The many lives of SHH in limb development and evolution

The SHH signaling pathway is essential for proper formation of the limb skeleton, as is required for the survival and expansion of distal chondrogenic progenitor cells. At the same time, SHH is important to specify digit identities along the anterior-posterior axis. Upon gain or loss of activity of the SHH pathway, bones are gained, lost or malformed, and such deregulation underlies the aetiology of various human congenital limb defects. Likewise, accumulating evidence suggests that evolutionary tampering with SHH signaling underlies the morphological diversification of the tetrapod appendicular skeleton. This review summarizes the roles of the SHH pathway in the context of limb development and evolution and incorporates recent evidence into a mechanistic view of how the positioning of digit condensations is integrated with the specification of distinct bone morphologies.