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Adrenal Zonation and Development

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Adrenal Disorders

Part of the book series: Contemporary Endocrinology ((COE))

Abstract

Proper development and steroidogenic function of the adrenal gland are essential for organism survival. The cortex in the adult adrenal is organized into concentric zones that produce distinct steroid hormones, the zona glomerulosa (zG) produces aldosterone, and the zona fasciculata (zF) produces corticosterone (in rodents) and cortisol (in humans). Homeostasis and regeneration of the cortex are linked to centripetal migration and direct cell fate conversion of cells from the zG to the zF. To define the mechanisms underlying adrenal zonation, it is essential to understand how tissue structure impacts steroidogenic function. This chapter highlights our current knowledge of adrenocortical homeostasis and zonation in the adult, with an emphasis on (1) the adrenal morphology and ultrastructure, (2) the signaling pathways implicated in the control of zonation, and (3) the cellular mechanisms associated with direct cell fate conversion of zG to zF cells, the major pathway underlying centripetal migration and cortical renewal during postnatal homeostasis.

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References

  1. Gallo-Payet N, Battista M-C (2014) Steroidogenesis-adrenal cell signal transduction. In: Terjung R (ed) Compr Physiol. Wiley, Hoboken, NJ, pp 889–964.

    Google Scholar 

  2. Yates R, Katugampola H, Cavlan D, Cogger K, Meimaridou E, Hughes C, Metherell L, Guasti L, King P (2013) Adrenocortical development, maintenance, and disease. In: Curr Top Dev Biol. Elsevier, pp 239–312.

    Google Scholar 

  3. Galati S-J, Hopkins SM, Cheesman KC, Zhuk RA, Levine AC. Primary aldosteronism: emerging trends. Trends Endocrinol Metab. 2013;24:421–30. doi:10.1016/j.tem.2013.05.003.

    Article  CAS  PubMed  Google Scholar 

  4. Magill SB (2014) Pathophysiology, diagnosis, and treatment of mineralocorticoid disorders. In: Terjung R (ed) Compr Physiol. Wiley, Hoboken, NJ, pp 1083–1119.

    Google Scholar 

  5. Pihlajoki M, Dörner J, Cochran RS, Heikinheimo M, Wilson DB (2015) Adrenocortical zonation, renewal, and remodeling. Front Endocrinol. doi: 10.3389/fendo.2015.00027.

  6. Morohashi K, Zubair M. The fetal and adult adrenal cortex. Mol Cell Endocrinol. 2011;336:193–7. doi:10.1016/j.mce.2010.11.026.

    Article  CAS  PubMed  Google Scholar 

  7. Hershkovitz L, Beuschlein F, Klammer S, Krup M, Weinstein Y. Adrenal 20alpha-hydroxysteroid dehydrogenase in the mouse catabolizes progesterone and 11-deoxycorticosterone and is restricted to the X-zone. Endocrinology. 2007;148:976–88. doi:10.1210/en.2006-1100.

    Article  CAS  PubMed  Google Scholar 

  8. Xing Y, Lerario AM, Rainey W, Hammer GD. Development of adrenal cortex zonation. Endocrinol Metab Clin N Am. 2015;44:243–74. doi:10.1016/j.ecl.2015.02.001.

    Article  Google Scholar 

  9. Wood MA, Acharya A, Finco I, Swonger JM, Elston MJ, Tallquist MD, Hammer GD. Fetal adrenal capsular cells serve as progenitor cells for steroidogenic and stromal adrenocortical cell lineages in M. musculus. Development. 2013;140:4522–32. doi:10.1242/dev.092775.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Zubair M, Parker KL, Morohashi K. Developmental links between the fetal and adult zones of the adrenal cortex revealed by lineage tracing. Mol Cell Biol. 2008;28:7030–40. doi:10.1128/MCB.00900-08.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Walczak EM, Hammer GD. Regulation of the adrenocortical stem cell niche: implications for disease. Nat Rev Endocrinol. 2014;11:14–28. doi:10.1038/nrendo.2014.166.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Nussdorfer GG. Cytophysiology of the adrenal zona glomerulosa. Int Rev Cytol. 1980;64:307–68.

    Article  CAS  PubMed  Google Scholar 

  13. Otis M, Campbell S, Payet MD, Gallo-Payet N. Expression of extracellular matrix proteins and integrins in rat adrenal gland: importance for ACTH-associated functions. J Endocrinol. 2007;193:331–47. doi:10.1677/JOE-07-0055.

    Article  CAS  PubMed  Google Scholar 

  14. Black VH, Robbins D, McNamara N, Huima T. A correlated thin-section and freeze-fracture analysis of guinea pig adrenocortical cells. Am J Anat. 1979;156:453–503. doi:10.1002/aja.1001560404.

