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Comment |
Identification of a Stanniocalcin Paralog, STC2, in Fish and the Paracrine Actions of STC2 in the Mammalian Ovary Luo CW, et al 2004 .
Stanniocalcin is a glycoprotein hormone important in the maintenance of calcium and phosphate homeostasis in fish. Two related mammalian stanniocalcin genes, STC1 and STC2, were found to be expressed in various tissues as paracrine regulators. We have demonstrated the existence of a second stanniocalcin gene in fish, named as fish STC2, with only 30% identity to fish STC1. However, phylogenetic analysis and comparison of the genomic structure of STC genes in vertebrates indicated that STC1 and STC2 genes were likely derived from a common ancestor gene. Based on the prominent expression of mammalian STC1 in the ovary, we tested STC2 expression in rat ovary and the regulation of STC2 expression by gonadotropins. Treatment of immature rats with pregnant mare serum gonadotropin increased STC2 transcripts whereas subsequent treatment with human chorionic gonadotropin suppressed STC2 expression. Real-time PCR analyses further demonstrated that STC2 is mainly expressed in theca layers. In situ hybridization studies also revealed that STC2 is expressed in theca cell layers of antral and preovulatory follicles following gonadotropin stimulation. To elucidate the physiological functions of STC2, recombinant human and fish STC2 proteins were generated and were found to be N-glycosylated homodimers. In cultured granulosa cells, treatment with human or fish STC2 suppressed FSH-induced progesterone, but not estradiol or cAMP, production. The STC2 suppression of progesterone production was associated with the inhibition of FSH-induced CYP11A and 3-beta-hydroxysteroid dehydrogenase expression. Thus, STC2 is a functional homodimeric glycoprotein and theca cell-derived STC2 could play a paracrine role during follicular development.
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Mutations |
2 mutations
Species: mouse
Mutation name: None
type: targeted overexpression
fertility: fertile
Comment: Gagliardi AD, et al 2004 reported that human stanniocalcin-2 exhibits potent growth suppressive properties in transgenic mice independent of growth hormone and IGFs.
STC-2 was discovered based on its primary amino acid sequence identity to the hormone, stanniocalcin (STC-1). The function of STC-2 has not been examined and the authors have generated two lines of transgenic mice overexpressing human STC-2 (hSTC-2) to gain insight into its potential functions through the identification of overt phenotypes. Analysis of mouse Stc2 gene expression indicates that unlike Stc1, it is not highly expressed during development, but exhibits overlapping expression with Stc1 in adult mice, with heart and skeletal muscle exhibiting the highest steady-state levels of Stc2 mRNA. Constitutive overexpression of hSTC-2 resulted in pre and post-natal growth restriction beginning as early as E12.5 and progressing such that mature hSTC-2 transgenic mice are ~45% smaller than wild-type littermates. hSTC-2 overexpression is also sometimes lethal as we observed 26-34% neonatal morbidity without obvious dysmorphology. hSTC-2 induced growth retardation is associated with developmental delay most notably in cranial suture formation. Organ allometry studies show that hSTC-2- induced dwarfism is associated with testicular organomegaly and a significant reduction in skeletal muscle mass that likely contributes to the dwarf phenotype. The hSTC-2 transgenic mice are also hyperphagic, but this does not result in obesity. Serum Ca(2+) and PO4 were unchanged in hSTC-2 transgenic mice even though STC-1 can regulate intra and extracellular calcium in mammals. Interestingly, the severe growth retardation induced by hSTC-2 is not associated with a decrease in growth hormone expression or that of the IGFs. Consequently, similar to STC-1, STC-2 can act as a potent growth inhibitor and reduce intramembranous and endochondral bone development and skeletal muscle growth implying that these tissues are specific physiological targets of stanniocalcins.
Species: mouse
Mutation name: None
type: null mutation
fertility: fertile
Comment: The murine stanniocalcin 2 gene is a negative regulator of post-natal growth. Chang AC et al. Stanniocalcin (STC), a secreted glycoprotein, was first studied in fish as a classical hormone with a role in regulating serum calcium levels. There are two closely related proteins in mammals, STC1 and STC2, with functions that are currently unclear. Both proteins are expressed in numerous mammalian tissues rather than being secreted from a specific endocrine gland. No phenotype has been detected yet in Stc1-null mice, and to investigate whether Stc2 could have compensated for the loss of Stc1 we have now generated Stc2(-/-) and Stc1(-/-) Stc2(-/-) mice. Although Stc1 is expressed in the ovary and in lactating mouse mammary glands, like the Stc1(-/-) mice, the Stc1(-/-) Stc2(-/-) mice had no detected decrease in fertility, fecundity or weight gain up until weaning. Serum calcium and phosphate levels were normal in Stc1(-/-) Stc2(-/-) mice, indicating it is unlikely that the mammalian stanniocalcins have a major physiologic role in mineral homeostasis. Mice with Stc2 deleted were 10-15% larger and grew at a faster rate than wild-type mice from 4 weeks onwards, and the Stc1(-/-) Stc2(-/-) mice had a similar growth phenotype. This effect was not mediated through the GH/IGF-1 axis. The results are consistent with STC2 being a negative regulator of post-natal growth.
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