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. 1993 Jan 1;120(1):235–243. doi: 10.1083/jcb.120.1.235

Parathyroid hormone-related peptide as an endogenous inducer of parietal endoderm differentiation

PMCID: PMC2119495  PMID: 8380175

Abstract

Parathyroid hormone related peptide (PTHrP), first identified in tumors from patients with the syndrome of "Humoral Hypercalcemia of Malignancy," can replace parathyroid hormone (PTH) in activating the PTH-receptor in responsive cells. Although PTHrP expression is widespread in various adult and fetal tissues, its normal biological function is as yet unknown. We have examined the possible role of PTHrP and the PTH/PTHrP-receptor in early mouse embryo development. Using F9 embryonal carcinoma (EC) cells and ES-5 embryonic stem (ES) cells as in vitro models, we demonstrate that during the differentiation of these cells towards primitive and parietal endoderm-like phenotypes, PTH/PTHrP-receptor mRNA is induced. This phenomenon is correlated with the appearance of functional adenylate cyclase coupled PTH/PTHrP- receptors. These receptors are the mouse homologues of the recently cloned rat bone and opossum kidney PTH/PTHrP-receptors. Addition of exogenous PTH or PTHrP to RA-treated EC or ES cells is an efficient replacement for dBcAMP in inducing full parietal endoderm differentiation. Endogenous PTHrP is detectable at very low levels in undifferentiated EC and ES cells, and is upregulated in their primitive and parietal endoderm-like derivatives as assessed by immunofluorescence. Using confocal laser scanning microscopy on preimplantation mouse embryos, PTHrP is detected from the late morula stage onwards in developing trophectoderm cells, but not in inner cell mass cells. In blastocyst stages PTHrP is in addition found in the first endoderm derivatives of the inner cell mass. Together these results indicate that the PTH/PTHrP-receptor signalling system serves as a para- or autocrine mechanism for parietal endoderm differentiation in the early mouse embryo, thus constituting the earliest hormone receptor system involved in embryogenesis defined to date.