    Article  CAS  PubMed  Google Scholar 

  15. Friend DS, Gilula NB. A distinctive cell contact in the rat adrenal cortex. J Cell Biol. 1972;53:148–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Rhodin JA. The ultrastructure of the adrenal cortex of the rat under normal and experimental conditions. J Ultrastruct Res. 1971;34:23–71.

    Article  CAS  PubMed  Google Scholar 

  17. Sato T. (1968) the fine structure of the mouse adrenal X zone. Z Für Zellforsch Mikrosk Anat Vienna Austria. 1948;87:315–29.

    Article  Google Scholar 

  18. Chida D, Nakagawa S, Nagai S, Sagara H, Katsumata H, Imaki T, Suzuki H, Mitani F, Ogishima T, Shimizu C, Kotaki H, Kakuta S, Sudo K, Koike T, Kubo M, Iwakura Y. Melanocortin 2 receptor is required for adrenal gland development, steroidogenesis, and neonatal gluconeogenesis. Proc Natl Acad Sci U S A. 2007;104:18205–10. doi:10.1073/pnas.0706953104.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Deane HW, Shaw JH, Greep RO. The effect of altered sodium or potassium intake on the width and cytochemistry of the zona glomerulosa of the rat’s adrenal cortex. Endocrinology. 1948;43:133–53. doi:10.1210/endo-43-3-133.

    Article  CAS  PubMed  Google Scholar 

  20. Freedman BD, Kempna PB, Carlone DL, Shah MS, Guagliardo NA, Barrett PQ, Gomez-Sanchez CE, Majzoub JA, Breault DT. Adrenocortical zonation results from lineage conversion of differentiated zona glomerulosa cells. Dev Cell. 2013;26:666–73. doi:10.1016/j.devcel.2013.07.016.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Karpac J, Ostwald D, Bui S, Hunnewell P, Shankar M, Hochgeschwender U. Development, maintenance, and function of the adrenal gland in early postnatal proopiomelanocortin-null mutant mice. Endocrinology. 2005;146:2555–62. doi:10.1210/en.2004-1290.

    Article  CAS  PubMed  Google Scholar 

  22. McEwan PE, Vinson GP, Kenyon CJ. Control of adrenal cell proliferation by AT1 receptors in response to angiotensin II and low-sodium diet. Am J Phys. 1999;276:E303–9.

    CAS  Google Scholar 

  23. McNeill H. Distribution of extracellular signal-regulated protein kinases 1 and 2 in the rat adrenal and their activation by angiotensin II. J Endocrinol. 2005;187:149–57. doi:10.1677/joe.1.06347.

    Article  CAS  PubMed  Google Scholar 

  24. Nishimoto K, Harris RBS, Rainey WE, Seki T. Sodium deficiency regulates rat adrenal zona glomerulosa gene expression. Endocrinology. 2014;155:1363–72. doi:10.1210/en.2013-1999.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Pulichino A-M, Vallette-Kasic S, Couture C, Gauthier Y, Brue T, David M, Malpuech G, Deal C, Van Vliet G, De Vroede M, Riepe FG, Partsch C-J, Sippell WG, Berberoglu M, Atasay B, Drouin J. Human and mouse TPIT gene mutations cause early onset pituitary ACTH deficiency. Genes Dev. 2003;17:711–6. doi:10.1101/gad.1065603.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Shelton JH, Jones AL. The fine structure of the mouse adrenal cortex and the ultrastructural changes in the zona glomerulosa with low and high sodium diets. Anat Rec. 1971;170:147–81. doi:10.1002/ar.1091700204.

    Article  CAS  PubMed  Google Scholar 

  27. Thomas M, Keramidas M, Monchaux E, Feige J-J. Dual hormonal regulation of endocrine tissue mass and vasculature by adrenocorticotropin in the adrenal cortex. Endocrinology. 2004;145:4320–9. doi:10.1210/en.2004-0179.

    Article  CAS  PubMed  Google Scholar 

  28. Berthon A, Drelon C, Ragazzon B, Boulkroun S, Tissier F, Amar L, Samson-Couterie B, Zennaro M-C, Plouin P-F, Skah S, Plateroti M, Lefèbvre H, Sahut-Barnola I, Batisse-Lignier M, Assié G, Lefrançois-Martinez A-M, Bertherat J, Martinez A, Val P. WNT/β-catenin signalling is activated in aldosterone-producing adenomas and controls aldosterone production. Hum Mol Genet. 2014;23:889–905. doi:10.1093/hmg/ddt484.

