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

English version České info

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.”

Vyšlo v časopise: Thymus-Associated Parathyroid Hormone Has Two Cellular Origins with Distinct Endocrine and Immunological Functions. PLoS Genet 6(12): e32767. doi:10.1371/journal.pgen.1001251
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1001251

Souhrn

Zdroje

1. RamasamyI

2006 Recent advances in physiological calcium homeostasis. Clin Chem Lab Med 44 237 273

2. ThakkerRV

2001 Genetic developments in hypoparathyroidism. Lancet 357 974 976

3. LiuZ

YuS

ManleyNR

2007 Gcm2 is required for the differentiation and survival of parathyroid precursor cells in the parathyroid/thymus primordia. Dev Biol 305 333 346

4. GuntherT

ChenZF

KimJ

PriemelM

RuegerJM

2000 Genetic ablation of parathyroid glands reveals another source of parathyroid hormone. Nature 406 199 203

5. PhitayakornR

McHenryCR

2006 Incidence and location of ectopic abnormal parathyroid glands. Am J Surg 191 418 423

6. MaretA

BourdeauI

DingC

KadkolSS

WestraWH

2004 Expression of GCMB by intrathymic parathyroid hormone-secreting adenomas indicates their parathyroid cell origin. J Clin Endocrinol Metab 89 8 12

7. MiaoD

HeB

KaraplisAC

GoltzmanD

2002 Parathyroid hormone is essential for normal fetal bone formation. J Clin Invest 109 1173 1182

8. XueY

KaraplisAC

HendyGN

GoltzmanD

MiaoD

2005 Genetic models show that parathyroid hormone and 1,25-dihydroxyvitamin D3 play distinct and synergistic roles in postnatal mineral ion homeostasis and skeletal development. Hum Mol Genet 14 1515 1528

9. BlackburnCC

ManleyNR

2004 Developing a new paradigm for thymus organogenesis. Nat Rev Immunol 4 278 289

10. ManleyNR

BlackburnCC

2003 A developmental look at thymus organogenesis: where do the non-hematopoietic cells in the thymus come from? Curr Opin Immunol 15 225 232

11. ManleyNR

CondieBG

2010 Transcriptional regulation of thymus organogenesis and thymic epithelial cell differentiation. Prog Mol Biol Transl Sci 92 103 120

12. GilmourJ

1937 The embryology of the parathyroid glands, the thymus, and certain associated rudiments. journal of Pathology 45 507 522

13. WellerG

1933 Development of the thyroid, parathyroid and thymus glands in man. Contrib Embryol 24 93 142

14. NorrisE

1938 The morphogenesis and histogenesis of the thymus gland in man: in which the origin of the Hassall's corpuscles of the human thymus is discovered. Contrib Embryol 27 193

15. Van DykeJ

1959 Aberrant parathyroid tissue and the thymus: postnatal development of accessory parathyroid glands n the rat. Anatomical Record 185 203

16. BaumberL

TufarelliC

PatelS

KingP

JohnsonCA

2005 Identification of a novel mutation disrupting the DNA binding activity of GCM2 in autosomal recessive familial isolated hypoparathyroidism. J Med Genet 42 443 448

17. DingC

BuckinghamB

LevineMA

2001 Familial isolated hypoparathyroidism caused by a mutation in the gene for the transcription factor GCMB. J Clin Invest 108 1215 1220

18. TuQ

PiM

KarsentyG

SimpsonL

LiuS

2003 Rescue of the skeletal phenotype in CasR-deficient mice by transfer onto the Gcm2 null background. J Clin Invest 111 1029 1037

19. SimmondsCS

KarsentyG

KaraplisAC

KovacsCS

2010 Parathyroid hormone regulates fetal-placental mineral homeostasis. Journal of Bone and Mineral Research 25 594 605

20. ChenC

KaluDN

1999 Strain differences in bone density and calcium metabolism between C3H/HeJ and C57BL/6J mice. Bone 25 413 420

21. GordonJ

BennettAR

BlackburnCC

ManleyNR

2001 Gcm2 and Foxn1 mark early parathyroid- and thymus-specific domains in the developing third pharyngeal pouch. Mech Dev 103 141 143

