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Thymus-Associated Parathyroid Hormone Has Two Cellular Origins with Distinct Endocrine and Immunological Functions

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      Abstract

      In mammals, parathyroid hormone (PTH) is a key regulator of extracellular calcium and inorganic phosphorus homeostasis. Although the parathyroid glands were thought to be the only source of PTH, extra-parathyroid PTH production in the thymus, which shares a common origin with parathyroids during organogenesis, has been proposed to provide an auxiliary source of PTH, resulting in a higher than expected survival rate for aparathyroid Gcm2 −/− mutants. However, the developmental ontogeny and cellular identity of these “thymic” PTH–expressing cells is unknown. We found that the lethality of aparathyroid Gcm2 −/− mutants was affected by genetic background without relation to serum PTH levels, suggesting a need to reconsider the physiological function of thymic PTH. We identified two sources of extra-parathyroid PTH in wild-type mice. Incomplete separation of the parathyroid and thymus organs during organogenesis resulted in misplaced, isolated parathyroid cells that were often attached to the thymus; this was the major source of thymic PTH in normal mice. Analysis of thymus and parathyroid organogenesis in human embryos showed a broadly similar result, indicating that these results may provide insight into human parathyroid development. In addition, medullary thymic epithelial cells (mTECs) express PTH in a Gcm2-independent manner that requires TEC differentiation and is consistent with expression as a self-antigen for negative selection. Genetic or surgical removal of the thymus indicated that thymus-derived PTH in Gcm2 −/− mutants did not provide auxiliary endocrine function. Our data show conclusively that the thymus does not serve as an auxiliary source of either serum PTH or parathyroid function. We further show that the normal process of parathyroid organogenesis in both mice and humans leads to the generation of multiple small parathyroid clusters in addition to the main parathyroid glands, that are the likely source of physiologically relevant “thymic PTH.”

      Author Summary

      Due to the important role of PTH in the regulation of physiological activities, disorders in PTH production can cause many diseases in humans. Thus it is very important to understand where PTH is produced and how it is regulated. Many people have been found to have ectopic and supernumerary parathyroid glands without clear ontogenesis. In addition, the thymus, which develops together with the parathyroid during embryogenesis, has been proposed to be an auxiliary source of PTH with endocrine function; however, PTH is also a tissue-restricted self-antigen expressed by the thymus. In this paper, we provide insights into the ontogeny and function of thymus-associated PTH. We found that ectopic and supernumerary parathyroid glands originate from the normal developmental process underlying the separation of parathyroid and thymus, resulting in misplaced parathyroids close or attached to thymus. In the thymus, thymic epithelial cells can produce a low level of PTH via a different mechanism than the parathyroid and provide functional data that TEC-derived PTH does not have endocrine function. In summary, our data show that the thymic source of PTH has no endocrine function and, instead, has an expression pattern in the thymus consistent with that of a self-antigen for negative selection.

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      Most cited references 42

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      Cre reporter strains produced by targeted insertion of EYFP and ECFP into the ROSA26 locus

      Background Several Cre reporter strains of mice have been described, in which a lacZ gene is turned on in cells expressing Cre recombinase, as well as their daughter cells, following Cre-mediated excision of a loxP-flanked transcriptional "stop" sequence. These mice are useful for cell lineage tracing experiments as well as for monitoring the expression of Cre transgenes. The green fluorescent protein (GFP) and variants such as EYFP and ECFP offer an advantage over lacZ as a reporter, in that they can be easily visualized without recourse to the vital substrates required to visualize β-gal in living tissue. Results In view of the general utility of targeting the ubiquitously expressed ROSA26 locus, we constructed a generic ROSA26 targeting vector. We then generated two reporter lines of mice by inserting EYFP or ECFP cDNAs into the ROSA26 locus, preceded by a loxP-flanked stop sequence. These strains were tested by crossing them with transgenic strains expressing Cre in a ubiquitous (β-actin-Cre) or a cell-specific (Isl1-Cre and En1-Cre) pattern. The resulting EYFP or ECFP expression patterns indicated that the reporter strains function as faithful monitors of Cre activity. Conclusions In contrast to existing lacZ reporter lines, where lacZ expression cannot easily be detected in living tissue, the EYFP and ECFP reporter strains are useful for monitoring the expression of Cre and tracing the lineage of these cells and their descendants in cultured embryos or organs. The non-overlapping emission spectra of EYFP and ECFP make them ideal for double labeling studies in living tissues.
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        Promiscuous gene expression in medullary thymic epithelial cells mirrors the peripheral self.