    Article  CAS  PubMed  Google Scholar 

  29. Berthon A, Sahut-Barnola I, Lambert-Langlais S, de Joussineau C, Damon-Soubeyrand C, Louiset E, Taketo MM, Tissier F, Bertherat J, Lefrançois-Martinez A-M, Martinez A, Val P. Constitutive beta-catenin activation induces adrenal hyperplasia and promotes adrenal cancer development. Hum Mol Genet. 2010;19:1561–76. doi:10.1093/hmg/ddq029.

    Article  CAS  PubMed  Google Scholar 

  30. Drelon C, Berthon A, Sahut-Barnola I, Mathieu M, Dumontet T, Rodriguez S, Batisse-Lignier M, Tabbal H, Tauveron I, Lefrançois-Martinez A-M, Pointud J-C, Gomez-Sanchez CE, Vainio S, Shan J, Sacco S, Schedl A, Stratakis CA, Martinez A, Val P. PKA inhibits WNT signalling in adrenal cortex zonation and prevents malignant tumour development. Nat Commun. 2016;7:12751. doi:10.1038/ncomms12751.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Heikkilä M, Peltoketo H, Leppäluoto J, Ilves M, Vuolteenaho O, Vainio S. Wnt-4 deficiency alters mouse adrenal cortex function, reducing aldosterone production. Endocrinology. 2002;143:4358–65. doi:10.1210/en.2002-220275.

    Article  PubMed  Google Scholar 

  32. Kim AC, Reuter AL, Zubair M, Else T, Serecky K, Bingham NC, Lavery GG, Parker KL, Hammer GD. Targeted disruption of beta-catenin in Sf1-expressing cells impairs development and maintenance of the adrenal cortex. Dev Camb Engl. 2008;135:2593–602. doi:10.1242/dev.021493.

    CAS  Google Scholar 

  33. Sahut-Barnola I, de Joussineau C, Val P, Lambert-Langlais S, Damon C, Lefrançois-Martinez A-M, Pointud J-C, Marceau G, Sapin V, Tissier F, Ragazzon B, Bertherat J, Kirschner LS, Stratakis CA, Martinez A. Cushing’s syndrome and fetal features resurgence in adrenal cortex-specific Prkar1a knockout mice. PLoS Genet. 2010;6:e1000980. doi:10.1371/journal.pgen.1000980.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Vidal V, Sacco S, Rocha AS, da Silva F, Panzolini C, Dumontet T, Doan TMP, Shan J, Rak-Raszewska A, Bird T, Vainio S, Martinez A, Schedl A. The adrenal capsule is a signaling center controlling cell renewal and zonation through Rspo3. Genes Dev. 2016;30:1389–94. doi:10.1101/gad.277756.116.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Bhandaru M, Kempe DS, Rotte A, Rexhepaj R, Kuhl D, Lang F. Hyperaldosteronism, hypervolemia, and increased blood pressure in mice expressing defective APC. Am J Physiol Regul Integr Comp Physiol. 2009;297:R571–5. doi:10.1152/ajpregu.00070.2009.

    Article  CAS  PubMed  Google Scholar 

  36. Clark AJ, Weber A. Adrenocorticotropin insensitivity syndromes. Endocr Rev. 1998;19:828–43. doi:10.1210/edrv.19.6.0351.

    Article  CAS  PubMed  Google Scholar 

  37. Côté M, Guillon G, Payet MD, Gallo-Payet N. Expression and regulation of adenylyl cyclase isoforms in the human adrenal gland. J Clin Endocrinol Metab. 2001;86:4495–503. doi:10.1210/jcem.86.9.7837.

    Article  PubMed  Google Scholar 

  38. Gorrigan RJ, Guasti L, King P, Clark AJ, Chan LF. Localisation of the melanocortin-2-receptor and its accessory proteins in the developing and adult adrenal gland. J Mol Endocrinol. 2011;46:227–32. doi:10.1530/JME-11-0011.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Berthon AS, Szarek E, Stratakis CA. PRKACA: the catalytic subunit of protein kinase a and adrenocortical tumors. Front Cell Dev Biol. 2015;3:26. doi:10.3389/fcell.2015.00026.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Boulkroun S, Fernandes-Rosa FL, Zennaro M-C. Molecular and cellular mechanisms of aldosterone producing adenoma development. Front Endocrinol. 2015;6:95. doi:10.3389/fendo.2015.00095.

    Article  Google Scholar 

  41. King P, Paul A, Laufer E. Shh signaling regulates adrenocortical development and identifies progenitors of steroidogenic lineages. Proc Natl Acad Sci. 2009;106:21185–90. doi:10.1073/pnas.0909471106.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Salmon TN, Zwemer RL. A study of the life history of cortico-adrenal gland cells of the rat by means of trypan blue injections. Anat Rec. 1941;80:421–9. doi:10.1002/ar.1090800404.

