Stanniocalcin (STC)-2 was discovered by its primary amino acid sequence identity to the hormone STC-1. The function of STC-2 has not been examined; thus we generated two lines of transgenic mice overexpressing human (h)STC-2 to gain insight into its potential functions through 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 highest steady-state levels of Stc2 mRNA. Constitutive overexpression of hSTC-2 resulted in pre-and postnatal growth restriction as early as embryonic day 12.5, progressing such that mature hSTC-2-transgenic mice are ϳ45% smaller than wild-type littermates. hSTC-2 overexpression is sometimes lethal; we observed 26 -34% neonatal morbidity without obvious dysmorphology. hSTC-2-induced growth retardation is associated with developmental delay, most notably 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 likely contributing to the dwarf phenotype. hSTC-2-transgenic mice are also hyperphagic, but this does not result in obesity. Serum Ca 2ϩ and PO4 were unchanged in hSTC-2-transgenic mice, although STC-1 can regulate intra-and extracellular Ca 2ϩ in mammals. Interestingly, severe growth retardation induced by hSTC-2 is not associated with a decrease in GH or IGF expression. 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.stanniocalcins; stanniocalcin-related protein; development STANNIOCALCINS REPRESENT a small family of secreted homodimeric glycoprotein hormones consisting of STC-1 and STC-2, also known as stanniocalcin-related protein (STCrP), that has been conserved from aquatic to terrestrial vertebrates. STC-1 and STC-2 do not show significant homology to any other known proteins, and this has hampered understanding of their function(s). Initially, it was assumed that mammalian STC-1 would mimic the function of fish STC-1 in mineral homeostasis, and there is evidence to support this (26, 37, 52). Recently, however, it has become clear that STC-1 has a significantly expanded role in mammals on the basis of its expression pattern (7), gain-of-function transgenic mouse studies (13, 49), and subcellular localization (29, 38).STC-2 was initially identified as a stanniocalcin by virtue of its 50% identity and 73% amino acid homology to a stretch of 76 amino acids located between positions 24 and 101 of human (h)STC-1 (8, 12, 18, 32). hSTC-2 amino acid sequence downstream of position 101 shows less identity (23%) to hSTC-1, and it is 45 amino acids larger even though the genes encoding these proteins have identical intron/exon junctions (18). Unlike with STC-1, studies examini...

In mammals stanniocalcin (STC) is widely expressed, and in the kidney and gut it regulates serum calcium levels by promoting phosphate reabsorption. To shed further light on its functional significance in mammals we have created several lines of mice that express a human STC (hSTC) transgene. Three lines expressed the hSTC transgene, but only two lines exhibited high expression and contained circulating hSTC, and in these animals there was a reduction in postnatal growth (30-50%) that persisted after weaning. Moreover, even wild-type pups exhibited a growth retardation phenotype when nursed by a transgenic foster mother, and this implies that hSTC overexpression deleteriously affects maternal behavior and/or lactation. The reproductive potential of female transgenic mice was also compromised, as evidenced by significantly smaller litter sizes, but transgenic male fertility was unchanged even though the transgene was most highly expressed in testes. Interestingly, transgene-derived serum hSTC increased significantly after puberty and was severalfold higher in females than in males, suggesting a gender-specific mechanism for maintaining elevated circulating levels of STC. Blood analysis revealed that both transgenic lines had elevated phosphate and decreased alkaline phosphatase levels, indicative of altered kidney and bone metabolism. These studies provide the first evidence that STC is involved in growth and reproduction and reaffirm its role in mineral homeostasis.