Embryology of the Orbit

Abstract

The orbit houses and protects the ocular globe and the supporting structures, and occupies a strategic position below the anterior skull base and adjacent to the paranasal sinuses. Its embryologic origins are inextricably intertwined with those of the central nervous system, skull base, and face. Although the orbit contains important contributions from four germ cell layers (surface ectoderm, neuroectoderm, neural crest, and mesoderm), a significant majority originate from the neural crest cells. The bones of the orbit, face, and anterior cranial vault are mostly neural crest in origin. The majority of the bones of the skull base are formed through endochondral ossification, whereas the cranial vault is formed through intramembranous ossification. Familiarity with the embryology and fetal development of the orbit can aid in understanding its anatomy, as well as many developmental anomalies and pathologic conditions that affect the orbit.

Introduction

The embryologic origins and fetal development of the orbit underlie its fundamental anatomy and relationships with the skull base, and contribute to an understanding of the pathophysiology behind many orbital anomalies, tumors, and other pathologic conditions. This article will review salient aspects of orbital embryology that are pertinent to orbital specialists and skull base surgeons.

Neurulation

The formation of the neural tube during week 4 of embryogenesis, a key step in the developing body plan, begins a chain of events that are critical to the development of the orbit. The folding of the neural plate forms the neural groove, and the neural tube is formed as the opposing edges of the neural plate subsequently fuse in a process known as neurulation. ¹ The ectoderm on the dorsal surface of the neural plate, which eventually lines the neural tube, becomes the neuroectoderm, from which the central nervous system will arise. At the crest of the ectodermal waves that fuse during neurulation are a population of cells referred to as neural crest cells that assume a paired position between the surface ectoderm and the neural tube ( Fig. 1 ). These cells, which are unique to vertebrates, become transiently migratory while undergoing a process of epithelium-to-mesenchyme transition (EMT); once they reach their many destinations throughout the head and body, neural crest cells interact with local mesenchymal cells to differentiate into a wide variety of cell types. Neural crest induction is driven by many molecular factors including bone morphogenetic protein (BMP), Wnt, fibroblast growth factor (FGF), retinoic acid, and Notch signals produced by the ectoderm, neuroectoderm, and mesoderm. ^{2 3} The relative contributions of neural crest cells to different tissues and structures have been elucidated experimentally in model organisms, including embryonic chimeras of chick and quail, and transparent zebrafish embryos in which neural crest cells were marked by fluorescent proteins such as green fluorescent protein (GFP). ^{2 3 4 5}

Fig. 1.

Cross-section of the cranial neural plate undergoing neurulation between days 20 and 24 (NP, neural plate; NT, neural tube).

Optic Vesicle Formation

During neurulation, the neuroectoderm within the neural groove/tube forms paired invaginations known as the optic vesicles. As the optic vesicle deepens and extends outward toward the surface ectoderm, the proximal portion of the vesicle constricts to form the optic stalk, the origins of the optic nerve (the only one of the cranial nerves to be part of the central nervous system). The distal end of the optic vesicle invaginates to form the goblet-shaped optic cup, the origins of the neurosensory retina and other intraocular tissues ( Table 1 ). During week 5, the surface ectoderm immediately opposite the optic cup will invaginate into the cup to form the lens pit, which will eventually result in the creation of the crystalline lens and ocular surface ( Fig. 2 ). At the same time, neural crest cells from the dorsal diencephalon and mesencephalon migrate to the optic vesicle, resulting in the formation of numerous globe structures, including portions of the sclera, corneal stroma and endothelium, trabecular meshwork, ciliary muscles, and uveal tract (iris, stroma of the ciliary body, and choroid). ^{1 4 5} Contributions to the globe from the resident mesoderm consist mainly of the temporal sclera, vitreous, and extraocular muscle fibers.

Table 1. Germ cell origins of globe structures.

Surface ectoderm

Corneal epithelium  Lens  Vitreous *

Neuroectoderm

Retina  Retinal pigment epithelium (RPE)  Pigmented ciliary epithelium  Nonpigmented ciliary epithelium  Iris muscles/epithelium  Vitreous *

Mesoderm

Temporal sclera *  Vitreous *  Vascular endothelium

Neural Crest

Corneal endothelium  Iris connective tissue  Corneal stroma  Trabecular meshwork  Ciliary muscles  Choroid  Sclera *

^*Shared contribution.

