Reciprocal interactions between the ureteric bud (UB) and the surrounding metanephric mesenchyme (MM) are crucial for kidney induction and development. Louis Reichardt's group have previously shown that, in the absence ofα8β1 integrin (Itga8) expression in the MM, the UB fails to invade the surrounding MM - the first step in kidney induction - causing kidney agenesis. Now, this group identifies nephronectin (Npnt) asα8β1 integrin's essential ligand. Npnt is expressed in the UB and mediates α8β1 integrin activity during early mouse kidney development (see ). The expression of glial cell line-derived growth factor (GDNF)- an important growth factor in kidney development - in the MM, they show, is stimulated in response to Npnt/α8β1 integrin activity. Using Npnt-null and Itga8-null mice, these researchers show that,in both strains, UBs form but fail to invade the MM, as Gdnfexpression is reduced. However, their other findings reveal that additional factors may contribute to normal Gdnf expression patterns during kidney development. One such factor is revealed in a study by Rolf Zeller's group on , who report that gremlin 1 (Grem1), a BMP antagonist, is upregulated in the mouse MM prior to UB outgrowth. The resultant reduction in Bmp4 activity establishes the epithelial-mesenchymal (e-m) Gdnf/Wnt11 autoregulatory feedback loop that is essential for the UB's initial outgrowth and branching. Moreover, they show that failed UB outgrowth and secondary branching can be rescued in cultured gremlin mutant kidney primordia by recombinant gremlin. Wnt11 expression at the epithelial tips and Gdnfexpression in the MM is also restored by gremlin in these cultures. The regulation of Bmp4 activity by gremlin, and the subsequent establishment of the e-m feedback loop, provides insight into the mechanisms that mediate the UB's invasion of the MM, the important first step in kidney development. Further insights in kidney development are also reported by Andrew McMahon's group on , who reveal that, at a later stage of kidney development, Wnt9b and Wnt4 signalling act via carefully modulated β-catenin-mediated canonical signalling during renal vesicle induction and mesenchymal-epithelial transition.
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