Journal of Developmental Biology Review The Skull’s Girder: A Brief Review of the Cranial Base Shankar Rengasamy Venugopalan 1,2 and Eric Van Otterloo 1,3,4,* 1 Iowa Institute for Oral Health Research, College of Dentistry, University of Iowa, Iowa City, IA 52242, USA; [email protected] 2 Department of Orthodontics, College of Dentistry, University of Iowa, Iowa City, IA 52242, USA 3 Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA 4 Department of Periodontics, College of Dentistry, University of Iowa, Iowa City, IA 52242, USA * Correspondence: [email protected] 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: neural crest; mesoderm; cranial base; craniofacial; endochondral Citation: Rengasamy Venugopalan, 1. Introduction S.; Van Otterloo, E. The Skull’s Girder: The cranial base, although inconspicuously tucked within the core of the cranium, A Brief Review of the Cranial Base. J. functions almost as an anatomical girder. The cranial base supports the brain and the Dev. Biol. 2021 9 , , 3. https://doi.org/ overlying cranial vault, while the viscerocranium (facial skeleton) largely ‘hangs’ from its 10.3390/jdb9010003 rostral end. Owing to its proximity and co-development with cranial sense organs—the otic, optic, and nasal placodes—the cranial base develops in an almost ‘jigsaw-like fashion’, Received: 14 December 2020 accommodating, protecting, and supporting these specialized organs. Likewise, given its Accepted: 19 January 2021 Published: 23 January 2021 anatomical location within the centrum of the head, just inferior to the brain, the cranial base is traversed by numerous nerves and blood vessels through its many foramina. Like Publisher’s Note: MDPI stays neutral the cranial vault above, the completed cranial base is a near seamless integration of tissues with regard to jurisdictional claims in derived from mesodermal or ectomesenchymal neural crest cell origin. However, in stark published maps and institutional affil- contrast to the calvaria or the neural crest cell derived viscerocranium—which undergo a iations. process of intramembranous ossification—the cranial base implements a ‘long bone strategy’ involving endochondral ossification. The embryonic development of the cranial base begins as a variety of separate cartilages, which fuse to form the singular chondrocranium that eventually undergoes endochondral ossification. Our understanding of the cranial base, relative to the easily accessible viscerocranial or neurocranial calvarial elements, is lacking Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. (see Figure1), especially at a high-level molecular resolution; this is partly due to the This article is an open access article cranial base’s central placement within the skull. Nonetheless, because of the anatomical distributed under the terms and proximity of the cranial base with viscero- and neurocranial elements, developmental conditions of the Creative Commons anomalies impacting the cranial base often manifest viscero- and neurocranial defects. As Attribution (CC BY) license (https:// such, expanding our knowledge of this concealed structural element will provide broad creativecommons.org/licenses/by/ insight into the development, disruption, and evolution of the craniofacial complex as a 4.0/). whole [1]. J. Dev. Biol. 2021, 9, 3. https://doi.org/10.3390/jdb9010003 https://www.mdpi.com/journal/jdb J. Dev. Biol. 2021, 9, x 2 of 17 J. Dev. Biol. 2021, 9, x 2 of 17 element will provide broad insight into the development, disruption, and evolution of the craniofacialelement will complex provide as broad a whole insight [1]. into the development, disruption, and evolution of the craniofacial complex as a whole [1]. J. Dev. Biol. 2021, 9, 3 2 of 17 Figure 1. Graph depicting a keyword search of the PubMed database showing the number of arti- Figure 1. Graph depicting a keyword search of the PubMed database showing the number clesFigure (results 1. Graphper 100,000) depicting containing a keyword the searchsearched of termthe PubM (resultsed fromdatabase 1965 showing to 2019 shown).the number Note, of arti- of articles (results per 100,000) containing the searched term (results from 1965 to 2019 ‘basicranium’,cles (results per‘skull 100,000) base’ and containing ‘cranial thebase’ search all tredack term together, (results while from ‘chondrocranium’ 1965 to 2019 shown). is indistin- Note, guishable‘basicranium’,shown). from Note,baseline ‘skull ‘basicranium’, base’ of the and X-axis. ‘cranial ‘skull(Gen base’erated base’ all andusing,track ‘cranial together, PubMed base’ while by Year: all ‘chondrocranium’ track http://es- together, while is indistin- perr.github.io/pubmed-by-year).guishable‘chondrocranium’ from baseline is of indistinguishable the X-axis. 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Here, we briefly review the developmental origins and progression of the mouse Here, we briefly review the developmental origins and progression of the mouse (Part 2.1,Here, Figure we 2A)briefly and reviewhuman the(Part developmental 2.2, Figure 2B) originscranial base,and progressionhighlight recent of the loss-of- mouse (Part 2.1, Figure2A) and human (Part 2.2, Figure2B) cranial base, highlight recent loss- function(Part 2.1, mouse Figure models 2A) and with human cranial (Part base 2.2, defects Figure 2B)and cranial the human base, highlightpathology recent associated loss-of- of-function mouse models with cranial base defects and the human pathology associated withfunction variants mouse in the models orthologous with cranial gene (Part base 2.3), defects and finally,and the conclude human pathology with a perspective associated with variants in the orthologous gene (Part 2.3), and finally, conclude with a perspective on onwith the futurevariants of incranial the orthologous base research gene (Part (Part 3). 2.3),Rather and than finally, all encompassing, conclude with thisa perspective review the future of cranial base research (Part 3). Rather than all encompassing, this review is is onmeant the tofuture extend of cranialand complement base research previo (Partus 3).reviews Rather of than the cranial all encompassing, base [2–6]. this review meantis meant to extend to extend and and complement complement previous previo reviewsus reviews of the of cranialthe cranial base base [2–6 ].[2–6]. Figure 2. Schematics illustrating a midsagittal plane of the cranial base, in relation to other cranial structures, in a mouse (A) Figure 2. Schematics illustrating a midsagittal plane of the cranial base, in relation to other cranial structures, in a mouse and a human (B). Note, scales are not equivalent. The major elements within this plane are the ethmoid (teal), presphenoid (AFigure) and a 2.human Schematics (B). Note, illustrating scales are a midsagittalnot equivalent. plane The of major the cranial elements base, within in relation this plane to other are thcraniale ethmoid structures, (teal), presphe-in a mouse noid(light(A )(light blue),and a blue), human basisphenoid basisphenoid (B). Note, (light scales (light red), are andred), not basioccipital and equivalent. basioccipital (green).The major(green). Major elements Majo growthr growthwithin zones thiszones (synchondroses) plane (synchondroses) are the ethmoid are highlighted are (teal), highlighted presphe- (dark red),noid including (light blue), the inter-sphenoidbasisphenoid (light and spheno-occipital red), and basioccipital synchondrosis. (green). Note,Major ingrowth panel B,zones the presphenoid(synchondroses) and are basisphenoid highlighted 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. J. Dev. Biol. 2021, 9, 3 3 of 17 2. Development and Developmental Origins of the Cranial Base—The Mouse and Chick as a Template Although described in exquisite detail elsewhere [7], briefly, the cartilage anlage of the cranial base (a subset of the chondrocranium) is composed of 14 paired cartilage