FGF signaling patterns cell fate at the interface between tendon and bone.

Tendon and bone are attached by a transitional connective tissue that is morphologically graded from tendinous to osseous and develops from bipotent progenitors that co-express scleraxis (Scx) and Sox9 (Scx⁺/Sox9⁺). Scx⁺/Sox9⁺ progenitors have the potential to differentiate into either tenocytes or chondrocytes, yet the developmental mechanism that spatially resolves their bipotency at the tendon-bone interface during embryogenesis remains unknown. Here, we demonstrate that development of Scx⁺/Sox9⁺ progenitors within the mammalian lower jaw requires FGF signaling. We find that loss of Fgfr2 in the mouse tendon-bone interface reduces Scx expression in Scx⁺/Sox9⁺ progenitors and induces their biased differentiation into Sox9⁺ chondrocytes. This expansion of Sox9⁺ chondrocytes, which is concomitant with decreased Notch2-Dll1 signaling, prevents formation of a mixed population of chondrocytes and tenocytes, and instead results in ectopic endochondral bone at tendon-bone attachment units. Our work shows that FGF signaling directs zonal patterning at the boundary between tendon and bone by regulating cell fate decisions through a mechanism that employs Notch signaling.

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