Human hands and feet contain bones of a particular size and shape arranged in a precise pattern. The secreted factor sonic hedgehog (SHH) acts through the conserved hedgehog (Hh) signaling pathway to regulate the digital pattern in the limbs of tetrapods (i.e. land-based vertebrates). Genetic analysis is now uncovering a remarkable set of pathogenetic mutations that alter the Hh pathway, thus compromising both digit number and identity. Several of these are regulatory mutations that have the surprising attribute of misdirecting expression of Hh ligands to ectopic sites in the developing limb buds. In addition, other mutations affect a fundamental structural property of the embryonic cell that is essential to Hh signaling. In this review, we focus on the role that the Hh pathway plays in limb development, and how the many human genetic defects in this pathway are providing clues to the mechanisms that regulate limb development.
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