β-catenin/cyclin D1 mediated development of suture mesenchyme in calvarial morphogenesis.
BACKGROUND
Mouse genetic study has demonstrated that Axin2 is essential for calvarial development and disease. Haploid deficiency of β-catenin alleviates the calvarial phenotype caused by Axin2 deficiency. This loss-of-function study provides evidence for the requirement of β-catenin in exerting the downstream effects of Axin2.


RESULTS
Here we utilize a gain-of-function analysis to further assess the role of β-catenin. A transgenic expression system permitting conditional activation of β-catenin in a spatiotemporal specific manner has been developed. Aberrant stimulation of β-catenin leads to increases in expansion of skeletogenic precursors and the enhancement of bone ossification reminiscent to the loss of Axin2. The constitutively active signal promotes specification of osteoprogenitors, but prevents their maturation into terminally differentiated osteoblasts, along the osteoblast lineage. However, the prevention does not interfere with bone synthesis, suggesting that mineralization occurs without the presence of mature osteoblasts. β-catenin signaling apparently plays a key role in suture development through modulation of calvarial morphogenetic signaling pathways. Furthermore, genetic inactivation of the β-catenin transcriptional target, cyclin D1, impairs expansion of the skeletogenic precursors contributing to deficiencies in calvarial ossification. There is a specific requirement for cyclin D1 in populating osteoprogenitor cell types at various developmental stages.


CONCLUSIONS
These findings advance our knowledge base of Wnt signaling in calvarial morphogenesis, suggesting a key regulatory pathway of Axin2/β-catenin/cyclin D1 in development of the suture mesenchyme.
Department of Biomedical Genetics, Center for Oral Biology, University of Rochester Medical Center, Rochester, NY 14642, USA.
Anthony J
AJ
Mirando
Takamitsu
T
Maruyama
Jiang
J
Fu
Hsiao-Man Ivy
HM
Yu
Wei
W
Hsu
D000818:Animals; D060466:Axin Protein; D015415:Biomarkers / Q000378:metabolism; D019485:Bone Morphogenetic Proteins / Q000235:genetics / Q000378:metabolism; D019070:Cell Lineage; D049109:Cell Proliferation; D002478:Cells, Cultured; D003393:Cranial Sutures / Q000033:anatomy & histology / Q000196:embryology / Q000378:metabolism; D019938:Cyclin D1 / Q000378:metabolism*; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism*; D005346:Fibroblast Growth Factors / Q000378:metabolism; D008648:Mesoderm / Q000033:anatomy & histology / Q000196:embryology / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009024:Morphogenesis / Q000502:physiology*; D010006:Osteoblasts / Q000166:cytology / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D012886:Skull / Q000033:anatomy & histology / Q000196:embryology / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology / Q000502:physiology; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
D060466:Axin Protein; C111729:Axin2 protein, mouse; D015415:Biomarkers; D019485:Bone Morphogenetic Proteins; D003598:Cytoskeletal Proteins; D051153:Wnt Proteins; D051176:beta Catenin; D019938:Cyclin D1; D005346:Fibroblast Growth Factors