Bone Morphogenetic Protein-1 Processes Insulin-like Growth Factor-binding Protein 3
JOURNAL OF BIOLOGICAL CHEMISTRY
Authors: Kim, Byoungjae; Huang, Guorui; Ho, Wen-Bin; Greenspan, Daniel S.
Abstract
The bone morphogenetic protein-1 (BMP1)-like metalloproteinases play key roles in extracellular matrix formation, by converting precursors into mature functional proteins involved in forming the extracellular matrix. The BMP1-like proteinases also play roles in activating growth factors, such as BMP2/4, myostatin, growth differentiation factor 11, and transforming growth factor beta 1, by cleaving extracellular antagonists. The extracellular insulin-like growth factor-binding proteins (IGFBPs) are involved in regulating the effects of insulin-like growth factors (IGFs) on growth, development, and metabolism. Of the six IGFBPs, IGFBP3 has the greatest interaction with the large pool of circulating IGFs. It is also produced locally in tissues and is itself regulated by proteolytic processing. Here, we show that BMP1 cleaves human and mouse IGFBP3 at a single conserved site, resulting in markedly reduced ability of cleaved IGFBP3 to bind IGF-I or to block IGF-I-induced cell signaling. In contrast, such cleavage is shown to result in enhanced IGF-I-independent ability of cleaved IGFBP3 to block FGF-induced proliferation and to induce Smad phosphorylation. Consistent with in vivo roles for such cleavage, it is shown that, whereas wild type mouse embryo fibroblasts (MEFs) produce cleaved IGFBP3, MEFs doubly null for the Bmp1 gene and for the Tll1 gene, which encodes the related metalloproteinase mammalian Tolloid-like 1 (mTLL1), produce only unprocessed IGFBP3, thus demonstrating endogenous BMP1-related proteinases to be responsible for IGFBP3-processing activity in MEFs. Similarly, in zebrafish embryos, overexpression of Bmp1a is shown to reverse an Igfbp3-induced phenotype, consistent with the ability of BMP1-like proteinases to cleave IGFBP3 in vivo.
Screening of SSR markers associated with scale cover pattern and mapped to a genetic linkage map of common carp (Cyprinus carpio L.)
JOURNAL OF APPLIED GENETICS
Authors: Xiao, Tongqian; Lu, Cuiyun; Xu, Yulan; Li, Chao; Zheng, Xianhu; Cao, Dingchen; Cheng, Lei; Mahboob, Shahid; Sun, Xiaowen
Abstract
Fish scale is an attractive model in bone physiology research and is also a crucial character for breeding new varieties. Thus, it is important to identify loci in the genome associated with scale formation. In this study, 290 microsatellite markers in common carp (Cyprinus carpio L.) were selected and tested for their segregation in a full-sib mapping panel containing 96 individuals (population 1). Association analysis identified seven simple sequence repeats (SSRs) (HLJ2509, HLJ3227, HLJ3675, HLJ3766, HLJ3863, FGFR1, FGFR7) that showed significant correlation with scale cover pattern in population 1. When the seven SSRs were investigated in two other populations, seven and five SSRs were significantly correlated with scale cover pattern in population 2 (116 individuals) and population 3 (57 individuals), respectively. The exceptions were FGFR1 and HLJ3227. A genetic linkage map was constructed using the 290 SSRs and 241 SSRs were mapped into 47 linkage groups (LGs), with 2-15 markers per LG. The map spanned 2,241.7 cM, with LG sizes that varied from 1.1 to 124.9 cM. All seven markers associated with scale cover mapped into LG3. We considered that a gene cluster that affected the scale cover pattern possibly existed in LG3. By aligning the seven markers with the zebrafish (Danio rerio) genome, we identified six candidate genes (atoh1a, ptch1, bmp1a, fgfr1a, fgf17, wnt5a) that may be associated with scale formation. We propose that the seven markers could be used with marker-assisted selection to breed a new variety of common carp, and the six candidate genes could help in understanding the scale cover mechanism.