Specific deletion of Axin1 leads to activation of beta-catenin/BMP signaling resulting in fibular hemimelia phenotype in mice

Axin1 is a key regulator of canonical Wnt signaling pathway. Roles of Axin1 in skeletal development and in disease occurrence have not been fully defined. Here, we report that Axin1 is essential for lower limb development. Specific deletion of Axin1 in limb mesenchymal cells leads to fibular hemimelia (FH)-like phenotype, associated with tarsal coalition. Further studies demonstrate that FH disease is associated with additional defects in Axin1 knockout (KO) mice, including decreased osteoclast formation and defects in angiogenesis. We then provide in vivo evidence showing that Axin1 controls limb development through both canonical beta-catenin and BMP signaling pathways. We demonstrate that inhibition of beta-catenin or BMP signaling could significantly reverse the FH phenotype in mice. Together, our findings reveal that integration of beta-catenin and BMP signaling by Axin1 is required for lower limb development. Defect in Axin1 signaling could lead to the development of FH disease.