): A key question in developmental biology is how growth and patterning are coordinated such that organs form with the appropriate three-dimensional structure. The vertebrate limb provides an excellent model system to study the cellular and molecular mechanisms that control embryonic growth, pattern formation and differentiation. The apical ectodermal ridge (AER) is critical for limb growth and patterning. Our studies, some of which were a direct outcome of the previous grant, have identified fibroblast growth factors (FGF) and bone morphogenetic proteins (BMP) as critical regulators of AER function. Here we will address how BMP signaling controls Fgf4 expression in the AER and the mechanism by which BMPs regulate AER function. We will also test the hypothesis that BMP acts at an earlier step to mediate formation of the AER through the transcription factor MSX and by interactions with the WNT signaling pathway. Finally, we will test the hypothesis that BMP acts through a different transcription factor, EN1, to control dorso-ventral patterning of the limb. Our knowledge of vertebrate limb development comes largely from studies in chick and mouse. The cellular and molecular processes are highly conserved between these organisms and we will take advantage of both of these systems to increase our understanding. The insight provided by these model organisms has proven directly applicable to understanding human limb development. Moreover, mutations in BMP, WNT, and FGF signaling pathways are all implicated in tumor formation, and tumor progression is associated with alterations in more than one of these pathways. A greater understanding of the manner in which BMP, WNT and FGF are coordinately regulated and how they cooperatively regulate gene expression in the limb should lead to a greater understanding of the etiology and consequences of their misregulated expression in cancers.
