Gcm2 Regulates the Maintenance of Parathyroid Cells in Adult Mice

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2019 Jan 25

PMID 30677043

Citations 21

Authors

Taku Yamada

Norifumi Tatsumi

Akane Anraku

Hideaki Suzuki

Sahoko Kamejima

Taketo Uchiyama

Ichiro Ohkido

Takashi Yokoo

Masataka Okabe

Affiliations

Soon will be listed here.

Abstract

Glial cells missing homolog 2 (GCM2), a zinc finger-type transcription factor, is essential for the development of parathyroid glands. It is considered to be a master regulator because the glands do not form when Gcm2 is deficient. Remarkably, Gcm2 expression is maintained throughout the fetal stage and after birth. Considering the Gcm2 function in embryonic stages, it is predicted that Gcm2 maintains parathyroid cell differentiation and survival in adults. However, there is a lack of research regarding the function of Gcm2 in adulthood. Therefore, we analyzed Gcm2 function in adult tamoxifen-inducible Gcm2 conditional knockout mice. One month after tamoxifen injection, Gcm2-knockout mice showed no significant difference in serum calcium, phosphate, and PTH levels and in the expressions of calcium-sensing receptor (Casr) and parathyroid hormone (Pth), whereas Ki-67 positive cells were decreased and terminal deoxynucleotidyl transferase (TdT) dUTP Nick-End Labeling (TUNEL) positive cell number did not change, as compared with those of controls. Seven months after tamoxifen injection, Gcm2-knockout mice showed shrinkage of the parathyroid glands and fewer parathyroid cells. A significant decrease was noted in Casr- and Pth-expressing cells and serum PTH and Ca levels, whereas serum phosphate levels increased, as compared with those of controls. All our results concluded that a reduction of Gcm2 expression leads to a reduction of parathyroid cell proliferation, an increase in cell death, and an attenuation of parathyroid function. Therefore, we indicate that Gcm2 plays a prominent role in adult parathyroid cell proliferation and maintenance.

Citing Articles

Induced Pluripotent Stem Cell-Derived Parathyroid Organoids Resemble Parathyroid Morphology and Function.

Senkal-Turhan S, Bulut-Okumus E, Aydin M, Turkmen N, Taslidere A, Sahin F Adv Sci (Weinh). 2024; 11(43):e2407567.

PMID: 39331961 PMC: 11578294. DOI: 10.1002/advs.202407567.

Single-cell analysis reveals transcriptional dynamics in healthy primary parathyroid tissue.

Venkat A, Carlino M, Lawton B, Prasad M, Amodio M, Gibson C Genome Res. 2024; 34(6):837-850.

PMID: 38977309 PMC: 11293540. DOI: 10.1101/gr.278215.123.

Directed differentiation of human embryonic stem cells into parathyroid cells and establishment of parathyroid organoids.

Wang G, Du Y, Cui X, Xu T, Li H, Dong M Cell Prolif. 2024; 57(8):e13634.

PMID: 38494923 PMC: 11294423. DOI: 10.1111/cpr.13634.

Epigenetic profiling reveals key genes and cis-regulatory networks specific to human parathyroids.

Jung Y, Zhao W, Li I, Jain D, Epstein C, Bernstein B Nat Commun. 2024; 15(1):2106.

PMID: 38453887 PMC: 10920874. DOI: 10.1038/s41467-024-46181-3.

Identification of conserved skeletal enhancers associated with craniosynostosis risk genes.

He X, Berenson A, Bernard M, Weber C, Cook L, Visel A Hum Mol Genet. 2023; 33(10):837-849.

PMID: 37883470 PMC: 11070136. DOI: 10.1093/hmg/ddad182.

References

Manley N . Thymus organogenesis and molecular mechanisms of thymic epithelial cell differentiation. Semin Immunol. 2000; 12(5):421-8. DOI: 10.1006/smim.2000.0263. View

Chen R, Goodman W . Role of the calcium-sensing receptor in parathyroid gland physiology. Am J Physiol Renal Physiol. 2004; 286(6):F1005-11. DOI: 10.1152/ajprenal.00013.2004. View

Canaff L, Hendy G . Human calcium-sensing receptor gene. Vitamin D response elements in promoters P1 and P2 confer transcriptional responsiveness to 1,25-dihydroxyvitamin D. J Biol Chem. 2002; 277(33):30337-50. DOI: 10.1074/jbc.M201804200. View

Tatsumi N, Kobayashi R, Yano T, Noda M, Fujimura K, Okada N . Molecular developmental mechanism in polypterid fish provides insight into the origin of vertebrate lungs. Sci Rep. 2016; 6:30580. PMC: 4964569. DOI: 10.1038/srep30580. View