    Article  Google Scholar 

  43. Kim AC, Barlaskar FM, Heaton JH, Else T, Kelly VR, Krill KT, Scheys JO, Simon DP, Trovato A, Yang W-H, Hammer GD. In search of adrenocortical stem and progenitor cells. Endocr Rev. 2009;30:241–63. doi:10.1210/er.2008-0039.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Eberhart CG, Argani P. Wnt signaling in human development: beta-catenin nuclear translocation in fetal lung, kidney, placenta, capillaries, adrenal, and cartilage. Pediatr Dev Pathol. 2001;4:351–7.

    Article  CAS  PubMed  Google Scholar 

  45. Halder SK, Takemori H, Hatano O, Nonaka Y, Wada A, Okamoto M. Cloning of a membrane-spanning protein with epidermal growth factor-like repeat motifs from adrenal glomerulosa cells. Endocrinology. 1998;139:3316–28. doi:10.1210/endo.139.7.6081.

    Article  CAS  PubMed  Google Scholar 

  46. Pignatti E, Leng S, Carlone DL, Breault DT. Regulation of zonation and homeostasis in the adrenal cortex. Mol Cell Endocrinol. 2017;441:146–55. doi:10.1016/j.mce.2016.09.003.

    Article  CAS  PubMed  Google Scholar 

  47. Romero DG, Yanes LL, de Rodriguez AF, Plonczynski MW, Welsh BL, Reckelhoff JF, Gomez-Sanchez EP, Gomez-Sanchez CE. Disabled-2 is expressed in adrenal zona glomerulosa and is involved in aldosterone secretion. Endocrinology. 2007;148:2644–52. doi:10.1210/en.2006-1509.

    Article  CAS  PubMed  Google Scholar 

  48. Davis RL, Weintraub H, Lassar AB. Expression of a single transfected cDNA converts fibroblasts to myoblasts. Cell. 1987;51:987–1000.

    Article  CAS  PubMed  Google Scholar 

  49. Crawford PA, Sadovsky Y, Milbrandt J. Nuclear receptor steroidogenic factor 1 directs embryonic stem cells toward the steroidogenic lineage. Mol Cell Biol. 1997;17:3997–4006.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Sakai N, Terami H, Suzuki S, Haga M, Nomoto K, Tsuchida N, Morohashi K, Saito N, Asada M, Hashimoto M, Harada D, Asahara H, Ishikawa T, Shimada F, Sakurada K. Identification of NR5A1 (SF-1/AD4BP) gene expression modulators by large-scale gain and loss of function studies. J Endocrinol. 2008;198:489–97. doi:10.1677/JOE-08-0027.

    Article  CAS  PubMed  Google Scholar 

  51. Bandiera R, Vidal VPI, Motamedi FJ, Clarkson M, Sahut-Barnola I, von Gise A, Pu WT, Hohenstein P, Martinez A, Schedl A. WT1 maintains adrenal-gonadal primordium identity and marks a population of AGP-like progenitors within the adrenal gland. Dev Cell. 2013;27:5–18. doi:10.1016/j.devcel.2013.09.003.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

We thank the members of the Breault laboratory, J. Majzoub, W. Engeland, and P. Barrett, for their helpful discussions. This research was supported by R01 DK 084056.

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Author notes

  1. Emanuele Pignatti, Sining Leng and Diana L. Carlone contributed equally to this work.

Authors and Affiliations

  1. Division of Endocrinology, Boston Children’s Hospital, Boston, MA, 02115, USA

    Emanuele Pignatti, Sining Leng, Diana L. Carlone & David T. Breault

  2. Department of Pediatrics, Harvard Medical School, Boston, MA, 02115, USA

    Emanuele Pignatti, Diana L. Carlone & David T. Breault

  3. Division of Medical Sciences, Harvard Medical School, Boston, MA, 02115, USA

    Sining Leng

  4. Harvard Stem Cell Institute, Cambridge, MA, 02138, USA

    Diana L. Carlone & David T. Breault

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  1. Emanuele Pignatti
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  2. Sining Leng
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  3. Diana L. Carlone
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  4. David T. Breault
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Correspondence to David T. Breault .

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Editors and Affiliations

  1. Div of Endocrinology and Bone Diseases, Icahn School of Medicine at Mount Sinai, New York, New York, USA

    Alice C. Levine

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Pignatti, E., Leng, S., Carlone, D.L., Breault, D.T. (2018). Adrenal Zonation and Development. In: Levine, A. (eds) Adrenal Disorders. Contemporary Endocrinology. Humana Press, Cham. https://doi.org/10.1007/978-3-319-62470-9_1

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  • DOI: https://doi.org/10.1007/978-3-319-62470-9_1

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