Embryology of the Skull Base and Vertebral Column

Abstract

The development of the human skeleton begins soon after conception; the skeleton continues to grow until a peak bone mass is achieved during young adulthood and then remodels throughout adult life. The formation of the skeleton depends on the basic biological processes of cell proliferation, migration, differentiation, and maturation. The genetic control of these fundamental processes, especially with regard to the development of the skeletal system, is not yet fully understood; however, homeobox genes, which regulate anatomic site-specific morphogenesis, have been shown to contain the codes for the architectural blueprint of the bones of the body. The specific genes, including those that encode a variety of transcription factors, growth factors, and receptors, involved in these processes are being defined; however, our current understanding of the embryology of the human skull base and vertebral column is still largely based on morphological studies of embryos. The human skull base and vertebral column are highly intricate structures, and this is reflected in the complexity of their embryological development. Although many of the basic processes of their formation are similar to those of the remainder of the skeleton, the presence of the brain and notochord and their inductive effects makes the development of these anatomic regions unique.

Keywords

Embryology, Homeobox genes, Notochord, Skull base, Spine, Vertebra

Outline
Introduction 3
The Skull Base 3
- Genetic Control of Skull Base Development 3
- Embryology of the Skull Base 4
Embryological Development of the Notochord and Vertebral Column 5
References 8

Introduction

The development of the human skeleton begins soon after conception; the skeleton continues to grow until a peak bone mass is achieved during young adulthood and then remodels throughout adult life. The formation of the skeleton depends on the basic biological processes of cell proliferation, migration, differentiation, and maturation. The genetic control of these fundamental processes, especially with regard to the development of the skeletal system, is not yet fully understood; however, homeobox genes, which regulate anatomic site-specific morphogenesis, have been shown to contain the codes for the architectural blueprint of the bones of the body. The specific genes, including those that encode a variety of transcription factors, growth factors, and receptors, involved in these processes are being defined ; however, our current understanding of the embryology of the human skull base and vertebral column is still largely based on morphological studies of embryos.

The human skull base and vertebral column are highly intricate structures; this is reflected in the complexity of their embryological development. Although many of the basic processes of their formation are similar to those of the remainder of the skeleton, the presence of the brain and notochord and their inductive effects makes the development of these anatomic regions unique.

The Skull Base

The human skull is the most intricate portion of the axial skeleton and has evolved to house the brain and sense organs and to facilitate the ingestion of food. The skull base is an anatomically complex and integrative region, and its shape has been influenced by phylogenetic, functional, and developmental forces. The skull base is defined as the portion that is in contact with, and supports, the inferior aspect of the brain and brainstem. It is composed of portions of a variety of different bones, including the occipital bone, temporal bone, sphenoid bone, orbital plates of the frontal bone, and the ethmoid’s cribriform plate.

Genetic Control of Skull Base Development

Genes regulating the development of the skull base include those from the Dickkopf family ( Dkk ), matrix metallopeptidase 9 ( MMP-9 ), Indian hedgehog , and Sonic hedgehog ( Shh ). Skull base chondrogenesis is thought to be delayed during embryogenesis compared with chondrogenesis of the axial skeleton due to its unresponsiveness to Shh signaling.

