Abstract
During the first month of life, the murine posterior-frontal suture (PF) of the cranial vault closes through endochondral ossification, while other sutures remain patent. These processes are tightly regulated by canonical Wnt signaling. Low levels of active canonical Wnt signaling enable endochondral ossification and therefore PF-suture closure, whereas constitutive activation of canonical Wnt causes PF-suture patency. We therefore sought to test this concept with a knockout mouse model. PF-sutures of Axin2−/− mice, which resemble a state of constantly activated canonical Wnt signaling, were investigated during the physiological time course of PF-suture closure and compared in detail with wild type littermates. Histological analysis revealed that the architecture in Axin2−/− PF-sutures was significantly altered in comparison to wild type. The distance between the endocranial layers was dramatically increased and suture closure was significantly delayed. Moreover, physiological endochondral ossification did not occur, rather an ectopic cartilage appeared between the endocranial and ectocranial bone layers at P7 which eventually involutes at P13. Quantitative PCR analysis showed the lack of Col10α1 upregulation in Axin2−/− PF-suture. Immunohistochemistry and gene expression analysis also revealed high levels of type II collagen as compared to type I collagen and absence of Mmp-9 in the cartilage of Axin2−/− PF-suture. Moreover, TUNEL staining showed a high percentage of apoptotic chondrocytes in Axin2−/− PF-sutures at P9 and P11 as compared to wild type. These data indicated that Axin2−/− PF-sutures lack physiological endochondral ossification, contain ectopic cartilage and display delayed suture closure.
Highlights
Mammalian skull vaults are composed of mesodermal and neural-crest derived bones and predominantly form through intramembranous ossification [1]
The first bony bridge between the osteogenic fronts in wild type PF-sutures was observed at P11, in contrast, the endocranial bone layers were still underdeveloped in Axin22/2 PF-sutures and osteogenic fronts were far apart
We have previously demonstrated that differential activation of canonical Wnt-signaling (cWnt) signaling determines cranial sutures closure
Summary
Mammalian skull vaults are composed of mesodermal and neural-crest derived bones and predominantly form through intramembranous ossification [1]. When osteogenic fronts approximate each other, they can either fuse or form a cranial suture. Among the four main cranial sutures of the skull vault: paired coronal (COR), paired lamboid (LAM), sagittal (SAG) and posterior-frontal (PF) [2], the PF-suture is unique in the fact that it undergoes physiological closure [3,4]. We have previously demonstrated that mouse PFsuture closure begins at P7 and ends between postnatal days 13 and 15, this process occurs through endochondral ossification [3]. An important regulator of skeletal development and endochondral ossification is canonical Wnt-signaling (cWnt). With regards to endochondral ossification, the interplay between cWnt signaling and Sox, the master gene for chondrogenesis is well described [7,8]. That cWnt-signaling represses terminal chondrogenesis [9,10,11]
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