BMP controls proximodistal outgrowth, via induction of the apical ectodermal ridge, and dorsoventral patterning in the vertebrate limb

Dorsoventral (DV) patterning of the vertebrate limb requires the function o f the transcription factor Engrailed 1 (EN1) in the ventral ectoderm. EN1 r estricts, to the dorsal half of the limb, the expression of the two genes k nown to specify dorsal pattern. Limb growth along the proximodistal (PD) ax is is controlled by the apical ectodermal ridge (AER), a specialized epithe lium that forms at the distal junction between dorsal and ventral ectoderm. Using retroviral-mediated misexpression of the bone morphogenetic protein (BMP) antagonist Noggin or an activated form of the BMP receptor in the chi ck limb, we demonstrate that BMP plays a key role in both DV patterning and AER induction. Thus, the DV and PD axes are linked by a common signal. Los s and gain of BMP function experiments show that BMP signaling is both nece ssary and sufficient to regulate EN1 expression, and consequently DV patter ning. Our results also indicate that BMPs are required during induction of the AER. Manipulation of BMP signaling results in either disruptions in the endogenous AER, leading to absent or severely truncated limbs or the forma tion of ectopic AERs that can direct outgrowth. Moreover, BMP controls the expression of the MSX transcription factors, and our results suggest that M SX acts downstream of BMP in AER induction. We propose that the BMP signal bifurcates at the level of EN1 and MSX to mediate differentially DV pattern ing and AER induction, respectively.