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. 1996 Nov;2(6):735–744.

Feedback control of glucocorticoid production is established during fetal development.

H M Reichardt 1, G Schütz 1
PMCID: PMC2230142  PMID: 8972488

Abstract

BACKGROUND: Glucocorticoids are involved in the regulation of metabolic, immunological, and developmental processes. Their synthesis is tightly controlled by feedback regulation through the hypothalamus-pituitary-adrenal (HPA) axis, allowing the organism to respond to stress in an adequate manner and to adapt to new situations. Disturbance of these regulatory mechanisms leads to major human diseases. By generating mice with a targeted mutation in the glucocorticoid receptor (GR) locus, it was possible to analyze the mechanism by which glucocorticoids control the HPA axis, under conditions where at least part of the feedback control was absent early in development. MATERIALS AND METHODS: RNase-protection and in situ hybridization assays were used to compare messenger RNA (mRNA) levels of genes involved in the control of the HPA axis in both GR-mutant and wild-type animals. RESULTS: Negative feedback regulation of the HPA axis by glucocorticoids, which is established around Day E16.5 of embryonic development in wild-type mice, does not occur in GR-mutants, resulting in an increased expression of proopiomelanocortin mRNA in the anterior lobe of the pituitary and of corticotropin-releasing hormone mRNA in the paraventricular nucleus of the hypothalamus. However, the expression of both arginine vasopressin and mineralocorticoid receptor in the brain is not affected. In the neurointermediate lobe of the pituitary, expression of the proopiomelanocortin gene was inversely regulated, compared with its expression in the anterior lobe. CONCLUSIONS: GR-dependent regulation of the HPA axis is established during fetal development, suggesting that maternal factors have an important role in influencing the HPA axis of the adult offspring.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Autelitano D. J., Clements J. A., Nikolaidis I., Canny B. J., Funder J. W. Concomitant dopaminergic and glucocorticoid control of pituitary proopiomelanocortin messenger ribonucleic acid and beta-endorphin levels. Endocrinology. 1987 Nov;121(5):1689–1696. doi: 10.1210/endo-121-5-1689. [DOI] [PubMed] [Google Scholar]
  2. Autelitano D. J., Lundblad J. R., Blum M., Roberts J. L. Hormonal regulation of POMC gene expression. Annu Rev Physiol. 1989;51:715–726. doi: 10.1146/annurev.ph.51.030189.003435. [DOI] [PubMed] [Google Scholar]
  3. Beato M., Herrlich P., Schütz G. Steroid hormone receptors: many actors in search of a plot. Cell. 1995 Dec 15;83(6):851–857. doi: 10.1016/0092-8674(95)90201-5. [DOI] [PubMed] [Google Scholar]
  4. Birnberg N. C., Lissitzky J. C., Hinman M., Herbert E. Glucocorticoids regulate proopiomelanocortin gene expression in vivo at the levels of transcription and secretion. Proc Natl Acad Sci U S A. 1983 Nov;80(22):6982–6986. doi: 10.1073/pnas.80.22.6982. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. 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]
  6. Cole T. J., Blendy J. A., Monaghan A. P., Krieglstein K., Schmid W., Aguzzi A., Fantuzzi G., Hummler E., Unsicker K., Schütz G. Targeted disruption of the glucocorticoid receptor gene blocks adrenergic chromaffin cell development and severely retards lung maturation. Genes Dev. 1995 Jul 1;9(13):1608–1621. doi: 10.1101/gad.9.13.1608. [DOI] [PubMed] [Google Scholar]
  7. Cullinan W. E., Herman J. P., Watson S. J. Ventral subicular interaction with the hypothalamic paraventricular nucleus: evidence for a relay in the bed nucleus of the stria terminalis. J Comp Neurol. 1993 Jun 1;332(1):1–20. doi: 10.1002/cne.903320102. [DOI] [PubMed] [Google Scholar]
  8. Drouin J., Sun Y. L., Chamberland M., Gauthier Y., De Léan A., Nemer M., Schmidt T. J. Novel glucocorticoid receptor complex with DNA element of the hormone-repressed POMC gene. EMBO J. 1993 Jan;12(1):145–156. doi: 10.1002/j.1460-2075.1993.tb05640.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Dupouy J. P., Chatelain A. In-vitro effects of corticosterone, synthetic ovine corticotrophin releasing factor and arginine vasopressin on the release of adrenocorticotrophin by fetal rat pituitary glands. J Endocrinol. 1984 Jun;101(3):339–344. doi: 10.1677/joe.0.1010339. [DOI] [PubMed] [Google Scholar]
  10. Herman J. P., Adams D., Prewitt C. Regulatory changes in neuroendocrine stress-integrative circuitry produced by a variable stress paradigm. Neuroendocrinology. 1995 Feb;61(2):180–190. doi: 10.1159/000126839. [DOI] [PubMed] [Google Scholar]
