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Wnt/β-catenin Signaling Regulates Cranial Base Development and Growth

¹ Department of Orthopaedic Surgery, Thomas Jefferson University College of Medicine, Philadelphia, PA 19107, USA;
² Department of Oral Pathology, Asahi University School of Dentistry, Mizuho, Gifu, 501-0296 Japan; and
³ Laboratory of Reproductive and Developmental Toxicology, National Institute of Environmental Health Sciences/NIH, Research Triangle Park, NC 27709, USA

View larger version (102K): [in this window] [in a new window]   Figure 1. Growth plate organization and endochondral and perichondrial bone formation are defective in β-catenin-deficient cranial bases and synchondroses. Skulls from E17.5 control (β-cateninfl/fl; A) and β-catenin-deficient (β-cateninfl/fl;Col2al-Cre; J) mice were analyzed by micro-computed tomography (µCT) and are shown in a ’bird’s-eye view’. The locations of intrasphenoidal (is) and spheno-occipital (so) synchondroses, and pre-sphenoidal (ps), basi-sphenoidal (bs), and basi-occipital (bo) bones are indicated in control (A–B). Parasagittal hemotoxylin and eosin (H&E)-stained sections of control (B) and β-catenin-deficient (K) cranial bases at E17.5. Alizarin-red-stained sections of control (C) and β-catenin-deficient (L) specimens. Note that the resting (rz), proliferative (pr), pre-hypertrophic (phz), and hypertrophic (hz) growth plate zones in control (G) are markedly abnormal in mutant synchondroses (P). The distance between pre-sphenoidal and basi-sphenoidal bones (L, indicated by a solid line) is much shorter than that in control (C, indicated by a solid line). Serial sections of the medial portion of E17.5 control (D–F, H–I) and β-catenin-deficient (M–O, Q–R) cranial bases were processed for in situ hybridization, for analysis of intrasphenoidal and spheno-occipital synchondrosis growth plates and associated endochondral and perichondrial bone formation. (S) Synchondrosis growth plate sections from E18.5 TOPGAL embryos were processed for β-galactosidase staining. Scale bars: 2.5 mm in J for A, J; 1 mm in O for B–F and K–O; and 60 µm in R for G–I and P–R.

View larger version (85K): [in this window] [in a new window]   Figure 2. Constitutive activation of β-catenin signaling causes cranial base abnormalities. (A) Parasagittal sections of CA-LEF1 cranial bases at E17.5 were stained with H&E, and the locations of intrasphenoidal (is) and spheno-occipital (so) synchondroses are indicated. (B,C) Boxed areas in A are shown at higher magnification. Serial sections from E17.5 CA-LEF1 (D–F, L–M) and wild-type (I–J) cranial bases were processed for in situ hybridization analysis of indicated genes during endochondral (D–F) and perichondrial bone formation (I,J and L,M). (G) Alizarin-red-stained sections of a CA-LEF1 embryo displayed the presence of ectopic (arrowhead) and intermingling (double arrowhead) mineralized tissue in intrasphenoidal (is) and spheno-occipital (so) synchondroses. Scale bars: 1 mm in A for A and D–G; 45 µm in B for B–C; and 55 µm in H for H–M.

View larger version (75K): [in this window] [in a new window]   Figure 3. Hedgehog and Wnt signaling is altered in β-catenin-deficient synchondroses. Serial sections of E17.5 control (A–G), β-catenin-deficient (H–N), and Ihh-deficient (O–U) spheno-occipital synchondroses were processed for gene expression analysis of indicated molecules. In controls, Patched 1 (C) and β-catenin (F) were expressed in the proliferative zone (pz; single arrows) and perichondrium (arrowheads) flanking the Ihh-expressing pre-hypertrophic chondrocytes (B), and PTHrP (D) and sFRP1 (G) were prominent in resting zone chondrocytes (rz). Note that in β-catenin-deficient synchondroses, the significant reduction of Ihh expression (I) was accompanied by reduced expression of Patched 1 (J), PTHrP (K), and sFRP1 (N). Note also that in Ihh–/–synchondroses, expression of PTHrP (R), β-catenin (T), and sFRP1 (U) was significantly reduced. Scale bar: 120 µm in O for A–U.

View larger version (46K): [in this window] [in a new window]   Figure 4. Model illustrating the phenotypic consequence of β-catenin and Ihh deficiency. (A) In wild-type synchondroses, PTHrP and sFRP1 induced by Ihh in the resting and proliferating zones would limit Wnt/β-catenin signaling in resident chondrocytes, establishing normal rates of chondrocyte development and maturation. (B) In β-catenin-deficient synchondroses, low, but widely expressed, PTHrP and sFRP1 would attenuate Wnt/β-catenin signaling throughout the growth plate, resulting in delayed synchondrosis development. (C) In Ihh–/–synchondroses, Wnt/β-catenin signaling would be widespread and would accelerate chondrocyte maturation, together with extremely low PTHrP and sFRP1 levels.

Journal of Dental Research, Vol. 87, No. 3, 244-249 (2008)
DOI: 10.1177/154405910808700309


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