Gremlin-mediated BMP antagonism induces the epithelial-mesenchymal feedback signaling controlling metanephric kidney and limb organogenesis.
2004
Epithelial-mesenchymal feedback signaling is the key to diverse
organogenetic processes such as limb bud development and branching
morphogenesis in kidney and lung rudiments. This study establishes that the
BMP antagonist gremlin ( Grem1 ) is essential to initiate these
epithelial-mesenchymal signaling interactions during limb and metanephric
kidney organogenesis. A Grem1 null mutation in the mouse generated by
gene targeting causes neonatal lethality because of the lack of kidneys and
lung septation defects. In early limb buds, mesenchymal Grem1 is
required to establish a functional apical ectodermal ridge and the
epithelial-mesenchymal feedback signaling that propagates the sonic hedgehog
morphogen. Furthermore, Grem1 -mediated BMP antagonism is essential to
induce metanephric kidney development as initiation of ureter growth,
branching and establishment of RET/GDNF feedback signaling are disrupted in
Grem1 -deficient embryos. As a consequence, the metanephric mesenchyme
is eliminated by apoptosis, in the same way as the core mesenchymal cells of
the limb bud.
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