Abstract
ABSTRACTWnt/β-catenin signaling is involved in patterning of bone primordia, but also plays an important role in the differentiation of chondrocytes and osteoblasts. During these processes the level of β-catenin must be tightly regulated. Excess β-catenin leads to conditions with increased bone mass, whereas loss of β-catenin is associated with osteoporosis or, in extreme cases, the absence of limbs. In this study, we examined skeletogenesis in mice, which retain only 25% of β-catenin. These embryos showed severe morphological abnormalities of which the lack of hindlimbs and misshaped front paws were the most striking. Surprisingly however, calcification of bone primordia occurred normally. Moreover, the Wnt-dependent regulatory network of transcription factors driving the differentiation of cartilage and bone, as well as the expression of extracellular matrix components, were preserved. These findings show that 25% β-catenin is insufficient for the correct patterning of bone primordia, but sufficient for their mineralization. Our approach helps to identify bone morphogenetic processes that can proceed normally even at low β-catenin levels, in contrast to those that require high β-catenin dosages. This information could be exploited to improve the treatment of bone diseases by fine-tuning the individual β-catenin dosage requirements.
Highlights
Canonical Wnt signaling activates the transcription of β-catenindependent target genes during many stages of bone development and maintenance (Duan and Bonewald, 2016), whereby a cytoplasmic multi-protein complex composed of the scaffolding proteins Axin and APC (Heuberger and Birchmeier, 2010; Munemitsu et al, 1995), and the kinases CK1α and GSK3β (Behrens et al, 1998; Munemitsu et al, 1995), tightly regulates the level of β-catenin
Homozygous expression of ROSA26::β-catenin leads to a β-catenin expression level of 25% compared to wild-type mice (Rudloff and Kemler, 2012)
Cre-mediated recombination in our knockdown embryos took place in all mesodermal and ectodermal tissues that are derived from the posterior embryo at midgastrulation, including the fore- and hindlimb primordia
Summary
Canonical Wnt signaling activates the transcription of β-catenindependent target genes during many stages of bone development and maintenance (Duan and Bonewald, 2016), whereby a cytoplasmic multi-protein complex composed of the scaffolding proteins Axin and APC (Heuberger and Birchmeier, 2010; Munemitsu et al, 1995), and the kinases CK1α and GSK3β (Behrens et al, 1998; Munemitsu et al, 1995), tightly regulates the level of β-catenin. Upon binding of a canonical Wnt ligand to the co-receptor pair Frizzled and Lrp5/6 (Heuberger and Birchmeier, 2010), the degradation machinery is Department of Clinical Research, Department of Nephrology and Hypertension, Bern University Hospital, University of Bern, Freiburgstrasse 15, Bern CH-3010, Switzerland. Additional players that affect the level of β-catenin during bone development and repair include the extracellular Wnt inhibitors Dickkopf and Sclerostin (Florio et al, 2016; Ke et al, 2012; Qiang et al, 2008)
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