The BMP antagonist Gremlin is required for proper patterning of the vertebrate limb. Gremlin modulates the BMP signal and maintains the FGF-Shh feedback loop.

During limb outgrowth, signaling by Bone morphogenetic proteins (BMPs) must be moderated to maintain the signaling loop between the Zone of Polarizing Activity (ZPA) and the Apical Ectodermal Ridge (AER). Gremlin (Cktsf1b1), an extracellular BMP antagonist, has been proposed to fulfil this function and therefore play an important role in limb patterning. We have tested this model directly by mutating the mouse gremlin gene. In the mutant limb, the feedback loop between the ZPA and the AER is interrupted resulting in abnormal skeletal pattern. We also show that the gremlin mutation is allelic to limb deformity (ld). Although BMPs and their antagonists have multiple roles in limb development, these experiments show that <i>gremlin</i> is the principal BMP antagonist required for early limb outgrowth and patterning.