Fig. 2.

Lateral view of the developing head at 32 days showing optic vesicle (OV) formation and neural crest cell migration from the diencephalon (DE) and mesencephalon (ME) to the optic vesicle (LP, lens pit; MdP, mandibular process; MxP, maxillary process; NFP, nasofrontal process; NT, neural tube).

Neural Crest Migration

The migration of cephalic neural crest cells from their position dorsal to the neural tube to the optic vesicle is arguably the most critical event in the development of the orbit ( Fig. 2 ). Numerous positive and negative signals guide this migration and are specific to each target site and cell type. Among the signals involved are complement factor C3a, Eph/ephrin, stromal cell–derived factor 1, vascular endothelial growth factor (VEGF), FGF, glial cell–derived neurotrophic factor (GDNF), retinoic acid, and thyroid hormone. ^{2 5} It has also been demonstrated that the optic vesicle itself plays a crucial role in guiding neural crest migration. ⁶ As mentioned earlier, neural crest cells have the ability to differentiate into several different cell and tissue types, including bone, cartilage, smooth muscle, neurons, Schwann cells, adipocytes, fibroblasts, pigment cells, odontoblasts, meninges, and others. Hence, it comes as no surprise that a majority of orbital structures are derived from the neural crest, including the majority of the orbital bones, the peripheral and autonomic nerves of the orbit, orbital fibroblasts and a percentage of adipocytes, cartilage, lacrimal gland acini, optic nerve sheath, and connective tissues, including Tenon's capsule, intramuscular septum, and extraocular muscle tendon sheaths ( Table 2 ). ⁷ Additionally, the adenohypophysis and cranial nerves, with the exception of the olfactory (I) and optic (II) nerves, are thought to have significant neural crest contributions. ⁸

Table 2. Germ cell origins of orbital and periocular structures.

Surface ectoderm

Lacrimal gland ductules  Conjunctiva  Lacrimal drainage system  Eyelid skin

Neuroectoderm

Optic nerve fibers

Mesoderm

Extraocular muscle fibers  Orbital fat *  Vascular endothelium  Sphenoid lesser wing *

Neural crest

Bones (except for portion of sphenoid lesser wing * )  Nerves (motor, sensory, autonomic)  Orbital fat *  Fibroblasts  Trochlea  Lacrimal gland acini  Optic nerve sheath  Vascular smooth muscle/stroma  Connective tissue   Tenon's capsule   Intramuscular septum   Orbital ligaments   Extraocular muscle tendons/sheaths   Levator aponeurosis   Tarsus

^*Shared contribution.

Neurocristopathies

Over the past several decades, it has come to be recognized that many diseases and conditions that previously seemed unrelated actually share a common defect in neural crest development. In light of the vital contribution of the neural crest to orbital embryology, it follows that many conditions that fall under the heading of neurocristopathies would affect the orbit and the skull base. Examples include Goldenhar's syndrome (hemifacial microsomia), Treacher Collins' syndrome (mandibulofacial dysostosis), neurofibromatosis type 1, Axenfeld–Rieger syndrome, Sturge–Weber syndrome, Möbius' syndrome, Noonan's syndrome, and CHARGE syndrome. ^{9 10} Neoplasms that share neural crest origins include melanoma, Merkel cell carcinoma, and neuroblastoma, which typically arises from the adrenal medulla or sympathetic nervous system (also neural crest derived) and is the most common orbital metastasis in children. ¹¹

