Neural crest cells represent a transient, multipotent population of stem cells that are a defining feature of vertebrate development. These cells are sometimes referred to as the “fourth germ layer” due to their extensive contributions to the developing embryo. They emerge early in development and embark on journeys to various locations throughout the embryo. Their importance lies in the vast array of cell types they generate, which form parts of many different organs and tissues. Understanding their development provides insight into both normal anatomy and the origins of certain congenital disorders.
Formation and Migration of Neural Crest Cells
Neural crest cells originate at the border of the neural plate, the structure that gives rise to the central nervous system, during a process called neurulation. As the neural plate folds to form the neural tube, which will become the brain and spinal cord, the cells at the “crest” of these folds are specified to become neural crest cells. The formation of these cells is directed by a combination of signaling molecules, including bone morphogenetic proteins (BMPs) and Wnt signals, produced by neighboring tissues. These signals activate transcription factors that define the neural crest territory.
Once formed, these cells must detach from the neural tube and begin their migration. To do this, they undergo a change known as an epithelial-to-mesenchymal transition (EMT). During EMT, the tightly connected epithelial cells lose their adhesions and acquire a migratory, mesenchymal character. This transformation allows them to break free from the neural tube and move independently.
The migration of neural crest cells is not random; it is a regulated process. The cells follow specific pathways, guided by a variety of molecular cues. Some of these cues are attractive, drawing the cells toward a particular destination, while others are repulsive, preventing them from entering certain territories. This guidance system ensures that the cells reach their correct locations to contribute to the formation of different tissues.
The Diverse Fates of Neural Crest Cells
Once neural crest cells complete their migration, they settle in various parts of the embryo and differentiate into a remarkable diversity of cell types. This multipotency is a hallmark of the neural crest, as cells from this single population give rise to tissues with very different functions. The specific fate of a neural crest cell is influenced by signals it encounters along its migratory path and at its final destination.
A major contribution of neural crest cells is to the peripheral nervous system. They form sensory neurons that allow us to feel touch and pain, and the autonomic ganglia that regulate involuntary functions like heart rate and digestion. They also produce Schwann cells, which create the myelin sheath that insulates nerve fibers. This includes the enteric nervous system, the “brain of the gut,” formed by neural crest cells that migrate into the intestinal wall.
Beyond the nervous system, neural crest cells are responsible for the pigment in our skin and hair. They differentiate into melanocytes, the cells that produce melanin. These cells migrate along a path just under the epidermis to distribute themselves throughout the skin. Defects in neural crest cell development can lead to pigmentation disorders.
The craniofacial skeleton, which provides the structure of the face and skull, is largely built by cranial neural crest cells. These cells migrate into the head and neck region, where they differentiate into the cartilage and bone that make up parts of the jaw, face, and skull. They also contribute to the formation of teeth, specifically the dentin, and the connective tissues that pattern the face.
In the endocrine system, neural crest cells give rise to the chromaffin cells of the adrenal medulla, which produce adrenaline. A specific subpopulation, the cardiac neural crest, migrates to the developing heart. There, they are instrumental in forming the septum that divides the aorta and the pulmonary artery and contribute to the development of the heart’s semilunar valves.
Neurocristopathies and Developmental Disorders
Errors in neural crest cell development can lead to a wide range of birth defects and health issues, collectively known as neurocristopathies. This term reflects the common origin of the defects in this single, migratory cell population. The symptoms of these disorders vary widely, affecting different body systems depending on which population of neural crest cells failed to develop or migrate correctly.
One example is Hirschsprung’s disease, which affects the large intestine. This condition arises from the failure of vagal neural crest cells to fully migrate into the lower part of the gut. Without the enteric neurons that these cells would have formed, the affected segment of the colon cannot relax and pass stool, leading to an intestinal blockage that requires surgical intervention.
Waardenburg syndrome illustrates how defects in a single cell lineage can cause a cluster of seemingly unrelated symptoms. This syndrome is characterized by patches of white hair, different colored eyes or unusually pale blue eyes, and hearing loss. These features are a direct result of the faulty development and migration of neural crest cells destined to become melanocytes and cells in the inner ear.
DiGeorge syndrome, also known as 22q11.2 deletion syndrome, is another disorder caused by a small deletion on chromosome 22. This deletion affects the development of structures derived from the cranial and cardiac neural crest. This leads to a combination of heart defects, abnormalities in the palate and facial structure, and problems with the thymus and parathyroid glands.