sizes were gel-purified using the Mini Elute Gel Extraction Kit (Qiagen), and 5–10 ng purified PCR product were subjected to direct sequence analysis using 1 pmol/µl sense primer and the fluorescent dideoxy terminator method of cycle sequencing (3700 DNA analyzer, PerkinElmer, PE Applied Biosystems, Foster City, CA).

Slot-blot analysis was subsequently used to confirm the identity of GCMB amplicons. An internal antisense oligonucleotide probe (5'-CTGGGGTTGGTAGAAAGAGGC-3') was labeled at the 3' end with digoxigenin using the digoxigenin (DIG) oligonucleotide tailing kit from Roche (Mannheim, Germany). RT-PCR products were denatured in 1 M NaOH, applied to a nylon membrane (Hybond-N+, Amersham Biosciences, Piscataway, NJ), and fixed by baking. The nylon membrane was hybridized with the DIG-labeled probe overnight at 37 C and subsequently washed in 0.2x standard saline citrate/0.1% sodium dodecyl sulfate for 10 min at 45 C. After probe hybridization, membranes were blocked and incubated with an anti-DIG alkaline phosphatase antibody (Roche; 1:10:000 dilution) for 30 min at 37 C. Antibody binding was detected using CDP-Star chemiluminescence (Roche), and the signal was detected by exposure to x-ray film.

Immunohistochemistry

Tissue sections (5 µm) from paraffin-embedded thymi from seven human subjects, 0–21 yr of age (including one fetal and one neonatal subject), were prepared. In addition, sections of two biopsy samples from transplanted thymus from two patients with DiGeorge syndrome were obtained. Sections were dewaxed in xylene, rehydrated in graded ethanol, and steamed in citric acid. Immunohistochemistry for PTH was performed using a 1:2000 dilution of a monoclonal mouse antihuman PTH-(1–34) antibody (QED Bioscience, San Diego, CA) and an avidin-biotin-peroxidase system with diaminobenzidine as peroxidase substrate (Ultravision Detection System Antimouse, horseradish peroxidase/diaminobenzidine, Lab Vision, Fremont, CA). Immunohistochemistry for gcma was performed using a polyclonal rabbit antihuman gcma antiserum (courtesy Dr. R. A. Lazzarini, Mount Sinai School of Medicine, New York, NY) as previously described (13).


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
RT-PCR analysis of mouse thymus confirmed expression of Gcm1 and Pth transcripts, which were verified by direct sequence analysis (data not shown; Table 2Go). Using specific antisera, we could not detect PTH or gcma by immunohistochemistry in any of the 9 human thymus specimens that we analyzed, comprising the 7 paraffin-embedded thymus samples and the 2 thymic transplant samples (Table 2Go). Moreover, using RT-PCR, we were unable to identify mRNA encoding GCMA, GCMB, or PTH in all 22 human thymus samples analyzed: 6 surgical and 3 whole thymus specimens from adult individuals, 6 fetal/neonatal whole thymus samples, as well as RNA extracts from 7 paraffin-embedded thymus specimens from 0- to 21-yr-old subjects. (Fig. 1Go and Table 2Go). To confirm the ability of the RT-PCR analysis to identify small quantities of GCMA mRNA, we determined that we could detect GCMA transcripts in as little as 5 ng total RNA from human placenta after 40 cycles of PCR, whereas no transcripts were detected using 1 µg total RNA from human thymus (not shown). The identities of PCR amplicons generated as positive controls for GCMA, PTH, and GCMB were verified by direct sequence analysis.


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  		TABLE 2. Analysis of gene expression in thymic tissue

 


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  		FIG. 1. RT-PCR analysis of normal human thymus RNA. Ten samples (lanes 1–10) of RNA from mature thymus are depicted; there is no expression of GCMA, GCMB, or PTH in any sample. By contrast, RT-PCR of GNAS1 was successful for each sample, confirming the presence of intact RNA. Positive controls were human placenta total RNA for GCMA and total RNA from eutopic parathyroid adenoma for GCMB, PTH, and GNAS1. The expected size of each amplicon is indicated by the arrow on the right.

 
RT-PCR analysis of RNA extracted from intrathymic PTH-producing adenomas was negative for GCMA and positive for GCMB in all 16 samples (Fig. 2Go and Table 1Go). PTH was detected by immunohistochemistry in the intrathymic parathyroid adenomas (Table 1Go). The identity of the GCMB amplicons was confirmed for two representative samples by direct sequence analysis and by hybridization to an internal oligonucleotide probe for all samples (Fig. 3Go). RT-PCR analysis of total RNA from 13 nonparathyroid endocrine tumors (7 pituitary adenomas, 3 adrenal adenomas, and 3 adrenal hyperplasias) was negative for GCMB, whereas expression of ubiquitous ß-actin confirmed intact mRNA (Fig. 4Go).



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  		FIG. 2. Analysis of RNA from intrathymic PTH-producing adenomas by RT-PCR (lanes 1–12). GCMA was not detected in any sample. By contrast, each sample was positive for GCMB. Human placenta total RNA was used as a positive control for GCMA and total RNA from eutopic parathyroid adenoma for GCMB. The expected size of each amplicon is indicated by the arrow on the right.

 


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  		FIG. 3. Slot-blot analysis of PCR products from intrathymic PTH-producing adenomas (three representative samples are shown in lanes 1–3). Positive chemiluminescence signals confirm the identity of the PCR products as GCMB transcripts.

