title: Disruption of PC1/3 expression in mice causes dwarfism and multiple neuroendocrine peptide processing defects.
abstract: The subtilisin-like proprotein convertases PC1/3 (SPC3) and PC2 (SPC2) are believed to be the major endoproteolytic processing enzymes of the regulated secretory pathway. They are expressed together or separately in neuroendocrine cells throughout the brain and dispersed endocrine system in both vertebrates and invertebrates. Disruption of the gene-encoding mouse PC1/3 has now been accomplished and results in a syndrome of severe postnatal growth impairment and multiple defects in processing many hormone precursors, including hypothalamic growth hormone-releasing hormone (GHRH), pituitary proopiomelanocortin to adrenocorticotropic hormone, islet proinsulin to insulin and intestinal proglucagon to glucagon-like peptide-1 and -2. Mice lacking PC1/3 are normal at birth, but fail to grow normally and are about 60% of normal size at 10 weeks. They lack mature GHRH, have low pituitary growth hormone (GH) and hepatic insulin-like growth factor-1 mRNA levels and resemble phenotypically the "little" mouse (Gaylinn, B. D., Dealmeida, V. I., Lyons, C. E., Jr., Wu, K. C., Mayo, K. E. & Thorner, M. O. (1999) Endocrinology 140, 5066-5074) that has a mutant GHRH receptor. Despite a severe defect in pituitary proopiomelanocortin processing to mature adrenocorticotropic hormone, blood corticosterone levels are essentially normal. There is marked hyperproinsulinemia but without impairment of glucose tolerance. In contrast, PC2-null mice lack mature glucagon and are chronically hypoglycemic (Furuta, M., Yano, H., Zhou, A., Rouille, Y., Holst, J., Carroll, R., Ravazzola, M., Orci, L., Furuta, H. & Steiner, D. (1997) Proc. Natl. Acad. Sci. USA 94, 6646-6651). The PC1/3-null mice differ from a human subject reported with compound heterozygosity for defects in this gene, who was of normal stature but markedly obese from early life. The PC1/3-null mice are not obese. The basis for these phenotypic differences is an interesting topic for further study. These findings prove the importance of PC1/3 as a key neuroendocrine convertase.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Chicago, and The Howard Hughes Medical Institute, 5841 South Maryland Avenue, Chicago, IL 60637, USA.
authors.forename: Xiaorong
authors.initials: X
authors.lastname: Zhu
authors.forename: An
authors.initials: A
authors.lastname: Zhou
authors.forename: Arunangsu
authors.initials: A
authors.lastname: Dey
authors.forename: Christina
authors.initials: C
authors.lastname: Norrbom
authors.forename: Raymond
authors.initials: R
authors.lastname: Carroll
authors.forename: Chunling
authors.initials: C
authors.lastname: Zhang
authors.forename: Virginie
authors.initials: V
authors.lastname: Laurent
authors.forename: Iris
authors.initials: I
authors.lastname: Lindberg
authors.forename: Randi
authors.initials: R
authors.lastname: Ugleholdt
authors.forename: Jens J
authors.initials: JJ
authors.lastname: Holst
authors.forename: Donald F
authors.initials: DF
authors.lastname: Steiner
mesh_terms: D000324:Adrenocorticotropic Hormone / Q000378:metabolism; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000235:genetics / Q000378:metabolism*; D003345:Corticosterone / Q000097:blood; D004392:Dwarfism / Q000201:enzymology* / Q000235:genetics; D015870:Gene Expression; D018390:Gene Targeting; D005934:Glucagon / Q000378:metabolism*; D052216:Glucagon-Like Peptide 1; D013006:Growth Hormone / Q000235:genetics; D013007:Growth Hormone-Releasing Hormone / Q000235:genetics / Q000378:metabolism*; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins; D009490:Neurosecretory Systems / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism*; D010455:Peptides / Q000378:metabolism*; D011333:Pro-Opiomelanocortin / Q000378:metabolism*; D052336:Proglucagon; D011384:Proinsulin / Q000378:metabolism*; D045664:Proprotein Convertase 1; D043484:Proprotein Convertases; D011498:Protein Precursors / Q000378:metabolism*; D011499:Protein Processing, Post-Translational
chemical_list: D009419:Nerve Tissue Proteins; D010446:Peptide Fragments; D010455:Peptides; D011498:Protein Precursors; C062302:pro-growth hormone releasing hormone, mouse; D052336:Proglucagon; D011333:Pro-Opiomelanocortin; D007334:Insulin-Like Growth Factor I; D052216:Glucagon-Like Peptide 1; D000324:Adrenocorticotropic Hormone; D013006:Growth Hormone; D005934:Glucagon; D013007:Growth Hormone-Releasing Hormone; D011384:Proinsulin; D043484:Proprotein Convertases; C473656:Pcsk1 protein, mouse; D045664:Proprotein Convertase 1; D016282:Aspartic Acid Endopeptidases; D003345:Corticosterone