Studies utilizing loss-of-function mutations generated in mice suggest that the Dlx homeobox gene may also play an important role in the formation of craniofacial structures. Dlx5 and Dlx6 are expressed in the perichondrium where they direct the normal progression of enchondral ossification; mice with loss of function of Dlx5 and Dlx6 genes show delayed cartilage maturation and downstream osteogenesis. Similarly, Msx homeobox gene family members have been isolated from a range of organisms including humans, and Msx1 and Msx2 are widely expressed in vertebrate embryonic development. They are characteristically expressed at sites where epithelial–mesenchymal interactions take place and are strongly expressed in developing craniofacial regions. Heterodimers form between Msx and other homeodomain proteins such as Dlx ; in vitro, the formation of heterodimers results in mutual functional antagonism, and these interactions may play a role in controlling craniofacial patterning in vivo. Msx regulatory proteins function as transcriptional repressors, and the Msx homeodomain interacts directly with the TATA-binding protein of the general transcription complex. The transforming growth factor-β/Msx2 signaling cascade has been shown via knockout mice experiments to be critical for the development of the caudal region of the skull where it regulates the proliferation of chondrocytes and prevents premature enchondral ossification. The Wolf-Hirschhorn syndrome candidate 1 ( Whsc1 ) gene has also been shown to be important for the ossification of cranial bone elements. In knockout mice, Whsc 1 deficiency leads to disrupted ossification of the occipital bone and associated decreased levels of alkaline phosphatase activity. This deficiency leads to decreased expression of the bone-related proteins osteopontin and collagen type 1a.

Most of the craniofacial skeletal elements originate from ectoderm-derived, multipotent neural crest cells that migrate ventrally from the closing dorsal neural folds. Bone morphogenetic protein (BMP) signaling has emerged as a key regulator of the development of neural crest cells and their derivates. Studies in mice have shown that precise regulation of BMP signaling is necessary for proper craniofacial development and coordination of self-renewal and differentiation pathways. BMP signaling is believed to regulate evolutionary change in craniofacial morphology. Downstream effector pathways for BMP signaling are complex and are not yet fully understood, but Smad, MapK, and microRNA processing and transcription elements are involved. Experimental evidence in mice has demonstrated that conditional overexpression of BMP-4 leads to dramatic facial skeletal changes and that the inactivation of BMP-2, BMP-4, and BMP-7 leads to complete or partial loss of multiple cranial neural crest–derived skeletal elements, emphasizing a critical role for BMP signaling in the development of membranous bone and cartilage. Noggin is a major BMP antagonist expressed during embryological development. In mice, lack of Noggin leads to abnormal skull base structure, with decreased anteroposterior and increased mediolateral lengths.

Embryology of the Skull Base

The occipital bone is one of the first bones of the skull to develop and consists of four parts, namely, one basilar, one squamous, and two condylar parts, that encircle the foramen magnum. Although some of the skull base bones form from intramembranous ossification, namely, the orbital plates of the frontal bone and the lateral aspects of the greater sphenoidal wings, most of the bones of the skull base are initially preformed in cartilage (enchondral ossification) and together they represent the chondrocranium.

The specific elements of the cranial base are derived from cells that originate in, and subsequently migrate from, the neural crest and paraxial mesoderm. The first two pharyngeal arches contribute to the cranial skeletal elements. Local factors, including cell–cell and cell–substrate interactions, control the migration so that the cells condense between the developing brain and foregut to produce the ectomeningeal capsule. The ectomeningeal capsule is the earliest morphological stage in the development of the skull and forms during the fourth week of intrauterine life, a time at which the development of the other major organ systems is already well underway. The cells that compose the ectomeningeal capsule differentiate into chondroblasts on the 40th day (week 7) of gestation. They form multiple centers of chondrification, (presphenoid cartilage, basisphenoid cartilage, nasal capsule, orbitosphenoid, alisphenoid, otic capsule, parachordal cartilage, and fused sclerotomes of the occipital somites), many of which are bilateral and symmetrical ( Fig. 1.1 ). The production of cartilage heralds the formation of the chondrocranium, and this process requires the presence of the brain and other neural structures because they exert important inductive forces. The development of the occipital bone depends on signaling from the rhombencephalon. By the eighth week of embryogenesis the separate centers of chondrification grow and fuse with one another, creating a solid cartilaginous structure known as the chondrobasicranium or the basal plate ( Figs. 1.1 and 1.2 ). The basal plate is perforated by preexisting structures, including cranial nerves and blood vessels, and these passageways eventually become the foramina of the mature skull base.