During embryonic development, a unique population of cells known as neural crest cells embarks on a precisely controlled migration. These cells are a temporary group of highly adaptable stem cells found only in vertebrates. Their migration is a foundational process, responsible for forming a diverse array of tissues and structures. Their contribution is so significant that they are sometimes called the “fourth germ layer,” alongside the ectoderm, mesoderm, and endoderm. This process is fundamental to building parts of the nervous system, face, and skin.
Formation and Delamination of Neural Crest Cells
The story of neural crest cells begins at the border of the neural plate, the structure destined to become the brain and spinal cord. At the junction between the neural plate and the surrounding surface ectoderm, signaling molecules like BMP and Wnt instruct these border cells to adopt a new identity. This process of induction designates them as neural crest precursors. These specified cells are initially part of an organized tissue layer, integrated with the cells around them.
Once specified, these cells must detach to begin their journey in a process called delamination, where they separate from the developing neural tube. Triggered by genetic signals, the cells undergo an epithelial-to-mesenchymal transition (EMT), changing from stationary epithelial cells into mobile, mesenchymal cells. This involves breaking down the connections that hold them in place and altering their internal structure to prepare for movement.
This detachment is a highly regulated event orchestrated by transcription factors like SNAI2 and FOXD3. These factors activate changes in cell adhesion and motility. The cells retract their connections to the neural tube and the overlying ectoderm, allowing them to emerge from their site of origin. As individual migratory cells, they are now poised to follow the directions that will guide them to their final destinations.
Guidance and Mechanisms of Movement
The migration of neural crest cells is a highly directed process governed by molecular road signs in the embryonic environment. These cues guide the cells along specific routes. Some signals act as chemoattractants, drawing the cells toward a particular area. Other signals function as repulsive cues, or chemorepellents, creating invisible barriers that prevent cells from entering certain territories.
A primary example of this guidance involves the Ephrin proteins and their Eph receptors. In the trunk of the embryo, neural crest cells express Eph receptors, while cells in the posterior half of each developing somite express Ephrin ligands. When a migrating cell encounters an Ephrin-expressing region, the interaction triggers a repulsive signal, causing it to retract and move away. This interaction channels the migrating cells through the anterior half of each somite, creating a segmented pattern of migration.
For a cell to move, it must become motile by reorganizing its internal scaffolding, known as the cytoskeleton, as part of the EMT. Small proteins from the Rho GTPase family, such as Rac1 and Cdc42, control the assembly and disassembly of actin filaments. This dynamic process allows the cell to extend protrusions, called lamellipodia and filopodia, in the direction of travel. These protrusions then adhere to the extracellular matrix and pull the rest of the cell body forward in a crawling-like motion.
Movement is also influenced by interactions between the cells themselves. A phenomenon called contact inhibition of locomotion ensures that cells move away from each other upon contact, preventing them from clumping. This helps them to spread out and cover greater distances. The combination of external guidance cues and internal cellular machinery allows for the coordinated migration of thousands of cells to their designated locations.
Pathways and Final Destinations
Once mobile, neural crest cells follow distinct migratory streams. These pathways are categorized based on their axial level of origin along the developing neural tube. The major routes include the cranial, trunk, vagal, and sacral pathways. Each gives rise to a unique set of tissues and cell types.
The cranial neural crest cells originate from the future head region and migrate into the pharyngeal arches, which are transient structures in the embryonic neck. These cells form the majority of the bones and cartilage of the face and skull, a role reserved for the mesoderm in other parts of the body. They also differentiate into neurons and glial cells for cranial nerves. Additionally, they form pigment cells and the odontoblasts that create the dentin of teeth.
Further down the body axis, the trunk neural crest cells follow two primary pathways. One group travels a dorsolateral route just beneath the ectoderm and differentiates into the pigment-producing melanocytes of the skin. The other group takes a ventrolateral path, migrating through the anterior portion of the somites. These cells form the sensory neurons of the dorsal root ganglia, sympathetic ganglia, and adrenal medulla, which are parts of the peripheral nervous system.
The vagal and sacral neural crest cells, located at the neck and tail-end levels, are responsible for colonizing the digestive tract. These cells migrate into the gut wall and differentiate into the neurons and glia of the enteric nervous system. This intrinsic nervous system is responsible for controlling peristalsis and other digestive functions. The vagal crest also contributes to the heart, forming smooth muscle and helping to separate the major arteries.
Clinical Significance of Migration Errors
Errors in the complex process of neural crest cell migration can have widespread consequences. When these cells fail to migrate, survive, or differentiate correctly, a range of birth defects known as neurocristopathies can occur.
Hirschsprung’s disease results from a failure of vagal and sacral neural crest cells to colonize the lower gastrointestinal tract. This leads to an absence of enteric neurons in a segment of the colon. Without these neurons to control muscle contractions, the affected bowel segment cannot relax, causing a functional blockage, severe constipation, and swelling.
Waardenburg syndrome is often caused by defects in the migration or survival of trunk neural crest cells. Since these cells are fated to become melanocytes, their absence leads to patches of pale skin and hair and differently colored eyes. The syndrome can also include hearing loss, as neural crest cells help develop structures within the inner ear.
Defects in the cranial neural crest pathway can lead to DiGeorge syndrome, also known as 22q11.2 deletion syndrome. This disorder involves craniofacial abnormalities like a small jaw and cleft palate, plus defects in the heart and thymus gland. These issues arise because cranial neural crest cells form many bones and tissues of the face and contribute to the large arteries of the heart.