New Insights Into Cranial Synchondrosis Development: A Mini Review

Abstract

The synchondroses formed via endochondral ossification in the cranial base are an important growth center for the neurocranium. Abnormalities in the synchondroses affect cranial base elongation and the development of adjacent regions, including the craniofacial bones. In the central region of the cranial base, there are two synchondroses present-the intersphenoid synchondrosis and the spheno-occipital synchondrosis. These synchondroses consist of mirror image bipolar growth plates. The cross-talk of several signaling pathways, including the parathyroid hormone-like hormone (PTHLH)/parathyroid hormone-related protein (PTHrP), Indian hedgehog (Ihh), Wnt/β-catenin, and fibroblast growth factor (FGF) pathways, as well as regulation by cilium assembly and the transcription factors encoded by the RUNX2, SIX1, SIX2, SIX4, and TBX1 genes, play critical roles in synchondrosis development. Deletions or activation of these gene products in mice causes the abnormal ossification of cranial synchondrosis and skeletal elements. Gene disruption leads to both similar and markedly different abnormalities in the development of intersphenoid synchondrosis and spheno-occipital synchondrosis, as well as in the phenotypes of synchondroses and skeletal bones. This paper reviews the development of cranial synchondroses, along with its regulation by the signaling pathways and transcription factors, highlighting the differences between intersphenoid synchondrosis and spheno-occipital synchondrosis.

Keywords: RUNX2; cartilage; cranial base; intersphenoid synchondrosis; mesoderm; neural crest; spheno-occipital synchondrosis.

FIGURE 1

The cranial base and synchondroses. (A) Ventral view of bone staining of the mouse cranial base at postnatal day (P) 0. The middle line of the cranial base is formed by the presphenoid, basisphenoid (BS), and basioccipital (BO) bones. Between the mineralized bones, there are two cartilaginous synchondroses, the intersphenoid synchondrosis (ISS) and the spheno-occipital synchondrosis (SOS). Please note that the presphenoid bone is invisible because of the palatine process (PA). AT, ala temporalis (greater wing) of the basisphenoid bone; CA, canalicular part of auditory capsule; EO, exoccipital bone; FB, facial bone; IOSA, intraoccipital synchondrosis; SAB, synchondrosis, alar-basisphenoidalis; SES, spheno-ethmoidal synchondrosis. (B) Safranin-O staining of the mouse cranial base at embryonic day (E) 16.5. The presphenoid (PS), basisphenoid (BS), and basioccipital (BO) bones are separated by two synchondroses, the intersphenoid synchondrosis (ISS) and spheno-occipital synchondrosis (SOS). The synchondrosis is composed of bipolar growth plates with a central resting (r), proliferating (p), and prehypertrophic (ph) zones. PA, palate; Rp, Rathke’s pouch. (C) Schematic illustration of the tissue origins of the cranial base derived from the neural crest shown in red and those derived from the mesoderm in blue (McBratney-Owen et al., 2008). BS, basisphenoid bone; BO, basioccipital bone; EO, exoccipital bone; PS, presphenoid bone. (D) STRING protein-protein interaction network of mouse genes involved in abnormal synchondroses. The network was constructed using the STRING tool, with mouse genes involved in abnormal synchondroses (Table 1) used as input. Different colors represent different kinds of evidence of connection between proteins. (E) (a) Skulls from wild-type and Tbx1-deficient mice at birth were analyzed by micro-computed tomography and are shown in a “bird’s eye view.” In Tbx1-deficient mice, the spheno-occipital synchondrosis (SOS) was completely mineralized (Funato et al., 2020). BO, basioccipital bone; BS, basisphenoid bone; ISS, intersphenoid synchondrosis; PA, palatine process. (b) A predicted model for TBX1-mediated regulation of endochondral ossification of SOS. By inhibiting the activity of RUNX2 and the expression of RUNX2 target genes, TBX1 negatively regulates chondrocyte differentiation as well as subsequent endochondral ossification in the SOS.