Wnt/beta-catenin signaling regulates cranial base development and growth.
Wnt proteins and beta-catenin signaling regulate major processes during embryonic development, and we hypothesized that they regulate cranial base synchondrosis development and growth. To address this issue, we analyzed cartilage-specific beta-catenin-deficient mice. Mutant synchondroses lacked typical growth plate zones, and endochondral ossification was delayed. In reciprocal transgenic experiments, cartilage overexpression of a constitutive active Lef1, a transcriptional mediator of Wnt/beta-catenin signaling, caused precocious chondrocyte hypertrophy and intermingling of immature and mature chondrocytes. The developmental changes seen in beta-catenin-deficient synchondroses were accompanied by marked reductions in Ihh and PTHrP as well as sFRP-1, an endogenous Wnt signaling antagonist and a potential Ihh signaling target. Thus, Wnt/beta-catenin signaling is essential for cranial base development and synchondrosis growth plate function. This pathway promotes chondrocyte maturation and ossification events, and may exert this important role by dampening the effects of Ihh-PTHrP together with sFRP-1.
Nagayama
M
M
Department of Orthopaedic Surgery, Thomas Jefferson University College of Medicine, Philadelphia, PA 19107, USA.
Iwamoto
M
M
Hargett
A
A
Kamiya
N
N
Tamamura
Y
Y
Young
B
B
Morrison
T
T
Takeuchi
H
H
Pacifici
M
M
Enomoto-Iwamoto
M
M
Koyama
E
E
D000818:Animals; D002356:Cartilage / Q000254:growth & development; D019902:Chondrocytes / Q000473:pathology; D024042:Collagen Type I / Q000032:analysis; D024043:Collagen Type II / Q000032:analysis; D024121:Collagen Type X / Q000032:analysis; D003393:Cranial Sutures / Q000254:growth & development*; D006132:Growth Plate / Q000254:growth & development; D053823:Hedgehog Proteins / Q000032:analysis; D006984:Hypertrophy; D036341:Intercellular Signaling Peptides and Proteins / Q000032:analysis; D051821:Lymphoid Enhancer-Binding Factor 1 / Q000235:genetics; D008565:Membrane Proteins / Q000032:analysis; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D010012:Osteogenesis / Q000235:genetics; D044162:Parathyroid Hormone-Related Protein / Q000032:analysis; D015398:Signal Transduction / Q000502:physiology*; D019291:Skull Base / Q000254:growth & development*; D000076182:Sp7 Transcription Factor; D014157:Transcription Factors / Q000032:analysis; D014158:Transcription, Genetic / Q000235:genetics; D051153:Wnt Proteins / Q000502:physiology*; D016335:Zinc Fingers; D051176:beta Catenin / Q000235:genetics / Q000502:physiology*; D000094742:Secreted Frizzled-Related Proteins
D024042:Collagen Type I; D024043:Collagen Type II; D024121:Collagen Type X; D053823:Hedgehog Proteins; D036341:Intercellular Signaling Peptides and Proteins; D051821:Lymphoid Enhancer-Binding Factor 1; D008565:Membrane Proteins; D044162:Parathyroid Hormone-Related Protein; D000076182:Sp7 Transcription Factor; D014157:Transcription Factors; D051153:Wnt Proteins; D051176:beta Catenin; C497574:Lef1 protein, mouse; C485539:Sfrp1 protein, mouse; D000094742:Secreted Frizzled-Related Proteins; C479466:Sp7 protein, mouse; C514061:ihh protein, mouse