        Expression of peripheral antigens in the thymus has been implicated in T cell tolerance and autoimmunity. Here we identified medullary thymic epithelial cells as being a unique cell type that expresses a diverse range of tissue-specific antigens. We found that this promiscuous gene expression was a cell-autonomous property of medullary epithelial cells and was maintained during the entire period of thymic T cell output. It may facilitate tolerance induction to self-antigens that would otherwise be temporally or spatially secluded from the immune system. However, the array of promiscuously expressed self-antigens appeared random rather than selected and was not confined to secluded self-antigens.
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          Promiscuous gene expression in thymic epithelial cells is regulated at multiple levels

          The role of central tolerance induction has recently been revised after the discovery of promiscuous expression of tissue-restricted self-antigens in the thymus. The extent of tissue representation afforded by this mechanism and its cellular and molecular regulation are barely defined. Here we show that medullary thymic epithelial cells (mTECs) are specialized to express a highly diverse set of genes representing essentially all tissues of the body. Most, but not all, of these genes are induced in functionally mature CD80hi mTECs. Although the autoimmune regulator (Aire) is responsible for inducing a large portion of this gene pool, numerous tissue-restricted genes are also up-regulated in mature mTECs in the absence of Aire. Promiscuously expressed genes tend to colocalize in clusters in the genome. Analysis of a particular gene locus revealed expression of clustered genes to be contiguous within such a cluster and to encompass both Aire-dependent and –independent genes. A role for epigenetic regulation is furthermore implied by the selective loss of imprinting of the insulin-like growth factor 2 gene in mTECs. Our data document a remarkable cellular and molecular specialization of the thymic stroma in order to mimic the transcriptome of multiple peripheral tissues and, thus, maximize the scope of central self-tolerance.
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            Author and article information

            Affiliations
            [1 ]Department of Genetics, University of Georgia, Athens, Georgia, United States of America
            [2 ]Medical Research Council Centre for Regenerative Medicine, Institute for Stem Cell Research, School of Biological Sciences, University of Edinburgh, Edinburgh, United Kingdom
            [3 ]Faculty of Medicine-Endocrinology, Memorial University of Newfoundland, St. John's, Newfoundland, Canada
            University of Washington, United States of America
            Author notes

            Conceived and designed the experiments: ZL AF CSK CCB NRM. Performed the experiments: ZL AF LC BJK. Analyzed the data: ZL AF LC BJK CSK CCB NRM. Wrote the paper: ZL AF LC CSK CCB NRM.

            Contributors
            Role: Editor
            Journal
            PLoS Genet
            plos
            plosgen
            PLoS Genetics
            Public Library of Science (San Francisco, USA )
            1553-7390
            1553-7404
            December 2010
            December 2010
            23 December 2010
            : 6
            : 12
            3009658
            21203493
            10-PLGE-RA-4126R2
            10.1371/journal.pgen.1001251
            (Editor)
            Liu et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
            Counts
            Pages: 12
            Categories
            Research Article
            Developmental Biology/Embryology
            Developmental Biology/Molecular Development
            Developmental Biology/Morphogenesis and Cell Biology
            Developmental Biology/Organogenesis
            Immunology/Autoimmunity
            Physiology/Endocrinology

            Genetics

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