GATA3 mediates nonclassical β-catenin signaling in skeletal cell fate determination and ectopic chondrogenesis

Skeletal precursors are mesenchymal in origin and can give rise to distinct sublineages. Their lineage commitment is modulated by various signaling pathways. The importance of Wnt signaling in skeletal lineage commitment has been implicated by the study of β-catenin-deficient mouse models. Ectopic chondrogenesis caused by the loss of β-catenin leads to a long-standing belief in canonical Wnt signaling that determines skeletal cell fate. As β-catenin has other functions, it remains unclear whether skeletogenic lineage commitment is solely orchestrated by canonical Wnt signaling. The study of the Wnt secretion regulator Gpr177/Wntless also raises concerns about current knowledge. Here, we show that skeletal cell fate is determined by β-catenin but independent of LEF/TCF transcription. Genomic and bioinformatic analyses further identify GATA3 as a mediator for the alternative signaling effects. GATA3 alone is sufficient to promote ectopic cartilage formation, demonstrating its essential role in mediating nonclassical β-catenin signaling in skeletogenic lineage specification.