DEVELOPMENT
53
RESEARCH ARTICLE
INTRODUCTIONThe formation of tubular epithelia from mesenchymal cells or preexisting ducts is a common feature of organ development. In the mammalian kidney, tubulogenesis first occurs during the formation of the pronephros. This primary embryonic kidney generates a single nephric (Wolffian) duct that elongates caudally towards the cloaca (Saxen, 1987). The nephric duct subsequently forms the second embryonic kidney, the mesonephros, by induction of mesonephric tubules in the adjacent mesenchymal nephric cord. When the nephric duct reaches the metanephric mesenchyme at the level of the hindlimb, interactions between both tissues initiate metanephros development by inducing budding and invasion of the ureter from the duct into the metanephric mesenchyme. The newly formed ureter branches and induces mesenchymal-epithelial transitions in the surrounding mesenchyme, thereby initiating the first of numerous cycles of nephron formation. Later during development, the nephric duct is transformed into the male genital tract (epididymis and vas deferens) or degenerates in female embryos. Hence, unraveling the molecular mechanisms of nephric duct morphogenesis is essential for our understanding of urogenital system development.Despite the central role of the pro-and mesonephros (referred to as pro/mesonephros) for kidney and genital tract formation, very few genes have so far been found to control the development of these two structures in the mouse. Notably, the Pax2 and Pax8 genes are both necessary and sufficient for the formation of the pronephros and all subsequent kidney structures (Bouchard et al., 2002). Pax2,Pax8 double-mutant embryos fail to specify the nephric lineage, as they neither undergo the initial epithelial-mesenchymal transitions leading to nephric duct formation nor activate early nephric marker genes (Bouchard et al., 2002). Pax2 and Pax8 are closely related members of the Pax family of sequence-specific transcription factors (Chi and Epstein, 2002). Pax8 -/-embryos have a severe defect in thyroid development but form normal kidneys (Mansouri et al., 1998). By contrast, Pax2 is necessary for metanephros development (Torres et al., 1995), as it controls the survival of the ureter and late nephric duct (Ostrom et al., 2000;Porteous et al., 2000;Torres et al., 1995;Bouchard, 2004) and induces the mesenchymal-epithelial transitions leading to nephron formation (Rothenpieler and Dressler, 1993). At the molecular level, Pax2 regulates the expression of important nephrogenic molecules such as Wt1 (Dehbi et al., 1996) and Gdnf (Brophy et al., 2001). These genes are expressed in the metanephric mesenchyme, and are necessary for metanephros induction and growth (Kuure et al., 2000). These data therefore point to a role of Pax2 in late mesonephros and metanephros development. However, the observation that Pax2
Pax8-/-embryos show a more severe phenotype than single-mutant embryos underscores not only the functional redundancy among the two Pax genes (Bouchard et al., 2000;Bouchard...