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. 1993 Jun 1;90(11):4922–4926. doi: 10.1073/pnas.90.11.4922

Ontogeny of the prohormone convertases PC1 and PC2 in the mouse hypophysis and their colocalization with corticotropin and alpha-melanotropin.

M Marcinkiewicz 1, R Day 1, N G Seidah 1, M Chrétien 1
PMCID: PMC46625  PMID: 8389457

Abstract

In the adult pituitary, anterior lobe corticotrophs and intermediate lobe melanotrophs differentially process proopiomelanocortin (POMC). Within the corticotrophs, POMC is processed mainly to corticotropin (ACTH) and beta-lipotropin, while alpha-melanotropin (alpha MSH) and beta-endorphin are the major end products in the melanotrophs. The observed transient presence of alpha MSH-like immunoreactivity during ontogeny suggested an age-dependent variation in POMC processing in the adenohypophysis. In this tissue, cell-specific POMC products are likely the result of differential expression of the two known prohormone convertases PC1 and PC2. In the present ontogeny study done in the mouse intermediate and anterior pituitary, we examined how the expression pattern of PC1 and PC2 mRNA transcripts correlates with that of ACTH and alpha MSH-like immunoreactivities. Our data demonstrated that both PC1 and PC2 transcripts can be detected in the presumptive adenohypophysis starting on embryonic day 15 (E15). In the intermediate lobe, PC1 and PC2 mRNAs appear on E18 and E16, respectively, and their levels increased during ontogeny, reaching maximal expression in the adult. Similarly, PC1 expression in the anterior pituitary increased from E15 to adulthood. However, PC2 mRNA expression peaked between postnatal days 1 (P1) and 14 (P14) and then decreased to adult levels. The distribution of PC1 and PC2 immunoreactivity is nicely correlated with the in situ hybridization data. In the anterior lobe, during the P1-P14 postnatal period, PC2 immunoreactivity was detected within cells synthesizing an alpha MSH-like peptide(s). This observation substantiates our earlier biochemical data suggesting that PC2 is the important convertase in the processing of POMC into alpha MSH. Furthermore, the demonstrated variation in the relative ratio of PC1/PC2 expression during ontogeny rationalizes the observed plasticity of POMC processing in the adenohypophysis. It is expected that beta-endorphin processing will follow that of alpha MSH.

