BMPR-IA signaling is required for the formation of the apical ectodermal ridge and dorsal-ventral patterning of the limb.
We demonstrate that signaling via the bone morphogenetic protein receptor IA (BMPR-IA) is required to establish two of the three cardinal axes of the limb: the proximal-distal axis and the dorsal-ventral axis. We generated a conditional knockout of the gene encoding BMPR-IA (Bmpr) that disrupted BMP signaling in the limb ectoderm. In the most severely affected embryos, this conditional mutation resulted in gross malformations of the limbs with complete agenesis of the hindlimbs. The proximal-distal axis is specified by the apical ectodermal ridge (AER), which forms from limb ectoderm at the distal tip of the embryonic limb bud. Analyses of the expression of molecular markers, such as Fgf8, demonstrate that formation of the AER was disrupted in the Bmpr mutants. Along the dorsal/ventral axis, loss of engrailed 1 (En1) expression in the non-ridge ectoderm of the mutants resulted in a dorsal transformation of the ventral limb structures. The expression pattern of Bmp4 and Bmp7 suggest that these growth factors play an instructive role in specifying dorsoventral pattern in the limb. This study demonstrates that BMPR-IA signaling plays a crucial role in AER formation and in the establishment of the dorsal/ventral patterning during limb development.
Ahn
K
K
Department of Neuroscience, University of Pennsylvania Medical School, Philadelphia, PA, USA.
Mishina
Y
Y
Hanks
M C
MC
Behringer
R R
RR
Crenshaw
E B
EB
D000818:Animals; D000943:Antigens, Differentiation; D019521:Body Patterning; D055415:Bone Morphogenetic Protein 4; D055419:Bone Morphogenetic Protein 7; D052005:Bone Morphogenetic Protein Receptors, Type I; D019485:Bone Morphogenetic Proteins / Q000302:isolation & purification; D004475:Ectoderm; D004848:Epithelium / Q000196:embryology; D005121:Extremities / Q000196:embryology*; D051524:Fibroblast Growth Factor 8; D005346:Fibroblast Growth Factors / Q000302:isolation & purification; D006614:Hindlimb / Q000002:abnormalities; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D019426:Integrases; D017880:Limb Deformities, Congenital; D008648:Mesoderm; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D020897:Organizers, Embryonic; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D017978:Receptors, Growth Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D016212:Transforming Growth Factor beta; D014764:Viral Proteins
D000943:Antigens, Differentiation; C525810:Bmp4 protein, mouse; D055415:Bone Morphogenetic Protein 4; D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins; C080330:En1 protein, mouse; C496457:Fgf8 protein, mouse; D018398:Homeodomain Proteins; D017978:Receptors, Growth Factor; D016212:Transforming Growth Factor beta; D014764:Viral Proteins; D051524:Fibroblast Growth Factor 8; D005346:Fibroblast Growth Factors; D017346:Protein Serine-Threonine Kinases; C498212:Bmpr1a protein, mouse; D052005:Bone Morphogenetic Protein Receptors, Type I; C045073:Cre recombinase; D019426:Integrases