Glypican-3 modulates BMP- and FGP-mediated effects during renal branching morphogenesis

The kidney of the Gpc3-/ mouse, a novel model of human renal dysplasia, is characterized by selective degeneration of medullary collecting ducts prece ded by enhanced cell proliferation and overgrowth during branching morphoge nesis. Here, we identify cellular and molecular mechanisms underlying this renal dysplasia. Glypican-3 (GPC3) deficiency was associated with abnormal and contrasting rates of proliferation and apoptosis in cortical (CCD) and medullary collecting duct (MCD) cells. In CCD, cell proliferation was incre ased threefold. In MCD, apoptosis was increased 16-fold. Expression of Gpc3 mRNA in ureteric bud and collecting duct cells suggested that GPC3 can exe rt direct effects in these cells. Indeed, GPC3 deficiency abrogated the inh ibitory activity of BMP2 on branch formation in embryonic kidney explants, converted BMP7-dependent inhibition to stimulation, and enhanced the stimul atory effects of KGF. Similar comparative differences were found in collect ing duct cell lines derived from GPC3-deficient and wild type mice and indu ced to form tubular progenitors in vitro, suggesting that GPC3 directly con trols collecting duct cell responses. We propose that GPC3 modulates the ac tions of stimulatory and inhibitory growth factors during branching morphog enesis. (C) 2001 Academic Press.