The neural crest is a transient population of migratory, multipotent progenitor cells that appears briefly during embryonic development. Unique to vertebrates, this group gives rise to an array of tissues across multiple organ systems. Due to its extensive contributions, the neural crest is often informally referred to as the “fourth germ layer,” alongside the traditional ectoderm, mesoderm, and endoderm. Its development is a defining feature of the vertebrate lineage, enabling the evolution of complex structures like the jaw and the peripheral nervous system.
Origin and Early Development
Neural crest cells originate at the boundary between the neural plate (which forms the central nervous system) and the non-neural ectoderm (which forms the epidermis). This region, known as the neural plate border, is where neural crest induction occurs through a complex interplay of signaling molecules. Signals from both tissues converge here to activate a gene regulatory network, specifying the cells as neural crest precursors.
As the neural plate folds inward to form the neural tube, induced neural crest cells position themselves along the dorsal ridge. To begin migration, these cells must break away from the organized epithelial sheet. This escape is accomplished through Epithelial-to-Mesenchymal Transition (EMT), where cells lose adhesion and polarity. Following EMT, the cells delaminate, transforming into individual, mobile mesenchymal cells ready to migrate.
The Great Migrators
Once delaminated, neural crest cells (NCCs) are known for their long-range migratory capabilities. They navigate the embryonic landscape in distinct, coordinated streams categorized by axial origin: cranial, trunk, vagal, and sacral neural crest. The pathways these cells take are highly controlled by the extracellular matrix and by specific molecular cues that either attract or repel the migrating cells.
In the trunk region, NCCs choose one of two major routes. The ventrolateral pathway takes cells through the anterior half of the somites, which are blocks of mesoderm. Cells following this route give rise to the peripheral nervous system and adrenal gland. Alternatively, the dorsolateral pathway directs cells beneath the outer layer of ectoderm, leading them toward the skin where they differentiate into pigment cells.
Cranial neural crest cells arise from the head region and migrate in three large, discrete streams into the pharyngeal arches, structures that form much of the face and neck. Inhibitory signals, such as Eph/ephrin signaling, prevent the different cell populations from mixing. The vagal and sacral streams colonize the developing gut, where they form the complex nervous system that controls intestinal motility.
Derivatives: The Diverse Cell Fates
The diversity of cells and tissues generated by the neural crest is significant, particularly its contribution to the Peripheral Nervous System (PNS). Derivatives form the sensory neurons of the dorsal root ganglia, which relay information from the body to the spinal cord. They also generate the sympathetic and parasympathetic ganglia, regulating involuntary bodily functions, and supporting glial cells like Schwann cells.
Cranial neural crest cells are uniquely responsible for the majority of the skeletal and connective tissues in the face and neck, a population often termed ectomesenchyme. These cells form the cartilage and bone of the jaw, the middle ear ossicles (incus and malleus), and the dentin in teeth. This craniofacial contribution is distinct because bone and cartilage elsewhere are derived from the mesoderm.
Beyond the nervous system and skeleton, neural crest cells differentiate into various other cell types:
- Melanocytes, the pigment-producing cells responsible for the color of skin and hair.
- Chromaffin cells of the adrenal medulla, which produce catecholamines like epinephrine (adrenaline).
- The enteric nervous system, the “second brain” of the gut, populated by vagal and sacral streams.
- The cardiac neural crest, which partitions the outflow tract of the heart for proper circulation.
When Things Go Wrong
Given the neural crest’s extensive involvement in organogenesis, defects in its development can lead to a wide spectrum of congenital anomalies collectively known as neurocristopathies. These disorders can arise from a failure of NCCs to be properly induced, to migrate to their correct destination, or to differentiate into the appropriate cell type once they arrive. The resulting conditions often affect multiple systems simultaneously, reflecting the cell population’s diverse contributions.
Neurocristopathies include:
- Craniofacial defects, such as DiGeorge syndrome or Goldenhar syndrome, which cause defects in the bones and cartilage of the head and face.
- Hirschsprung’s disease, caused by the failure of vagal and sacral NCCs to colonize the lower gut, resulting in a lack of enteric neurons and severe intestinal obstruction.
- Pigmentation disorders like Waardenburg syndrome, which presents with patches of white hair, skin depigmentation, and sometimes deafness due to melanocyte defects.
- Cancers, as the migratory and proliferative nature of NCCs makes their derivatives susceptible to malignancies like neuroblastoma (from sympathetic precursors) and melanoma (from melanocytes).