Publications

The frizzled (fz) locus of Drosophila encodes a protein (Fz) with a seven-transmembrane-domain profile characteristic of G-protein-coupled receptors. In Drosophila, genetic evidence suggests that Fz functions to transmit and transduce polarity signals in epidermal cells during hair and bristle development. We have isolated from a UMR 106 rat osteosarcoma cell library a cDNA (fz-1) encoding a predicted 641-residue protein (Fz-1) with 46% homology with Drosophila Fz. We also identified a second cDNA (fz-2) encoding a protein (Fz-2) of 570 amino acids that is 80% homologous with Fz-1, with divergence most evident in the extracellular domains. Southern blots of rat genomic DNA indicated that fz-1 and fz-2 represent distinct genes. Northern analysis revealed the presence of a single fz-1 mRNA (4.7 kilobases) and two fz-2 mRNAs (2.5 and 4.5 kilobases) in rat tissues. The fz-1 and fz-2 genes are widely expressed in rat tissues with the highest steady-state levels of mRNA in kidney, liver, heart, uterus, and ovary. fz-1 and -2 mRNA levels were greater in neonatal than in corresponding adult tissues. Treatment of UMR 106 cells with bone resorbing agents including parathyroid hormone, epidermal growth factor, and 1,25-dihydroxyvitamin D3 produced increases in fz-1 and -2 mRNA levels. We suggest that hormonal induction of Fz proteins in osteoblasts serves to promote intercellular signaling required for functional responses such as increased bone resorption. Fz-1 and Fz-2 may represent products of a gene family whose members serve as transducers or intercellular transmitters of signals required for normal morphogenesis and/or differentiated function in diverse tissues.

The extracellular matrix, comprising the glomerular basement membrane and the mesangial matrix, plays a crucial role in glomerular structure and function. The glomerular extracellular matrix is composed of collagens, proteoglycans and glycoproteins. The distorted balance between synthesis and degradation of extracellular matrix proteins is a hallmark of many forms of glomerulonephritis, such as glomerulosclerosis. The degradation of the matrix occurs through the action of a group of extracellularly active metalloproteinases. Within the glomerulus these enzymes are synthesized by the epithelial and the mesangial cells. The molecular structure of the mesangial metalloproteinases, including their in vitro regulation, was analyzed and the in vivo synthesis of these proteinases was documented for cases of idiopathic rapid progressive glomerulonephritis and anti-Thy 1.1 nephritis. The therapeutic change in the activity and expression of the glomerular metalloproteinases, resulting in the restoration of physiologic matrix metabolic balance, opens up a new perspective for the therapy of glomerular inflammatory processes.