Gremlin-mediated BMP antagonism induces the epithelial-mesenchymal feedback signaling controlling metanephric kidney and limb organogenesis

Abstract

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.

Anteroposterior patterning in the limb and digit specification: Contribution of mouse genetics

“…However, Fgf8 expression is only slightly reduced (Kuhlman and Niswander, 1997). Therefore, the defects in limb patterning in the mutant are likely due to Shh down-regulation rather than to AER disruption (Khokha et al, 2003;Michos et al, 2004). Noticeably, Shh induces Gremlin in adjacent cells but not in Shh-producing cells or their descendants, which provides a mechanism to terminate the Shh-Fgf4 loop as ZPA-derived cells expand .…”

“…It should be noticed, however, that the Gremlin null phenotype is less se-vere than the Shh phenotype (Khokha et al, 2003;Michos et al, 2004). Furthermore, Shh is down-regulated in the Gremlin mutant (see below), and this finding might be the primary cause of its phenotype.…”

“…Shh is necessary to maintain the AER posteriorly (Laufer et al, 1994;Niswander et al, 1994). This maintenance is mediated by the inhibition of BMP activity (Bmp2, Bmp4, Bmp7), an anti-AER factor, through the production of Gremlin Khokha et al, 2003;Michos et al, 2004). As a result, Fgf4 is undetectable in the Gremlin mutant AER.…”

Msx1 and Msx2 in limb mesenchyme modulate digit number and identity

“…Conversely, both Msx1 and Msx2 are up-regulated in the limb mesenchyme by a null mutation of Gremlin, a potent BMP inhibitor expressed in the limb (Khokha et al, 2003;Michos et al, 2004). Nevertheless, although a mesenchyme-specific null mutation of Bmpr1a leads to a drastic down-regulation of the two Msx genes (Ovchinnikov et al, 2006), residual expression is still detectable for both Msx1 and Msx2 anteriorly, raising the possibility that, in this region, Msx genes are controlled by other factors such as, for example, Gli3R (Lallemand et al, 2009).…”

GDNF/Ret signaling and the development of the kidney

“…(52) Furthermore, knockout of Gremlin, a secreted BMP inhibitor, causes renal agenesis, implicating a BMP signal in the suppression of UB formation. (53) Neither the BMP4 nor the Gremlin mutation affects the expression of GDNF, (51,53) suggesting that BMP signaling acts downstream of, or in parallel with, Ret signaling to fine-tune the positioning of the UB by GDNF. A similar situation occurs during lung branching morphogenesis, where FGF10 expression (which plays a somewhat analogous role to that of GDNF in ureter budding) overlies a broad region of endoderm, and negative regulation by BMP4 appears to determine the precise site of endodermal budding.…”