The neural crest is a remarkable population of cells that exists briefly during the early development of a vertebrate embryo. These cells arise from the ectoderm, one of the three primary germ layers, but they quickly separate to form an astonishing variety of mature tissues. Due to their versatility and ability to contribute to many different organ systems, the neural crest is often called “the fourth germ layer.” This transient group of migratory cells is unique to vertebrates and is responsible for constructing numerous complex structures, ranging from the nerves that control digestion to the bones that shape the face.
The Origin and Journey of Neural Crest Cells
The neural crest forms at the dorsal border of the closing neural tube during neurulation. The neural tube eventually develops into the brain and spinal cord. Neural crest cells are induced where the neural plate meets the non-neural ectoderm, initially existing as a tightly packed epithelial sheet.
To begin their journey, these cells undergo a dramatic reorganization known as the epithelial-to-mesenchymal transition (EMT). This transition involves losing cell-to-cell adhesion, allowing the cells to delaminate, or break away, from the dorsal side of the neural tube. Once freed, the mesenchymal cells become highly motile and invasive, migrating long distances throughout the developing embryo.
The migratory pathways are broadly categorized into four main streams, and the stream a cell takes largely determines its final fate. Cranial neural crest cells migrate into the head and neck region. Trunk neural crest cells follow two distinct paths down the body axis, while vagal and sacral cells migrate to the far ends of the digestive tract. These cells follow specific signaling cues to reach their final destinations where they differentiate into specialized tissues.
Contribution to the Peripheral Nervous System
A primary function of the neural crest is to build the entire peripheral nervous system (PNS), which includes all nerves and associated structures outside the brain and spinal cord. Cells following the ventral migration pathway in the trunk differentiate into the sensory neurons of the dorsal root ganglia. These ganglia lie adjacent to the spinal cord and relay sensory information, such as touch and pain, from the body to the central nervous system.
Other migrating cells form the sympathetic and parasympathetic ganglia, which constitute the autonomic nervous system. Sympathetic ganglia are organized into chains near the spinal cord, responsible for the body’s “fight or flight” responses. Parasympathetic ganglia are located closer to or within target organs, controlling routine functions like digestion and heart rate.
The neural crest also provides supporting cells of the PNS, including Schwann cells and satellite glia. Schwann cells generate the myelin sheath that insulates peripheral nerve axons, speeding up electrical signal transmission. Satellite glia surround neuron cell bodies within the ganglia, providing physical and metabolic support.
Formation of Non-Neural Tissues and Structures
The versatility of neural crest cells is demonstrated by their ability to form tissues with no direct nervous system function. A significant portion of cranial neural crest cells differentiate into ectomesenchyme, an embryonic connective tissue. This tissue forms nearly all the cartilage and bone in the face and front of the skull, including the jaw, middle ear bones, and dentin within teeth. The cranial neural crest is responsible for the complex craniofacial structure of every vertebrate.
In the trunk region, a subset of neural crest cells migrates dorsolaterally beneath the skin to produce melanocytes, or pigment cells. These cells synthesize melanin and are responsible for the color of the skin, hair, and eyes. Melanocytes are found throughout the body, reflecting the extensive migratory path these precursor cells take.
Within the adrenal gland, the neural crest contributes to the adrenal medulla, the inner core of the gland. The cells differentiate into chromaffin cells, which are specialized neuroendocrine cells. These cells synthesize and secrete catecholamines, such as adrenaline and noradrenaline, directly into the bloodstream in response to stress.
A specialized population known as the cardiac neural crest migrates to the developing heart, contributing to the formation of the outflow tract. These cells help create the spiral septum that divides the single large embryonic vessel into the two great arteries: the aorta and the pulmonary artery. This septation is required for the proper separation of oxygenated and deoxygenated blood flow in the adult circulation.
When Development Goes Wrong: Neurocristopathies
Defects in the formation, migration, or differentiation of neural crest cells result in a group of birth defects known as neurocristopathies. Because the neural crest contributes to many different organ systems, these disorders often present with a wide range of seemingly unrelated symptoms.
One example is Hirschsprung disease, where vagal and sacral neural crest cells fail to migrate completely to the lower gastrointestinal tract. This failure results in a segment of the colon lacking the necessary enteric ganglia, leading to a functional obstruction and severe problems with gut motility.
Another condition is Waardenburg syndrome, characterized by hearing loss and pigmentary abnormalities, such as a white forelock or different colored eyes. This syndrome results from defects in the neural crest cells that give rise to melanocytes and the sensory neurons of the inner ear. DiGeorge Syndrome, often associated with a deletion on chromosome 22, involves defects in the cardiac neural crest, leading to congenital heart defects and craniofacial anomalies.