  11. Holmes M. C., Yau J. L., French K. L., Seckl J. R. The effect of adrenalectomy on 5-hydroxytryptamine and corticosteroid receptor subtype messenger RNA expression in rat hippocampus. Neuroscience. 1995 Jan;64(2):327–337. doi: 10.1016/0306-4522(94)00407-v. [DOI] [PubMed] [Google Scholar]
  12. Hyodo S., Yamada C., Takezawa T., Urano A. Expression of provasopressin gene during ontogeny in the hypothalamus of developing mice. Neuroscience. 1992;46(1):241–250. doi: 10.1016/0306-4522(92)90024-v. [DOI] [PubMed] [Google Scholar]
  13. Joëls M., de Kloet E. R. Mineralocorticoid and glucocorticoid receptors in the brain. Implications for ion permeability and transmitter systems. Prog Neurobiol. 1994 May;43(1):1–36. doi: 10.1016/0301-0082(94)90014-0. [DOI] [PubMed] [Google Scholar]
  14. Kaestner K. H., Ntambi J. M., Kelly T. J., Jr, Lane M. D. Differentiation-induced gene expression in 3T3-L1 preadipocytes. A second differentially expressed gene encoding stearoyl-CoA desaturase. J Biol Chem. 1989 Sep 5;264(25):14755–14761. [PubMed] [Google Scholar]
  15. Keegan C. E., Herman J. P., Karolyi I. J., O'Shea K. S., Camper S. A., Seasholtz A. F. Differential expression of corticotropin-releasing hormone in developing mouse embryos and adult brain. Endocrinology. 1994 Jun;134(6):2547–2555. doi: 10.1210/endo.134.6.8194481. [DOI] [PubMed] [Google Scholar]
  16. Lindley S. E., Lookingland K. J., Moore K. E. Dopaminergic and beta-adrenergic receptor control of alpha-melanocyte-stimulating hormone secretion during stress. Neuroendocrinology. 1990 Jul;52(1):46–51. doi: 10.1159/000125537. [DOI] [PubMed] [Google Scholar]
  17. Lugo D. I., Pintar J. E. Ontogeny of basal and regulated proopiomelanocortin-derived peptide secretion from fetal and neonatal pituitary intermediate lobe cells: melanotrophs exhibit transient glucocorticoid responses during development. Dev Biol. 1996 Jan 10;173(1):110–118. doi: 10.1006/dbio.1996.0010. [DOI] [PubMed] [Google Scholar]
  18. Lugo D. I., Pintar J. E. Ontogeny of basal and regulated secretion from POMC cells of the developing anterior lobe of the rat pituitary gland. Dev Biol. 1996 Jan 10;173(1):95–109. doi: 10.1006/dbio.1996.0009. [DOI] [PubMed] [Google Scholar]
  19. Makino S., Smith M. A., Gold P. W. Increased expression of corticotropin-releasing hormone and vasopressin messenger ribonucleic acid (mRNA) in the hypothalamic paraventricular nucleus during repeated stress: association with reduction in glucocorticoid receptor mRNA levels. Endocrinology. 1995 Aug;136(8):3299–3309. doi: 10.1210/endo.136.8.7628364. [DOI] [PubMed] [Google Scholar]
  20. Michelsohn A. M., Anderson D. J. Changes in competence determine the timing of two sequential glucocorticoid effects on sympathoadrenal progenitors. Neuron. 1992 Mar;8(3):589–604. doi: 10.1016/0896-6273(92)90285-l. [DOI] [PubMed] [Google Scholar]
  21. Muglia L., Jacobson L., Dikkes P., Majzoub J. A. Corticotropin-releasing hormone deficiency reveals major fetal but not adult glucocorticoid need. Nature. 1995 Feb 2;373(6513):427–432. doi: 10.1038/373427a0. [DOI] [PubMed] [Google Scholar]
  22. Plotsky P. M., Sawchenko P. E. Hypophysial-portal plasma levels, median eminence content, and immunohistochemical staining of corticotropin-releasing factor, arginine vasopressin, and oxytocin after pharmacological adrenalectomy. Endocrinology. 1987 Apr;120(4):1361–1369. doi: 10.1210/endo-120-4-1361. [DOI] [PubMed] [Google Scholar]
  23. Plotsky P. M., Thrivikraman K. V., Meaney M. J. Central and feedback regulation of hypothalamic corticotropin-releasing factor secretion. Ciba Found Symp. 1993;172:59–84. doi: 10.1002/9780470514368.ch4. [DOI] [PubMed] [Google Scholar]
  24. Reul J. M., Stec I., Wiegers G. J., Labeur M. S., Linthorst A. C., Arzt E., Holsboer F. Prenatal immune challenge alters the hypothalamic-pituitary-adrenocortical axis in adult rats. J Clin Invest. 1994 Jun;93(6):2600–2607. doi: 10.1172/JCI117272. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Sawchenko P. E., Imaki T., Potter E., Kovács K., Imaki J., Vale W. The functional neuroanatomy of corticotropin-releasing factor. Ciba Found Symp. 1993;172:5–29. doi: 10.1002/9780470514368.ch2. [DOI] [PubMed] [Google Scholar]
  26. Tamura T., Sumita K., Fujino I., Aoyama A., Horikoshi M., Hoffmann A., Roeder R. G., Muramatsu M., Mikoshiba K. Striking homology of the 'variable' N-terminal as well as the 'conserved core' domains of the mouse and human TATA-factors (TFIID). Nucleic Acids Res. 1991 Jul 25;19(14):3861–3865. doi: 10.1093/nar/19.14.3861. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Young W. S., 3rd Regulation of gene expression in the hypothalamus: hybridization histochemical studies. Ciba Found Symp. 1992;168:127–143. [PubMed] [Google Scholar]

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