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1 Department of Biochemistry, Faculty of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada; London Regional Cancer Centre, London, Ontario, Canada
2 London Regional Cancer Centre, London, Ontario, Canada
3 Department of Physiology and Pharmacology, Faculty of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada
4 Department of Oncology, Faculty of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada; Department of Biochemistry, Faculty of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada; London Regional Cancer Centre, London, Ontario, Canada
* To whom correspondence should be addressed. E-mail: dimattia{at}uwo.ca.
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 we 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. Our 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 Ca2+ 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.
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