Disruption of Wnt production in Shh lineage causes bone malformation in mice, mimicking human Malik-Percin-type syndactyly.

Here, we show that Shh-Cre-mediated deletion of Wntless, the Wnt cargo protein, in mouse posterior limb mesenchyme causes bone syndactyly of the 3rd and 4th digits, resembling the human Malik-Percin type. The Shh descendants gradiently distributed from digit 5 to posterior half of digit 3 in wild-type limbs, however, they abnormally increased in posterior digit 3 in Wntless^Shh-Cre . Wntless^Shh-Cre limbs displayed altered expression of hedgehog pathway genes and impaired noncanonical Wnt signaling activity. We further showed that the anterior limb mesenchymal cells in the Wls^Shh-Cre served as a source of Wnt5a to reorientate the adjacent Wls-lacking Shh lineage cells to move anteriorly and subsequently led to syndactyly, suggesting that aberrant mesenchymal cell movement/condensation may underlie the pathogenesis of syndactyly.

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