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Selected References

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  1. Abou-Samra A. B., Jüppner H., Force T., Freeman M. W., Kong X. F., Schipani E., Urena P., Richards J., Bonventre J. V., Potts J. T., Jr Expression cloning of a common receptor for parathyroid hormone and parathyroid hormone-related peptide from rat osteoblast-like cells: a single receptor stimulates intracellular accumulation of both cAMP and inositol trisphosphates and increases intracellular free calcium. Proc Natl Acad Sci U S A. 1992 Apr 1;89(7):2732–2736. doi: 10.1073/pnas.89.7.2732. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Adamson E. D., Strickland S., Tu M., Kahan B. A teratocarcinoma-derived endoderm stem cell line (1H5) that can differentiate into extra-embryonic endoderm cell types. Differentiation. 1985;29(1):68–76. doi: 10.1111/j.1432-0436.1985.tb00294.x. [DOI] [PubMed] [Google Scholar]
  3. Atillasoy E. J., Burtis W. J., Milstone L. M. Immunohistochemical localization of parathyroid hormone-related protein (PTHRP) in normal human skin. J Invest Dermatol. 1991 Feb;96(2):277–280. doi: 10.1111/1523-1747.ep12464480. [DOI] [PubMed] [Google Scholar]
  4. Barlow D. P., Green N. M., Kurkinen M., Hogan B. L. Sequencing of laminin B chain cDNAs reveals C-terminal regions of coiled-coil alpha-helix. EMBO J. 1984 Oct;3(10):2355–2362. doi: 10.1002/j.1460-2075.1984.tb02140.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Campos R. V., Asa S. L., Drucker D. J. Immunocytochemical localization of parathyroid hormone-like peptide in the rat fetus. Cancer Res. 1991 Dec 1;51(23 Pt 1):6351–6357. [PubMed] [Google Scholar]
  6. Chan S. D., Strewler G. J., King K. L., Nissenson R. A. Expression of a parathyroid hormone-like protein and its receptor during differentiation of embryonal carcinoma cells. Mol Endocrinol. 1990 Apr;4(4):638–646. doi: 10.1210/mend-4-4-638. [DOI] [PubMed] [Google Scholar]
  7. Chomczynski P., Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987 Apr;162(1):156–159. doi: 10.1006/abio.1987.9999. [DOI] [PubMed] [Google Scholar]
  8. Drucker D. J., Asa S. L., Henderson J., Goltzman D. The parathyroid hormone-like peptide gene is expressed in the normal and neoplastic human endocrine pancreas. Mol Endocrinol. 1989 Oct;3(10):1589–1595. doi: 10.1210/mend-3-10-1589. [DOI] [PubMed] [Google Scholar]
  9. Evain D., Binet E., Anderson W. B. Alterations in calcitonin and parathyroid hormone responsiveness of adenylate cyclase in F9 embryonal carcinoma cells treated with retinoic acid and dibutyryl cyclic AMP. J Cell Physiol. 1981 Dec;109(3):453–459. doi: 10.1002/jcp.1041090311. [DOI] [PubMed] [Google Scholar]
  10. Evans M. J., Kaufman M. H. Establishment in culture of pluripotential cells from mouse embryos. Nature. 1981 Jul 9;292(5819):154–156. doi: 10.1038/292154a0. [DOI] [PubMed] [Google Scholar]
  11. Fort P., Marty L., Piechaczyk M., el Sabrouty S., Dani C., Jeanteur P., Blanchard J. M. Various rat adult tissues express only one major mRNA species from the glyceraldehyde-3-phosphate-dehydrogenase multigenic family. Nucleic Acids Res. 1985 Mar 11;13(5):1431–1442. doi: 10.1093/nar/13.5.1431. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Gardner R. L. Regeneration of endoderm from primitive ectoderm in the mouse embryo: fact or artifact? J Embryol Exp Morphol. 1985 Aug;88:303–326. [PubMed] [Google Scholar]
  13. Hogan B. L., Taylor A., Adamson E. Cell interactions modulate embryonal carcinoma cell differentiation into parietal or visceral endoderm. Nature. 1981 May 21;291(5812):235–237. doi: 10.1038/291235a0. [DOI] [PubMed] [Google Scholar]
  14. Hogan B. L., Tilly R. Cell interactions and endoderm differentiation in cultured mouse embryos. J Embryol Exp Morphol. 1981 Apr;62:379–394. [PubMed] [Google Scholar]
  15. Jüppner H., Abou-Samra A. B., Freeman M., Kong X. F., Schipani E., Richards J., Kolakowski L. F., Jr, Hock J., Potts J. T., Jr, Kronenberg H. M. A G protein-linked receptor for parathyroid hormone and parathyroid hormone-related peptide. Science. 1991 Nov 15;254(5034):1024–1026. doi: 10.1126/science.1658941. [DOI] [PubMed] [Google Scholar]
  16. Liapi C., Gerbaud P., Anderson W. B., Brion D. E. Altered hormonal responses: markers for embryonal and embryonic carcinoma stem cells and their differentiated derivatives. J Cell Physiol. 1987 Nov;133(2):405–408. doi: 10.1002/jcp.1041330229. [DOI] [PubMed] [Google Scholar]
  17. Martin G. R. Isolation of a pluripotent cell line from early mouse embryos cultured in medium conditioned by teratocarcinoma stem cells. Proc Natl Acad Sci U S A. 1981 Dec;78(12):7634–7638. doi: 10.1073/pnas.78.12.7634. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Mollenhauer H. H., Morré D. J., Rowe L. D. Alteration of intracellular traffic by monensin; mechanism, specificity and relationship to toxicity. Biochim Biophys Acta. 1990 May 7;1031(2):225–246. doi: 10.1016/0304-4157(90)90008-Z. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Moniz C., Burton P. B., Malik A. N., Dixit M., Banga J. P., Nicolaides K., Quirke P., Knight D. E., McGregor A. M. Parathyroid hormone-related peptide in normal human fetal development. J Mol Endocrinol. 1990 Dec;5(3):259–266. doi: 10.1677/jme.0.0050259. [DOI] [PubMed] [Google Scholar]
  20. Mummery C. L., Feyen A., Freund E., Shen S. Characteristics of embryonic stem cell differentiation: a comparison with two embryonal carcinoma cell lines. Cell Differ Dev. 1990 Jun;30(3):195–206. doi: 10.1016/0922-3371(90)90139-n. [DOI] [PubMed] [Google Scholar]
  21. Orloff J. J., Wu T. L., Stewart A. F. Parathyroid hormone-like proteins: biochemical responses and receptor interactions. Endocr Rev. 1989 Nov;10(4):476–495. doi: 10.1210/edrv-10-4-476. [DOI] [PubMed] [Google Scholar]
  22. Senior P. V., Heath D. A., Beck F. Expression of parathyroid hormone-related protein mRNA in the rat before birth: demonstration by hybridization histochemistry. J Mol Endocrinol. 1991 Jun;6(3):281–290. doi: 10.1677/jme.0.0060281. [DOI] [PubMed] [Google Scholar]
  23. Slager H. G., Lawson K. A., van den Eijnden-van Raaij A. J., de Laat S. W., Mummery C. L. Differential localization of TGF-beta 2 in mouse preimplantation and early postimplantation development. Dev Biol. 1991 Jun;145(2):205–218. doi: 10.1016/0012-1606(91)90120-r. [DOI] [PubMed] [Google Scholar]
  24. Smith A. G., Heath J. K., Donaldson D. D., Wong G. G., Moreau J., Stahl M., Rogers D. Inhibition of pluripotential embryonic stem cell differentiation by purified polypeptides. Nature. 1988 Dec 15;336(6200):688–690. doi: 10.1038/336688a0. [DOI] [PubMed] [Google Scholar]
  25. Strickland S. Mouse teratocarcinoma cells: prospects for the study of embryogenesis and neoplasia. Cell. 1981 May;24(2):277–278. doi: 10.1016/0092-8674(81)90313-5. [DOI] [PubMed] [Google Scholar]
  26. Strickland S., Smith K. K., Marotti K. R. Hormonal induction of differentiation in teratocarcinoma stem cells: generation of parietal endoderm by retinoic acid and dibutyryl cAMP. Cell. 1980 Sep;21(2):347–355. doi: 10.1016/0092-8674(80)90471-7. [DOI] [PubMed] [Google Scholar]
  27. Vestweber D., Kemler R. Rabbit antiserum against a purified surface glycoprotein decompacts mouse preimplantation embryos and reacts with specific adult tissues. Exp Cell Res. 1984 May;152(1):169–178. doi: 10.1016/0014-4827(84)90241-6. [DOI] [PubMed] [Google Scholar]
  28. White J. G., Amos W. B., Fordham M. An evaluation of confocal versus conventional imaging of biological structures by fluorescence light microscopy. J Cell Biol. 1987 Jul;105(1):41–48. doi: 10.1083/jcb.105.1.41. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Williams R. L., Hilton D. J., Pease S., Willson T. A., Stewart C. L., Gearing D. P., Wagner E. F., Metcalf D., Nicola N. A., Gough N. M. Myeloid leukaemia inhibitory factor maintains the developmental potential of embryonic stem cells. Nature. 1988 Dec 15;336(6200):684–687. doi: 10.1038/336684a0. [DOI] [PubMed] [Google Scholar]

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