Craniofacial Bone Development

Unlike the axial skeleton, which is mesodermal in origin, the majority of the bones of the skull base, face, and anterior cranial vault (frontal, sphenoid, squamous temporal, ethmoid, maxilla, zygoma, nasal, palatine, and mandible) are derived from the neural crest ( Table 3 ). By contrast, the posterior skull, including the parietal, occipital, and petrous temporal bones, is formed from mesoderm, as well as a small contribution to the lesser sphenoid wings (via the hypochiasmatic cartilage), where several extraocular muscles attach. ¹² The sutures of the cranial vault are formed by a mixture of neural crest- and mesoderm-derived mesenchymal cells. ¹³ The formation of bone in the craniofacial skeleton is also distinguished by two different types of ossification. Some bones go through a cartilaginous phase before ossifying (endochondral), whereas others are formed through the direct ossification of mesenchymal membranes (intramembranous). ¹⁴ The majority of the bones of the skull base are endochondral, whereas the cranial vault and facial buttresses are primarily formed via intramembranous ossification ( Table 3 ). The clinical significance of these embryologic distinctions is unclear, but they may hypothetically influence the treatment of craniofacial conditions in areas such as surgery, bone grafting, and bone regeneration.

Table 3. Craniofacial bones: germ cell origins and ossification types.

	Neural crest	Mesoderm
Intramembranous	Frontal Maxilla Zygoma Lacrimal Palatine Mandible	Parietal Occipital a
Endochondral	Ethmoid Sphenoid body/greater wing Sphenoid lesser wing a Squamous temporal Nasal Vomer Auditory ossicles	Occipital a Petrous temporal Sphenoid lesser wing a

^aShared contribution.

Facial Development

The embryology of the orbit is closely linked to the development of the face. The face is formed by five prominences that appear in the fourth week: a frontonasal prominence and paired maxillary and mandibular prominences ( Fig. 2 ). The pharyngeal arches form caudal to the mandibular prominence and do not contribute to the development of the orbit or the skull base. Medial and lateral nasal processes form within the frontonasal prominence during week 5, and will subsequently migrate and fuse in the midline to form the nose and the philtrum. ¹ The lens pits form in the surface ectoderm lateral to the lateral nasal processes and are initially oriented 180 degrees from each other. As the orbits develop, they will migrate medially along with the nasal processes until they reach their final positions ∼45 degrees from each other. The nasolacrimal duct forms at the junction between the lateral nasal process and the maxillary prominence. It is important to emphasize the critical roles of the developing forebrain and eye in the organization of the developing face. ¹⁵

Orbital Development

By 8 weeks, many of the major structures of the orbit are present, including the extraocular muscles, optic nerve, and a rudimentary globe. ¹⁶ Ossification of the orbital bones also begins during this week and continues to full term and beyond. The orbital floor of the fetus is occupied by the primordial orbital muscle of Müller, which becomes gradually replaced by connective tissue throughout fetal development. ¹⁷ (This muscle is unrelated to the Müller muscle that serves as part of the upper lid retractor complex.) The function of the orbital muscle of Müller is unclear, but it is believed to be a transient evolutionary remnant related to the muscle that covers the lateral orbit in animals that lack a complete lateral orbital wall. ^{18 19} The orbital fat develops from an anlage of mesenchyme and blood vessels between weeks 14 and 32. As previously noted, orbital fat originates from both neural crest cell and mesoderm, with the intraconal and superomedial preaponeurotic fat believed to be of neural crest origin. The shared embryologic origins of orbital fibroblasts, adipocytes and preadipocyte mesenchymal stem cells, and the roles of retinoids and thyroid hormone in regulating orbital neural crest development, may play a role in the pathogenesis of thyroid eye disease.

Conclusion

Much more than just a bony fat-filled box that houses the eye, the orbit is a remarkable anatomical treasure trove whose complexity is reflected in its fascinating embryologic origins. The eye and orbit play a critical role in the development of the skull base and the face. The outsized contribution of the neural crest cell in orbital embryology goes a long way toward explaining the involvement of the orbit in a host of anomalies and diseases. Continued dedicated research is undoubtedly warranted to further elucidate the mechanisms behind its development and guide future treatments and therapies for orbital and skull base disease.

Funding Statement

Funding None.

Pearls and Tips.

• The orbital bones and many other orbital structures are derived from neural crest cells.

• Many neurocristopathies affect the orbit and globe.

• The majority of the bones of the skull base are formed through endochondral ossification.

• The orbit plays a major role in the development of the skull base and face.