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Selected References

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

  1. Allen R. G., Pintar J. E., Stack J., Kendall J. W. Biosynthesis and processing of pro-opiomelanocortin-derived peptides during fetal pituitary development. Dev Biol. 1984 Mar;102(1):43–50. doi: 10.1016/0012-1606(84)90173-8. [DOI] [PubMed] [Google Scholar]
  2. Benjannet S., Reudelhuber T., Mercure C., Rondeau N., Chrétien M., Seidah N. G. Proprotein conversion is determined by a multiplicity of factors including convertase processing, substrate specificity, and intracellular environment. Cell type-specific processing of human prorenin by the convertase PC1. J Biol Chem. 1992 Jun 5;267(16):11417–11423. [PubMed] [Google Scholar]
  3. Benjannet S., Rondeau N., Day R., Chrétien M., Seidah N. G. PC1 and PC2 are proprotein convertases capable of cleaving proopiomelanocortin at distinct pairs of basic residues. Proc Natl Acad Sci U S A. 1991 May 1;88(9):3564–3568. doi: 10.1073/pnas.88.9.3564. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Chrétien M., Sikstrom R. A., Lazure C., Mbikay M., Seidah N. G. Functional diversity of bioactive peptides in the nervous system itself: "how the brain may understand". Biosci Rep. 1989 Dec;9(6):693–700. doi: 10.1007/BF01114807. [DOI] [PubMed] [Google Scholar]
  5. Day R., Schafer M. K., Watson S. J., Chrétien M., Seidah N. G. Distribution and regulation of the prohormone convertases PC1 and PC2 in the rat pituitary. Mol Endocrinol. 1992 Mar;6(3):485–497. doi: 10.1210/mend.6.3.1316544. [DOI] [PubMed] [Google Scholar]
  6. Elkabes S., Loh Y. P., Nieburgs A., Wray S. Prenatal ontogenesis of pro-opiomelanocortin in the mouse central nervous system and pituitary gland: an in situ hybridization and immunocytochemical study. Brain Res Dev Brain Res. 1989 Mar 1;46(1):85–95. doi: 10.1016/0165-3806(89)90145-4. [DOI] [PubMed] [Google Scholar]
  7. Estivariz F. E., Friedman T. C., Chikuma T., Loh Y. P. Processing of adrenocorticotropin by two proteases in bovine intermediate lobe secretory vesicle membranes. A distinct acidic, tetrabasic residue-specific calcium-activated serine protease and a PC2-like enzyme. J Biol Chem. 1992 Apr 15;267(11):7456–7463. [PubMed] [Google Scholar]
  8. Girod C., Dubois M. P. Mise en évidence, par immunofluorescence, des cellules corticotropes et des cellules mélanotropes dans l'adénohypophyse du hamster doré (Mesocricetus auratus Waterh) C R Seances Soc Biol Fil. 1974;168(6-7):751–754. [PubMed] [Google Scholar]
  9. Hindelang C., Félix J. M., Laurent F. M., Klein M. J., Stoeckel M. E. Ontogenesis of proopiomelanocortin gene expression and regulation in the rat pituitary intermediate lobe. Mol Cell Endocrinol. 1990 May 7;70(3):225–235. doi: 10.1016/0303-7207(90)90213-r. [DOI] [PubMed] [Google Scholar]
  10. Khachaturian H., Alessi N. E., Munfakh N., Watson S. J. Ontogeny of opioid and related peptides in the rat cns and pituitary: an immunocytochemical study. Life Sci. 1983;33 (Suppl 1):61–64. doi: 10.1016/0024-3205(83)90444-7. [DOI] [PubMed] [Google Scholar]
  11. Lugo D. I., Roberts J. L., Pintar J. E. Analysis of proopiomelanocortin gene expression during prenatal development of the rat pituitary gland. Mol Endocrinol. 1989 Aug;3(8):1313–1324. doi: 10.1210/mend-3-8-1313. [DOI] [PubMed] [Google Scholar]
  12. Marcinkiewicz M., Benjannet S., Seidah N. G., Cantin M., Chrétien M. The pituitary polypeptide "7B2" is associated with LH/FSH and TSH cells and is localized within secretory vesicles. Cell Tissue Res. 1987 Oct;250(1):205–214. doi: 10.1007/BF00214673. [DOI] [PubMed] [Google Scholar]
  13. Noel G., Mains R. E. Plasticity of peptide biosynthesis in corticotropes: independent regulation of different steps in processing. Endocrinology. 1991 Sep;129(3):1317–1325. doi: 10.1210/endo-129-3-1317. [DOI] [PubMed] [Google Scholar]
  14. Pintar J. E., Lugo D. I. Proopiomelanocortin gene expression, prohormone processing, and secretion during rat pituitary development. Ann N Y Acad Sci. 1987;512:318–327. doi: 10.1111/j.1749-6632.1987.tb24970.x. [DOI] [PubMed] [Google Scholar]
