Reduction of BMP4 activity by gremlin 1 enables ureteric bud outgrowth and GDNF/WNT11 feedback signalling during kidney branching morphogenesis

Abstract

Antagonists act to restrict and negatively modulate the activity of secreted signals during progression of embryogenesis. In mouse embryos lacking the extra-cellular BMP antagonist gremlin 1 (Grem1), metanephric development is disrupted at the stage of initiating ureteric bud outgrowth. Treatment of mutant kidney rudiments in culture with recombinant gremlin 1 protein induces additional epithelial buds and restores outgrowth and branching. All epithelial buds express Wnt11, and Gdnf is significantly upregulated in the surrounding mesenchyme, indicating that epithelial-mesenchymal (e-m) feedback signalling is restored. In the wild type, Bmp4 is expressed by the mesenchyme enveloping the Wolffian duct and ureteric bud and Grem1 is upregulated in the mesenchyme around the nascent ureteric bud prior to initiation of its outgrowth. In agreement, BMP activity is reduced locally as revealed by lower levels of nuclear pSMAD protein in the mesenchyme. By contrast, in Grem1-deficient kidney rudiments, pSMAD proteins are detected in many cell nuclei in the metanephric mesenchyme, indicative of excessive BMP signal transduction. Indeed, genetic lowering of BMP4 levels in Grem1-deficient mouse embryos completely restores ureteric bud outgrowth and branching morphogenesis. The reduction of BMP4 levels in Grem1 mutant embryos enables normal progression of renal development and restores adult kidney morphology and functions. This study establishes that initiation of metanephric kidney development requires the reduction of BMP4 activity by the antagonist gremlin 1 in the mesenchyme, which in turn enables ureteric bud outgrowth and establishment of autoregulatory GDNF/WNT11 feedback signalling.

WT1 controls antagonistic FGF and BMP-pSMAD pathways in early renal progenitors

“…The notion that BMP signalling acts pro-apoptotic may therefore seem at a first glance surprising. However, immunostaining and reporter assays indicate an absence of pSMAD signalling from early renal progenitors 47,48 . In vitro experiments suggest that BMP7 promotes progenitor proliferation via a JNK-dependent mechanism 34 .…”

Chordin-like 1 and Twisted Gastrulation 1 Regulate BMP Signaling following Kidney Injury

“…A complex system for the control of BMP signaling by both BMP antagonists and agonists is therefore required. 44 These modulators are essential to BMP function, and their inactivation strongly influences the kidney's response to acute and chronic injury. 21,45 The response of the S3 segment to BMPs is of particular relevance to acute ischemic injury because this is the site of the most profound cellular damage.…”

Deletion of Gremlin1 increases cell proliferation and migration responses in mouse embryonic fibroblasts

“…In addition, the temporospatial changes in both Grem1 and its target BMPs are likely to also determine whether Grem1 can drive or inhibit cell proliferation in each specific cellular context. Grem1 has been shown to bind and inhibit BMP2, BMP-4 and BMP7 in the process of limb development and in fibrosis of the lung and kidney [10,12,30,31]. In addition, recent data has shown that Grem1 acts as an agonist at the VEGFR2 receptor, triggering angiogenic sprouting of endothelial cells [15].…”

“…Mice lacking Grem1 do not develop kidneys [10,11], likely due to an inappropriately strong drive from BMP-4 during development [11]. Deletion of one allele of BMP-4 is sufficient to rescue kidney development in grem1−/− mice, highlighting the signalling interplay between these two proteins [12]. Grem1 can also bind to precursor BMP-4 intracellularly, preventing its secretion and thus inhibiting its action at the BMP receptor [13].…”