BMP signaling during bone pattern determination in the developing limb.
To examine the role of BMP signaling during limb pattern formation, we isolated chicken cDNAs encoding type I (BRK-1 and BRK-2) and type II (BRK-3) receptors for bone morphogenetic proteins. BRK-2 and BRK-3, which constitute dual-affinity signaling receptor complexes for BMPs, are co-expressed in condensing precartilaginous cells, while BRK-1 is weakly expressed in the limb mesenchyme. BRK-3 is also expressed in the apical ectodermal ridge and interdigital limb mesenchyme. BRK-2 is intensely expressed in the posterior-distal region of the limb bud. During digit duplication by implanting Sonic hedgehog-producing cells, BRK-2 expression is induced anteriorly in the new digit forming region as observed for BMP-2 and BMP-7 expression in the limb bud. Dominant-negative effects on BMP signaling were obtained by over-expressing kinase domain-deficient forms of the receptors. Chondrogenesis of limb mesenchymal cells is markedly inhibited by dominant-negative BRK-2 and BRK-3, but not by BRK-1. Although the bone pattern was not disturbed by expressing individual dominant-negative BRK independently, preferential distal and posterior limb truncations resulted from co-expressing the dominant-negative forms of BRK-2 and BRK-3 in the whole limb bud, thus providing evidence that BMPs are essential morphogenetic signals for limb bone patterning.
Kawakami
Y
Y
Department of Molecular Biology, Kawasaki Medical School, Kurashiki, Japan.
Ishikawa
T
T
Shimabara
M
M
Tanda
N
N
Enomoto-Iwamoto
M
M
Iwamoto
M
M
Kuwana
T
T
Ueki
A
A
Noji
S
S
Nohno
T
T
D000595:Amino Acid Sequence; D000818:Animals; D052004:Bone Morphogenetic Protein Receptors; D052005:Bone Morphogenetic Protein Receptors, Type I; D052006:Bone Morphogenetic Protein Receptors, Type II; D019485:Bone Morphogenetic Proteins / Q000502:physiology*; D001842:Bone and Bones / Q000196:embryology; D002356:Cartilage / Q000196:embryology; D002478:Cells, Cultured; D002645:Chickens; D005121:Extremities / Q000196:embryology*; D005799:Genes, Dominant; D053823:Hedgehog Proteins; D008969:Molecular Sequence Data; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D011506:Proteins / Q000502:physiology; D011956:Receptors, Cell Surface / Q000502:physiology*; D017978:Receptors, Growth Factor / Q000502:physiology*; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D015534:Trans-Activators
D019485:Bone Morphogenetic Proteins; D053823:Hedgehog Proteins; D011506:Proteins; D011956:Receptors, Cell Surface; D017978:Receptors, Growth Factor; D015534:Trans-Activators; D017346:Protein Serine-Threonine Kinases; D052004:Bone Morphogenetic Protein Receptors; D052005:Bone Morphogenetic Protein Receptors, Type I; D052006:Bone Morphogenetic Protein Receptors, Type II