A pivotal Wnt antagonist role promoting digit joint specification by constraining Wnt activity

Using genetic and genomic approaches, we found instead that canonical Wnts can cooperate with Bmps to enhance pSmad1/5 activity and initiate chondrogenic commitment in digit tip progenitors. 5’HoxdD/D mutant digits are characterized by elevated Bmp and pSmad1/5 activity and subsequent joint loss. We show that expressing stabilized bcatenin (bcatCA) in interdigit mesenchyme rescues 5’HoxdD/D digit joint loss non-autonomously, by inducing secreted Wnt antagonists and normalizing digit tip pSmad1/5 levels.

Indeed, genetic removal of Dkk2 in 5’HoxdD/D prevented joint rescue by bcatCA. Furthermore, elevating Wnt activity with Gsk3b antagonists in limb bud culture stabilized pSmad1/5 levels and enhanced Bmp activity. Elevated pSmad1/5, as seen in 5’HoxdD/D, accelerates chondrogenic commitment, impeding a switch of phalanx forming region (PFR) cells in the digit tip to interzone (joint progenitor) fate.