The Skull's Girder: A Brief Review of the Cranial Base

Abstract

The cranial base is a multifunctional bony platform within the core of the cranium, spanning rostral to caudal ends. This structure provides support for the brain and skull vault above, serves as a link between the head and the vertebral column below, and seamlessly integrates with the facial skeleton at its rostral end. Unique from the majority of the cranial skeleton, the cranial base develops from a cartilage intermediate-the chondrocranium-through the process of endochondral ossification. Owing to the intimate association of the cranial base with nearly all aspects of the head, congenital birth defects impacting these structures often coincide with anomalies of the cranial base. Despite this critical importance, studies investigating the genetic control of cranial base development and associated disorders lags in comparison to other craniofacial structures. Here, we highlight and review developmental and genetic aspects of the cranial base, including its transition from cartilage to bone, dual embryological origins, and vignettes of transcription factors controlling its formation.

Keywords: cranial base; craniofacial; endochondral; mesoderm; neural crest.

Figure 1

Graph depicting a keyword search of the PubMed database showing the number of articles (results per 100,000) containing the searched term (results from 1965 to 2019 shown). Note, ‘basicranium’, ‘skull base’ and ‘cranial base’ all track together, while ‘chondrocranium’ is indistinguishable from baseline of the X-axis. (Generated using, PubMed by Year: http://esperr.github.io/pubmed-by-year).

Figure 2

Schematics illustrating a midsagittal plane of the cranial base, in relation to other cranial structures, in a mouse (A) and a human (B). Note, scales are not equivalent. The major elements within this plane are the ethmoid (teal), presphenoid (light blue), basisphenoid (light red), and basioccipital (green). Major growth zones (synchondroses) are highlighted (dark red), including the inter-sphenoid and spheno-occipital synchondrosis. Note, in panel B, the presphenoid and basisphenoid have fused into the sphenoid (gradient of light blue and red), so the inter-sphenoid synchondrosis is not demarcated. The relative units of the skull, including the neurocranium (calvaria and the cranial base) and the viscerocranium (facial bones) are denoted. Rostral is to the left and caudal is to the right. The lower jaw (mandible) is not depicted. Abbreviations: ISS, inter-sphenoid synchondrosis; SOS, spheno-occipital synchondrosis.

Figure 3

(A) (Top) Block schematic of viscerocranium, calvaria, and chondro/basicranium. (Bottom) Key for panels B, C, and D, highlighting orientation of rostral-caudal axis and neural crest—mesoderm color scheme. (B) Basic diagram of chondrocranial elements (along a midsagittal plane), highlighting the crisp neural crest—mesoderm interface at Rathke’s pouch (rp). The exception to this boundary is the hypochiasmatic cartilages (denoted by asterisk), which are mesoderm derived. (C) Same as B, but highlighting elements found within the basicranium (similar to Figure 2, just schematized). Note, the shades of blue are meant to provide a relative reference to their chondrocranial precursors, although boundaries are not meant to be exact. Also highlighted are the synchondroses (e.g., SES, ISS, SOS). The neural crest—mesoderm interface is found near the anterior-posterior pituitary (ap/pp), although this interface is substantially intermixed (indicated by red/black hash) within the basicranium. (D) Summary of the phenotypes in the 3 loss-of-function models covered in this review and where defects are located relative to the cranial base. Abbreviations: ap, anterior pituitary; cv, calvaria; ISS, inter-sphenoid synchondrosis; pp, posterior pituitary; rp, Rathke’s pouch; SOS, spheno-occipital synchondrosis; vc, viscerocranium.

Figure 4

(A) Diagram representing hypothetical gene regulatory networks (GRNs) for neural crest intramembranous (red outline, dark grey fill), neural crest endochondral (red outline, light blue fill), cranial mesoderm endochondral (black outline, green fill), and trunk mesoderm endochondral (black outline, light grey fill) modes of ossification. Note, while each large circle represents a collective of GRNs, these processes could be broken down into cell-type specific GRNs, including ‘mesenchymal precursor’ (m), chondroblast/cyte (c), and osteoblast/cyte (o)—represented by the small circles in A. (B) The prevailing notion would suggest that anterior or posterior cranial base GRNs are composed of reutilized GRN ‘modules’ from other tissues. For example, the anterior cranial base ‘SIX2 module’ [52] is the same that is used in neural crest derived viscerocranial elements. Likewise, for the posterior cranial base ‘TBX1 module’ [68] and other TBX1 GRNs. (C) Venn diagrams conceptualizing GRN overlap between these different skeletal populations. Whether novelties exist for anterior and posterior cranial base GRNs (regions denoted by ‘?’) remains to be fully realized. Abbreviations: c, chondroblast/cyte; CB, cranial base; GRN, gene regulatory network; m, mesenchymal precursor; o, osteoblast/cyte.