In vivo evidence that BMP signaling is necessary for apoptosis in the mouse limb.
To determine the role of Bone morphogenetic protein (BMP) signaling in murine limb development in vivo, the keratin 14 promoter was used to drive expression of the BMP antagonist Noggin in transgenic mice. Phosphorylation and nuclear translocation of Smad1/5 were dramatically reduced in limbs of the transgenic animals, confirming the inhibition of BMP signaling. These mice developed extensive limb soft tissue syndactyly and postaxial polydactyly. Apoptosis in the developing limb necrotic zones was reduced with incomplete regression of the interdigital tissue. The postaxial extra digit is also consistent with a role for BMPs in regulating apoptosis. Furthermore, there was persistent expression of Fgf8, suggesting a delay in the regression of the AER. However, Msx1 and Msx2 expression was unchanged in these transgenic mice, implying that induction of these genes is not essential for mediating BMP-induced interdigital apoptosis in mice. These abnormalities were rescued by coexpressing BMP4 under the same promoter in double transgenic mice, suggesting that the limb abnormalities are a direct effect of inhibiting BMP signaling.
Guha
Udayan
U
Department of Nueroscience, Albert Einstein College of Medicine, Bronx, New York 10461, USA. guha@aecom.yu.edu
Gomes
William A
WA
Kobayashi
Tatsuya
T
Pestell
Richard G
RG
Kessler
John A
JA
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins / Q000235:genetics / Q000378:metabolism*; D002352:Carrier Proteins; D019938:Cyclin D1 / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D005121:Extremities / Q000254:growth & development* / Q000473:pathology*; D005260:Female; D051524:Fibroblast Growth Factor 8; D005346:Fibroblast Growth Factors / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D053823:Hedgehog Proteins; D018398:Homeodomain Proteins / Q000235:genetics; D053547:Keratin-14; D007633:Keratins / Q000235:genetics; D051957:MSX1 Transcription Factor; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009336:Necrosis; D010766:Phosphorylation; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013576:Syndactyly / Q000235:genetics; D015534:Trans-Activators / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics; D029961:Zebrafish Proteins; D000099176:Noggin Protein
D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins; D002352:Carrier Proteins; D019938:Cyclin D1; D004268:DNA-Binding Proteins; D051524:Fibroblast Growth Factor 8; D005346:Fibroblast Growth Factors; D053823:Hedgehog Proteins; D018398:Homeodomain Proteins; D053547:Keratin-14; D007633:Keratins; D051957:MSX1 Transcription Factor; D011506:Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D029961:Zebrafish Proteins; D000099176:Noggin Protein; C525810:Bmp4 protein, mouse; C496457:Fgf8 protein, mouse; C490944:Hoxd10 protein, mouse; C489520:Hoxd4 protein, mouse; C507446:Krt14 protein, mouse; C084119:MSX2 protein; C525813:bmp4 protein, zebrafish; C099223:hoxd10a protein, zebrafish