Cell Migration, Proliferation and Differentiation

Three core cellular behaviours underlie essentially all morphological change in development: migration, proliferation, and differentiation. Every developmental process, including gastrulation, neurulation, folding and organogenesis, is built from these three mechanisms operating in a controlled, coordinated fashion at a specific time and place.

Migration is the directed movement of cells from their site of origin to a distant final functional location. It is guided by chemical signals, extracellular matrix cues, and cell surface adhesion molecules. Together they specify both the direction of travel and the point at which migration should stop.

Neural crest cells are the most extensive and best-characterised migratory cell population in the embryo. After delamination from the closing neural folds, they disperse along defined pathways to an extraordinarily wide range of destinations.

• Cranial neural crest cells migrate into the pharyngeal arches and facial prominences. They form the majority of the bones and connective tissue of the face and skull, the dental pulp, and the membranous portion of the interventricular septum and outflow tract septum of the heart.
• Trunk neural crest cells migrate along two routes. A ventral pathway gives rise to the sensory and autonomic ganglia and the adrenal medulla. A dorsolateral pathway beneath the surface ectoderm gives rise to melanocytes.

Primordial germ cells undergo an equally striking long-distance migration. They arise extraembryonically in the wall of the yolk sac near the allantois. They migrate through the developing gut wall and dorsal mesentery to reach the genital ridges, the site of the developing gonad, by around week 5 to 6.

Failure of this migration, or migration to an aberrant location, is the developmental basis of ectopic germ cell tumours found outside the normal gonadal location, along the migratory path the cells failed to complete.

Cardiac progenitor cells, myoblast precursors destined for the limbs, and the cells forming the walls of the developing gut also undergo defined migratory movements as an essential step in their formation. Directed cell migration is a general mechanism used across very different organ systems, not a phenomenon confined to the nervous system.

Proliferation is controlled cell division, expanding the number of cells within a developing tissue. Its rate, location, and orientation are tightly regulated throughout development rather than uniform.

Localised, regionally concentrated proliferation is a direct mechanical driver of tissue outgrowth. The limb buds form and elongate substantially through concentrated proliferation of the underlying mesenchyme beneath a specialised signalling region of the overlying ectoderm, the apical ectodermal ridge. Outgrowth continues only as long as this proliferative signalling is sustained.

Similarly, the branching growth of organs such as the lung and kidney depends on repeated, localised bursts of proliferation at the growing tips of the branching epithelium.

The orientation of the plane of cell division also directly shapes the final form of a growing structure. A dividing cell may split along an axis that expands the tissue in width or one that expands it in length. Misregulation of division plane orientation is increasingly recognised as a contributor to specific structural anomalies, including some forms of disordered tubular organ elongation.

Differentiation is the progressive restriction of a cell's developmental potential as it acquires the structural and functional characteristics of a mature, specialised cell type. It is driven by the sequential, ordered activation and repression of specific genes.

Differentiation proceeds through a series of progressively more restricted states:

• A totipotent cell, present only in the very earliest cleavage-stage blastomeres, can form both the entire embryo and the extraembryonic tissues such as the placenta.
• A pluripotent cell, such as those of the inner cell mass or epiblast, can form any cell type of the embryo proper but not the extraembryonic tissues.
• A multipotent cell is restricted to a limited range of related cell types within a specific tissue lineage. The haematopoietic stem cell is a classic postnatal example.
• A fully differentiated, or terminally differentiated, cell has a fixed, specialised identity and, in the great majority of tissues, no longer divides.

This progressive restriction of potential is generally considered a one-way process under normal physiological conditions. A fully differentiated cell does not normally revert to an earlier, more potent state. This is why most tissue regeneration in the adult body relies on a persisting population of undifferentiated or multipotent stem cells retained within that tissue, rather than on dedifferentiation of mature, specialised cells.

Migration, proliferation, and differentiation are not independent, sequential steps applied one after another to a given cell population. They are typically interleaved and occur simultaneously in different parts of the same developing structure.

Neural crest cells, for example, continue to proliferate while they migrate. They differentiate into their final specialised cell type only once they reach their destination and receive the appropriate local inductive signal from the surrounding tissue.

The final identity a migratory cell adopts is therefore determined jointly by its origin and by the inductive environment it migrates into, not by its origin alone. This is the mechanistic basis for the same neural crest population forming such a strikingly diverse range of adult structures, depending on where within the embryo each cell ends up.