The CREB family of activators is required for endochondral bone development.
We have evaluated the importance of the CREB family of transcriptional activators for endochondral bone formation by expressing a potent dominant negative CREB inhibitor (A-CREB) in growth plate chondrocytes of transgenic mice. A-CREB transgenic mice exhibited short-limbed dwarfism and died minutes after birth, apparently due to respiratory failure from a diminished rib cage circumference. Consistent with the robust Ser133 phosphorylation and, hence, activation of CREB in chondrocytes within the proliferative zone of wild-type cartilage during development, chondrocytes in A-CREB mutant cartilage exhibited a profound decrease in proliferative index and a delay in hypertrophy. Correspondingly, the expression of certain signaling molecules in cartilage, most notably the Indian hedgehog (Ihh) receptor patched (Ptch), was lower in A-CREB expressing versus wild-type chondrocytes. CREB appears to promote Ptch expression in proliferating chondrocytes via an Ihh-independent pathway; phospho-CREB levels were comparable in cartilage from Ihh(-/-) and wild-type mice. These results demonstrate the presence of a distinct signaling pathway in developing bone that potentiates Ihh signaling and regulates chondrocyte proliferation, at least in part, via the CREB family of activators.
Long
F
F
The Salk Institute for Biological Studies, Peptide Biology Laboratories, La Jolla, CA 92037, USA.
Schipani
E
E
Asahara
H
H
Kronenberg
H
H
Montminy
M
M
D000818:Animals; D001846:Bone Development / Q000235:genetics*; D001842:Bone and Bones / Q000166:cytology / Q000196:embryology* / Q000378:metabolism; D002455:Cell Division; D002478:Cells, Cultured; D002642:Chick Embryo; D019902:Chondrocytes / Q000166:cytology* / Q000378:metabolism; D003094:Collagen / Q000235:genetics; D017362:Cyclic AMP Response Element-Binding Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D005314:Embryonic and Fetal Development / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D005822:Genetic Vectors; D006132:Growth Plate / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D053823:Hedgehog Proteins; D017403:In Situ Hybridization; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D011506:Proteins / Q000378:metabolism; D015398:Signal Transduction; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
D017362:Cyclic AMP Response Element-Binding Protein; D053823:Hedgehog Proteins; D011506:Proteins; D015534:Trans-Activators; D003094:Collagen