 


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  		FIG. 4. RT-PCR analysis of total RNA from 13 nonparathyroid endocrine tumors (lanes 2–8, pituitary adenomas; lanes 9–11, adrenal adenomas; lanes 12–14, adrenal hyperplasias; lane 15, H2O) was negative for GCMB, whereas expression of ubiquitous ß-actin confirmed intact mRNA (Fig. 4Go). RNA from a eutopic parathyroid adenoma served as a positive control (lane 1).

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Characterization of the Gcm2-/- transgenic mouse provided the first evidence that the thymus serves as an auxiliary source for PTH in the mouse, with calcium-regulated secretion of PTH from a small subset of thymic epithelial cells that coexpress the genes encoding PTH, calcium-sensing receptors, and Gcm1 (10). We therefore attempted to determine whether the human thymus contains PTH-secreting cells as well. For example, many patients with DiGeorge syndrome and congenital hypoparathyroidism experience spontaneous recovery of parathyroid function (14), and it is conceivable that this phenomenon is based upon compensatory production of PTH from thymic epithelial cells. As the PTH-producing cells of the mouse thymus are restricted to discrete subcortical regions and not scattered throughout the thymus, we also analyzed RNA samples prepared from whole human thymus samples to avoid potential sampling errors. However, our analysis of thymus RNA obtained from microtome sections or whole organs from fetal, neonatal, and adult subjects failed to demonstrate expression of PTH or GCMA. By contrast, using similar experimental techniques, we could confirm the expression of PTH and Gcm1 in the mouse thymus as previously reported (10). These results provide strong evidence that normal human thymus does not produce PTH and are consistent with the observation that circulating levels of PTH are either very low or undetectable in subjects with hypoparathyroidism due to homozygous mutation of the GCMB genes (11). Further evidence that human thymic tissue is not a significant source of PTH comes from studies of patients with complete DiGeorge syndrome who have received thymic transplants (15, 16). Despite reconstitution of a normal immune system, these patients continue to have low or undetectable serum levels of PTH (Markert, M. L., unpublished observation). Consistent with these observations, we were unable to detect PTH, GCMA, or GCMB mRNA in biopsy samples of functioning transplanted thymic tissue from two patients with DiGeorge syndrome.

Our results provide further evidence that embryological development of the thymus and parathyroids differs between humans and rodents. Rodents, such as mice and rats, possess only one pair of parathyroids, as opposed to most other mammals, including humans, that develop two pairs (17). In man the inferior parathyroids derive from the dorsal segment of the third endodermal pouch, and the superior parathyroids derive from the dorsal segment of the fourth pouch (18). In the mouse (19) and the rat (20), however, there is only one pair of parathyroids, which derives from differentiation of the dorsal segment of the third pharyngeal pouch between 11 and 11.5 d of embryonic life (17). The dorsal wall of the fourth pouch, which in most mammals produces the second pair of parathyroids, degenerates at this precise stage of mouse organogenesis for unknown reasons (17). Thus, it is conceivable that epithelial cells within the rodent thymus acquire the ability to produce PTH to compensate for the lack of a second pair of parathyroids glands. Interestingly, the coexpression of PTH and Gcm1, rather than Gcm2, in these cells strongly suggests that under certain circumstances Gcm1 can subserve the embryological functions of Gcm2.

A second goal of our study was to determine whether intrathymic adenomas that produce PTH are derived from thymic epithelial cells or parathyroid cells. All of the intrathymic PTH-producing adenomas that we analyzed expressed the parathyroid-specific GCMB gene and not GCMA. By contrast, RT-PCR analysis of 13 nonparathyroid endocrine tumors was negative for GCMB, indicating that this marker is specific not only for regular parathyroid tissue (21), but also for tumors of parathyroid origin. Although it is theoretically possible that ectopic expression of GCMB in thymic epithelial cells has induced transition to a PTH-producing adenoma, it is much more likely that these tumors are derived from parathyroid cells that had migrated errantly during embryogenesis.

Although recent evidence supports a fundamental role for GCMB in the development of the differentiated parathyroid phenotype, the function of GCMB in mature parathyroid tissue or in a parathyroid adenoma is presently unknown. Anomalous expression of GCMB by some nonparathyroid cancers (22, 23, 24) may account for the ectopic production of PTH by these neoplasms. It is also possible that continued expression of GCMB is required for maintenance of the differentiated phenotype that allows sustained production of PTH (21). Some parathyroid cancers stop synthesizing PTH as they become undifferentiated, and it is tempting to speculate that this change is preceded by loss of GCMB expression.

In summary, our study confirms that mouse thymus serves as an auxiliary source of PTH and indicates that human thymus does not subserve a similar function. Finally, our results demonstrate that intrathymic parathyroid adenomas express GCMB and not GCMA, and are thus more likely to be derived from true parathyroid cells rather than from thymic epithelial cells.


   Acknowledgments
 
We gratefully acknowledge the generous contribution of thymic samples and biopsy sections of transplanted thymus tissues from Prof. B. Bodey and Dr. M. L. Markert, and samples of RNA from endocrine tissues from Dr. C. Stratakis.


   Footnotes
 
This work was supported in part by a grant from the Endocrine Fellows Foundation.

Abbreviation: DIG, Digoxigenin.

Received April 25, 2003.

Accepted September 17, 2003.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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