22. AndersonG

MooreNC

OwenJJ

JenkinsonEJ

1996 Cellular interactions in thymocyte development. Ann Rev Immunol 14 73 99

23. DerbinskiJ

SchulteA

KyewskiB

KleinL

2001 Promiscuous gene expression in medullary thymic epithelial cells mirrors the peripheral self. Nat Immunol 2 1032 1039

24. DerbinskiJ

GablerJ

BrorsB

TierlingS

JonnakutyS

2005 Promiscuous gene expression in thymic epithelial cells is regulated at multiple levels. J Exp Med 202 33 45

25. HollanderGA

WangB

NichogiannopoulouA

PlatenburgPP

van EwijkW

1995 Developmental control point in the induction of thymic cortex regulated by a subpopulation of prothymocytes. Nature 373 350 353

26. KlugDB

CarterC

CrouchE

RoopD

ContiCJ

1998 Interdependence of cortical thymic epithelial cell differentiation and T-lineage commitment. Proc Natl Acad Sci U S A 95 11822 11827

27. BlackburnCC

AugustineCL

LiR

HarveyRP

MalinMA

1996 The nu gene acts cell-autonomously and is required for differentiation of thymic epithelial progenitors. Proc Natl Acad Sci USA 93 5742 5746

28. ChisakaO

CapecchiMR

1991 Regionally restricted developmental defects resulting from targeted disruption of the mouse homeobox gene hox-1.5. Nature 350 473 479

29. ManleyNR

CapecchiMR

1995 The role of Hoxa-3 in mouse thymus and thyroid development. Development 121 1989 2003

30. HabenerJF

KronenbergHM

1978 Parathyroid hormone biosynthesis: structure and function of biosynthetic precursors. Fed Proc 37 2561 2566

31. HendyGN

BennettHP

GibbsBF

LazureC

DayR

1995 Proparathyroid hormone is preferentially cleaved to parathyroid hormone by the prohormone convertase furin. A mass spectrometric study. J Biol Chem 270 9517 9525

32. SetogutiT

InoueY

WildP

1995 The biological significance of storage granules in rat parathyroid cells. Microsc Res Tech 32 148 163

33. KronenbergHM

2004 GCMB–another serendipitous gift from evolution to clinical investigators. J Clin Endocrinol Metab 89 6 7

34. WangC

1976 The anatomic basis of parathyroid surgery. Ann Surg 183 271 275

35. BoydJD

1950 Development of the thyroid and parathyroid glands and the thymus. Ann R Coll Surg Engl 7 455 471

36. GillardGO

FarrAG

2005 Contrasting models of promiscuous gene expression by thymic epithelium. J Exp Med 202 15 19

37. DerbinskiJ

PintoS

RoschS

HexelK

KyewskiB

2008 Promiscuous gene expression patterns in single medullary thymic epithelial cells argue for a stochastic mechanism. Proc Natl Acad Sci U S A 105 657 662

38. GäblerJ

2008 Regulation der promisken Genexpression auf molekularer und zellulärer Ebene in medullären Thymusepithelzellen. Heidelberg University of Heidelberg

39. DooleyJ

EricksonM

FarrA

2009 Lessons from Thymic Epithelial Heterogeneity: FoxN1 and Tissue-Restricted Gene Expression by Extrathymic, Endodermally Derived Epithelium. J Immunol 183 5042 5049

40. SrinivasS

WatanabeT

LinCS

WilliamCM

TanabeY

2001 Cre reporter strains produced by targeted insertion of EYFP and ECFP into the ROSA26 locus. BMC Dev Biol 1 4

41. GordonJ

XiaoS

HughesB3rd

SuDM

NavarreSP

2007 Specific expression of lacZ and cre recombinase in fetal thymic epithelial cells by multiplex gene targeting at the Foxn1 locus. BMC Dev Biol 7 69

42. SuD

EllisS

NapierA

LeeK

ManleyNR

2001 Hoxa3 and pax1 regulate epithelial cell death and proliferation during thymus and parathyroid organogenesis. Dev Biol 236 316 329

43. GrayDH

ChidgeyAP

BoydRL

2002 Analysis of thymic stromal cell populations using flow cytometry. J Immunol Methods 260 15 28

44. KovacsCS

ManleyNR