Function of BMPs in the apical ectoderm of the developing mouse limb.

Several bone morphogenetic proteins (BMPs) are expressed in the apical ectodermal ridge (AER), a critical signaling center that directs the outgrowth and patterning of limb mesoderm, but little is known about their function. To study the functions of apical ectodermal BMPs, an AER-specific promoter element from the Msx2 gene was used to target expression of the potent BMP antagonist noggin to the apical ectoderm of the limbs of transgenic mice. Msx2-noggin mutant mice have severely malformed limbs characterized by syndactyly, postaxial polydactyly, and dorsal transformations of ventral structures indicated by absence of ventral footpads and presence of supernumerary ventral nails. Mutant limb buds exhibit a dorsoventral (DV) and anteroposterior (AP) expansion in the extent of the AER. AER activity persists longer than normal and is maintained in regions of the apical ectoderm where its activity normally ceases. Mutant limbs possess a broad band of mesodermal tissue along the distal periphery that is absent from normal limbs and which fails to undergo the apoptosis that normally occurs in the subectodermal mesoderm. Taken together, our results suggest that apical ectodermal BMPs may delimit the boundaries of the AER by preventing adjacent nonridge ectodermal cells from becoming AER cells; negatively modulate AER activity and thus fine-tune the strength of AER signaling; and regulate the apoptosis of the distal subectodermal mesoderm that occurs as AER activity attenuates, an event that is essential for normal limb development. Our results also confirm that ectodermal BMP signaling regulates DV patterning.