  15. Robba C., Rebuffat P., Mazzocchi G., Nussdorfer G. G. Long-term trophic action of alpha-melanocyte-stimulating hormone on the zona glomerulosa of the rat adrenal cortex. Acta Endocrinol (Copenh) 1986 Jul;112(3):404–408. doi: 10.1530/acta.0.1120404. [DOI] [PubMed] [Google Scholar]
  16. Sato S. M., Mains R. E. Plasticity in the adrenocorticotropin-related peptides produced by primary cultures of neonatal rat pituitary. Endocrinology. 1988 Jan;122(1):68–77. doi: 10.1210/endo-122-1-68. [DOI] [PubMed] [Google Scholar]
  17. Sato S. M., Mains R. E. The synthesis and processing of pro-ACTH/endorphin in the developing rat pituitary. Ann N Y Acad Sci. 1987;512:286–299. doi: 10.1111/j.1749-6632.1987.tb24967.x. [DOI] [PubMed] [Google Scholar]
  18. Schäfer M. K., Day R., Cullinan W. E., Chrétien M., Seidah N. G., Watson S. J. Gene expression of prohormone and proprotein convertases in the rat CNS: a comparative in situ hybridization analysis. J Neurosci. 1993 Mar;13(3):1258–1279. doi: 10.1523/JNEUROSCI.13-03-01258.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Seidah N. G., Day R., Benjannet S., Rondeau N., Boudreault A., Reudelhuber T., Schafer M. K., Watson S. J., Chrétien M. The prohormone and proprotein processing enzymes PC1 and PC2: structure, selective cleavage of mouse POMC and human renin at pairs of basic residues, cellular expression, tissue distribution, and mRNA regulation. NIDA Res Monogr. 1992;126:132–150. [PubMed] [Google Scholar]
  20. Seidah N. G., Fournier H., Boileau G., Benjannet S., Rondeau N., Chrétien M. The cDNA structure of the porcine pro-hormone convertase PC2 and the comparative processing by PC1 and PC2 of the N-terminal glycopeptide segment of porcine POMC. FEBS Lett. 1992 Oct 5;310(3):235–239. doi: 10.1016/0014-5793(92)81339-n. [DOI] [PubMed] [Google Scholar]
  21. Seidah N. G., Gaspar L., Mion P., Marcinkiewicz M., Mbikay M., Chrétien M. cDNA sequence of two distinct pituitary proteins homologous to Kex2 and furin gene products: tissue-specific mRNAs encoding candidates for pro-hormone processing proteinases. DNA Cell Biol. 1990 Jul-Aug;9(6):415–424. doi: 10.1089/dna.1990.9.415. [DOI] [PubMed] [Google Scholar]
  22. Seidah N. G., Marcinkiewicz M., Benjannet S., Gaspar L., Beaubien G., Mattei M. G., Lazure C., Mbikay M., Chrétien M. Cloning and primary sequence of a mouse candidate prohormone convertase PC1 homologous to PC2, Furin, and Kex2: distinct chromosomal localization and messenger RNA distribution in brain and pituitary compared to PC2. Mol Endocrinol. 1991 Jan;5(1):111–122. doi: 10.1210/mend-5-1-111. [DOI] [PubMed] [Google Scholar]
  23. Smeekens S. P., Avruch A. S., LaMendola J., Chan S. J., Steiner D. F. Identification of a cDNA encoding a second putative prohormone convertase related to PC2 in AtT20 cells and islets of Langerhans. Proc Natl Acad Sci U S A. 1991 Jan 15;88(2):340–344. doi: 10.1073/pnas.88.2.340. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Smeekens S. P., Steiner D. F. Identification of a human insulinoma cDNA encoding a novel mammalian protein structurally related to the yeast dibasic processing protease Kex2. J Biol Chem. 1990 Feb 25;265(6):2997–3000. [PubMed] [Google Scholar]
  25. Swaab D. F., Boer G. J., Visser M. The fetal brain and intrauterine growth. Postgrad Med J. 1978;54 (Suppl 1):63–73. [PubMed] [Google Scholar]
  26. Tanaka S., Kurosumi K. Differential subcellular localization of ACTH and alpha-MSH in corticotropes of the rat anterior pituitary. Cell Tissue Res. 1986;243(2):229–238. doi: 10.1007/BF00251036. [DOI] [PubMed] [Google Scholar]
  27. Thomas L., Leduc R., Thorne B. A., Smeekens S. P., Steiner D. F., Thomas G. Kex2-like endoproteases PC2 and PC3 accurately cleave a model prohormone in mammalian cells: evidence for a common core of neuroendocrine processing enzymes. Proc Natl Acad Sci U S A. 1991 Jun 15;88(12):5297–5301. doi: 10.1073/pnas.88.12.5297. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Tramu G., Pillez A., Leonardelli J. An efficient method of antibody elution for the successive or simultaneous localization of two antigens by immunocytochemistry. J Histochem Cytochem. 1978 Apr;26(4):322–324. doi: 10.1177/26.4.207771. [DOI] [PubMed] [Google Scholar]

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