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Specific Deletion of Axin1 Leads to Activation of β-Catenin/BMP Signaling Resulting in Fibular Hemimelia Phenotype in Mice

Axin1 and Axin2 are key regulators of canonical Wnt signaling pathway. The roles of Axin1 and Axin2 in skeletal development and in disease development have not been fully defined. Here, we reported that Axin1 and Axin2 are 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 demonstrated that FH disease is associated with additional defects resembling to the proximal femoral focal deficiency (PFFD) in Axin1/Axin2 double knockout (KO) mice. We then provided in vivo evidence showing that Axin1 controls limb development through both canonical β-catenin and BMP signaling pathways. We demonstrated that inhibition of β-catenin or BMP signaling could significantly reverse the FH phenotype in mice. Together, our findings revealed that integration of Wnt and BMP signaling by Axin1 is required for lower limb development. Defects in Axin1 and Axin2 signaling could lead to the development of FH disease.