Endocrine Unit Massachusetts General Hospital and Harvard Medical School Boston, Massachusetts 02114
Address all correspondence and requests for reprints to: Henry M. Kronenberg, M.D., Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114.
Glial cell missingnot exactly the name you or I would choose for a gene that directs the construction of parathyroid glands. How this happened is a great story, one that illustrates the way medical progress requires the efforts of broad-based basic science, combined with savvy follow-up by patient-oriented scientists. In this issue of JCEM, Maret et al. (1) apply current understanding of the glial cell missing family to clarify the origins of human parathyroid adenomas buried in the thymus gland. Here, I will expand on their nice summary of the field and speculate a bit about future directions.
The story starts with geneticists studying neural development in the fruit fly, Drosophila melanogaster. Glial cell missing (gcm) was found to encode a crucial transcription factor that determines glial vs. neural cell fates (reviewed in Ref. 2). In the absence of gcm, cells fated to become glia became neurons instead. Remarkably, expression of gcm in cells not fated to become glia converted those cells to glia. Neurobiologists eager to understand how the mammalian nervous system is constructed found two relatives of Drosophila gcm in the mammalian genome, called gcm1 and gcm2 in rodents and GCMA and GCMB in humans. Both mammalian gcm proteins closely resemble their Drosophila counterpart in their DNA-binding regions. Remarkably, rat gcm1 could substitute for Drosophila gcm in glial cells in vivo (3).
Surprisingly, these investigators found that neither mammalian gcm family member was expressed in the brain, except at trace levels during development. Instead, gcm1 was expressed primarily in the placenta, and gcm2 was expressed primarily in the parathyroid gland, two tissues novel to relatively recent vertebrate species. Ablation of the gcm1 gene in mice led to early death because of malfunction of the placental labyrinth (4, 5). Ablation of gcm2 led to complete absence of parathyroid glands (6). The resultant mice, not surprisingly, were hypocalcemic and hyperphosphatemic. Surprisingly though, they still made some PTH. The source of the hormone was a very small cluster of cells in the thymus. These cells synthesized PTH and expressed the calcium-sensing receptor, as expected for parathyroid chief cells. They also expressed gcm1; it is possible that this gcm1 expression explains the small number of parathyroid cells in the thymus, even in mice missing gcm2. Thus, Gunther et al. (6) had not only discovered the essential role for gcm2 in parathyroid gland formation, but they had also discovered that the murine thymus is the host for a small number of PTH-producing cells.
The mouse, like the rat but unlike most species with parathyroid glands, has only two parathyroid glands. Parathyroids in most species develop from endodermal cells found in the third and fourth branchial pouches. The endoderm of the third pouch also forms the thymus, whereas the endoderm of the fourth pouch also forms the calcitonin-producing C cells of the thyroid. In the mouse, the endoderm of the fourth branchial pouch fails to produce parathyroid tissue. A still incompletely understood cascade of transcription factors determines cell fates within the third and fourth branchial pouches. The activities of hoxa3, pax 1, pax 9, and eya1 all contribute to initial expression and/or maintenance of expression of gcm2 in the future parathyroid tissue (7, 8, 9, 10), although, unlike gcm2, these other transcription factors are expressed in many pharyngeal tissues.
For clinical investigators, the next crucial question was how much the fascinating journey of the gcm transcription factors from Drosophila to mouse has relevance to human biology and disease. Ding et al. (11) provided an important part of the answer when they identified a family with a large, homozygous, intragenic deletion within the GCMB gene. The affected proband presented at 5 wk of age with generalized seizures and was found to be severely hypoparathyroid. Initially, the patients PTH level was undetectable using a two-site immunoradiometric assay, but rose into the low normal range by 19 months of age. The findings in this family strongly suggest that, just as in the mouse, GCMB is required for formation of parathyroid glands. The eventual modest secretion of PTH from some source into the blood stream raises the question of whether a source of PTH analogous to the thymic source in mice also exists in humans.
Now Maret et al. (1) examine directly the possible location of PTH-producing cells in the human thymus and explore the origin of parathyroid adenomas that can be commonly found buried within thymic tissue. Using sensitive PCR technology, they fail to find evidence of PTH or GCMA mRNA in fetal or adult human thymus. They then ask whether parathyroid adenomas sometimes found in the thymus synthesize GCMA instead of GCMB; this observation might be predicted from the pattern of gcm gene expression in the mouse thymus. Instead, however, they find that human parathyroid adenomas synthesize GCMB exclusively. These glands, therefore, represent parathyroid glands formed in the normal manner along with the thymus in the third branchial pouch. Somewhat anomalous migration, a quite common normal variation, presumably explains the location of the adenomas within the thymus. Little is understood about the control of migration of organs in the neck, although the finding of anomalous migration of parathyroid tissue in mice with hox group 3 gene mutations (12) suggests that hox genes not only specify tissue identity but also influence tissue migration.
Where can we guess this story is heading? The continued expression of GCMB in adult parathyroid tissue suggests that this transcription factor may have a continuing role in parathyroid gland biology. Perhaps GCMB regulates expression of the PTH gene and other genes expressed in the parathyroid. Alternatively, GCMB may regulate proliferation or programmed cell death of parathyroid cells. In any case, the striking specificity of expression of GCMB virtually exclusively in the parathyroid chief cell makes it an appealing target for possible drug development. One might speculate that small molecules that interact only with GCMB might allow manipulation of parathyroid chief cell function with few if any extraneous effects. One can hope that we are only near the beginning of human applications of this scientific story that began with the study of glial cell development in Drosophila.
Footnotes
Abbreviation: gcm or GCM, Glial cell missing.
Received November 10, 2003.
Accepted November 10, 2003.
References
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