Kamitani-Kawamoto A, Hamada M, Moriguchi T, Miyai M, Saji F, Hatamura I . MafB interacts with Gcm2 and regulates parathyroid hormone expression and parathyroid development. J Bone Miner Res. 2011; 26(10):2463-72. DOI: 10.1002/jbmr.458. View

Liu Z, Yu S, Manley N . Gcm2 is required for the differentiation and survival of parathyroid precursor cells in the parathyroid/thymus primordia. Dev Biol. 2007; 305(1):333-46. PMC: 1931567. DOI: 10.1016/j.ydbio.2007.02.014. View

Su D, Ellis S, Napier A, Lee K, Manley N . Hoxa3 and pax1 regulate epithelial cell death and proliferation during thymus and parathyroid organogenesis. Dev Biol. 2001; 236(2):316-29. DOI: 10.1006/dbio.2001.0342. View

Chojnowski J, Masuda K, Trau H, Thomas K, Capecchi M, Manley N . Multiple roles for HOXA3 in regulating thymus and parathyroid differentiation and morphogenesis in mouse. Development. 2014; 141(19):3697-708. PMC: 4197593. DOI: 10.1242/dev.110833. View

Han S, Tsunekage Y, Kataoka K . Gata3 cooperates with Gcm2 and MafB to activate parathyroid hormone gene expression by interacting with SP1. Mol Cell Endocrinol. 2015; 411:113-20. DOI: 10.1016/j.mce.2015.04.018. View

10.

Gordon J, Bennett A, Blackburn C, Manley N . Gcm2 and Foxn1 mark early parathyroid- and thymus-specific domains in the developing third pharyngeal pouch. Mech Dev. 2001; 103(1-2):141-3. DOI: 10.1016/s0925-4773(01)00333-1. View

11.

Mizobuchi M, Ritter C, Krits I, Slatopolsky E, Sicard G, Brown A . Calcium-sensing receptor expression is regulated by glial cells missing-2 in human parathyroid cells. J Bone Miner Res. 2009; 24(7):1173-9. PMC: 2697623. DOI: 10.1359/jbmr.090211. View

12.

Stephen A, Chen K, Milas M, Siperstein A . The coming of age of radiation-induced hyperparathyroidism: evolving patterns of thyroid and parathyroid disease after head and neck irradiation. Surgery. 2005; 136(6):1143-53. DOI: 10.1016/j.surg.2004.06.042. View

13.

DAgruma L, Coco M, Guarnieri V, Battista C, Canaff L, Salcuni A . Increased prevalence of the GCM2 polymorphism, Y282D, in primary hyperparathyroidism: analysis of three Italian cohorts. J Clin Endocrinol Metab. 2014; 99(12):E2794-8. DOI: 10.1210/jc.2014-2857. View

14.

Chang W, Shoback D . Extracellular Ca2+-sensing receptors--an overview. Cell Calcium. 2004; 35(3):183-96. DOI: 10.1016/j.ceca.2003.10.012. View

15.

Hendy G, Canaff L, Cole D . The CASR gene: alternative splicing and transcriptional control, and calcium-sensing receptor (CaSR) protein: structure and ligand binding sites. Best Pract Res Clin Endocrinol Metab. 2013; 27(3):285-301. DOI: 10.1016/j.beem.2013.02.009. View

16.

Kawahara M, Iwasaki Y, Sakaguchi K, Taguchi T, Nishiyama M, Nigawara T . Involvement of GCMB in the transcriptional regulation of the human parathyroid hormone gene in a parathyroid-derived cell line PT-r: effects of calcium and 1,25(OH)2D3. Bone. 2010; 47(3):534-41. DOI: 10.1016/j.bone.2010.05.031. View

17.

Morito N, Yoh K, Usui T, Oishi H, Ojima M, Fujita A . Transcription factor MafB may play an important role in secondary hyperparathyroidism. Kidney Int. 2017; 93(1):54-68. DOI: 10.1016/j.kint.2017.06.023. View

18.

Kim J, Jones B, Zock C, Chen Z, Wang H, Goodman C . Isolation and characterization of mammalian homologs of the Drosophila gene glial cells missing. Proc Natl Acad Sci U S A. 1998; 95(21):12364-9. PMC: 22837. DOI: 10.1073/pnas.95.21.12364. View

19.

Yuan Z, Opas E, Vrikshajanani C, Libutti S, Levine M . Generation of mice encoding a conditional null allele of Gcm2. Transgenic Res. 2014; 23(4):631-41. PMC: 4086301. DOI: 10.1007/s11248-014-9799-7. View

20.

Guan B, Welch J, Sapp J, Ling H, Li Y, Johnston J . GCM2-Activating Mutations in Familial Isolated Hyperparathyroidism. Am J Hum Genet. 2016; 99(5):1034-1044. PMC: 5097944. DOI: 10.1016/j.ajhg.2016.08.018. View