RENAL AGENESIS IN MICE HOMOZYGOUS FOR A GENE TRAP MUTATION IN THE GENE ENCODING HEPARAN-SULFATE 2-SULFOTRANSFERASE

Heparan sulfate proteoglycans have been implicated in the presentation of a number of secreted signaling molecules to their signal-transduci ng receptors. We have characterized a gene trap mutation in the gene e ncoding a heparan sulfate biosynthetic enzyme, heparan sulfate 2-sulfo transferase (HS2ST). Transgenic mice were generated from embryonic see m cells harboring this insertion, lacZ reporter gene activity in heter ozygous embryos demonstrates that the gene is expressed differentially during embryogenesis, presumably directing dynamic changes in heparan sulfate structure. Moreover, mice homozygous for the Hs2st gene trap allele die in the neonatal period, exhibiting bilateral renal agenesis and defects of the eye and the skeleton. Analysis of kidney developme nt in Hs2st mutants reveals that the gene is not required for two earl y events-ureteric bud outgrowth from the Wolffian duct and initial ind uction of Pax-2 expression in the metanephric mesenchyme. It is requir ed, however, for mesenchymal condensation around the ureteric bud and initiation of branching morphogenesis. Because 2-O-sulfation has been shown to influence the functional interactions of ligands with heparan sulfate in vitro, we discuss the possibility that the Hs2st mutant ph enotype is a consequence of compromised interactions between growth fa ctors and their signal-transducing receptors.These data provide the fi rst genetic evidence that the regulated synthesis of differentially gl ycosylated proteoglycans can affect morphogenesis during vertebrate de velopment.