Programmed Cell Death and Morphogenesis

Programmed cell death is as essential to normal development as cell proliferation and differentiation. Its role is frequently underappreciated by students who think of development purely as building and adding tissue.

A substantial proportion of normal morphogenesis is achieved not by growth alone but by the precisely controlled removal of specific cells in a specific pattern.

Apoptosis is programmed cell death, an active, genetically regulated process. The cell dismantles itself in an orderly fashion, without releasing its contents into the surrounding tissue and without triggering inflammation.

This contrasts clearly with necrosis, uncontrolled cell death following injury, which does provoke an inflammatory response.

Developmental apoptosis sculpts tissue shape by removing cells in a precisely defined spatial and temporal pattern. It effectively carves a final structure out of a simpler, initially more extensive tissue mass, rather than building that structure directly by targeted growth alone.

Interdigital apoptosis is the clearest and most frequently cited example of developmental cell death, and provides a directly visible illustration of the principle.

The hand and foot initially form as a single, continuous, paddle-shaped plate, with no separation between the future digits. Digital rays, condensations of mesenchyme that will form the skeleton of each individual finger or toe, appear within this plate, but the tissue between adjacent rays, the interdigital mesenchyme, is initially still present as continuous tissue connecting the digits.

Apoptosis is then activated specifically within this interdigital tissue, in a precisely timed and spatially restricted pattern, removing the tissue between the digital rays and thereby separating the single paddle-shaped plate into individual, distinct fingers or toes. This process is essentially complete by the end of the embryonic period.

Failure of interdigital apoptosis produces cutaneous syndactyly, persistent soft tissue webbing between two or more digits, one of the more common isolated congenital limb anomalies, and a direct clinical illustration of what happens when a specific programmed cell death event fails to occur on schedule.

Apoptosis also contributes to the creation of a hollow lumen within structures that begin development as an initially solid cord or plug of cells.

The developing oesophagus, for a period during the embryonic period, becomes transiently occluded by a solid plug of proliferating epithelial cells; apoptosis, together with a degree of cell rearrangement, subsequently recanalises this segment, restoring luminal patency before birth. A comparable transient occlusion and apoptosis-mediated recanalisation occurs at points along the developing intestinal tract. Failure of recanalisation at these sites is the developmental basis of specific forms of oesophageal and intestinal atresia and stenosis.

Apoptosis contributes to the fusion of initially separate tissue processes into a single, continuous structure. It removes the epithelial cells at the point of contact between the two approaching tissue edges. The underlying mesenchyme of each process can then merge into a single, continuous mass.

This mechanism operates during fusion of the facial prominences to form the upper lip and palate, during fusion of the neural folds along the midline during neurulation, and during closure of the ventral body wall during embryonic folding.

In each case, the epithelial layer at the point of contact must be removed by apoptosis for genuine mesenchymal continuity, and therefore true structural fusion, to be achieved.

Simple physical apposition of two epithelial surfaces without this removal does not constitute successful fusion. It is one recognised mechanism underlying failure of normal fusion, such as in some forms of cleft lip and palate.

Several structures that are present only transiently during development are removed, in whole or in part, by apoptosis once they have served their developmental purpose and are no longer required.

The early embryo has two paired genital duct systems, the mesonephric ducts and paramesonephric ducts. The system not required for the individual's genetic sex undergoes apoptotic regression.

The paramesonephric ducts regress in the male embryo under the influence of anti-Mullerian hormone. The mesonephric ducts regress in the female embryo in the absence of testosterone support.

Similarly, the pronephros and much of the mesonephros are removed by apoptosis once superseded. These are transient, non-functional precursor kidney structures that appear and regress before the definitive metanephric kidney forms.

Alongside apoptosis, three further mechanical processes are the principal means by which a comparatively simple embryonic structure is remodelled into its complex, final three-dimensional adult form.

Folding converts a flat or simple tubular structure into a more complex three-dimensional shape through differential rates of growth between adjacent regions of tissue.

Cephalocaudal and lateral folding of the flat trilaminar disc into the cylindrical body form of the embryo is the most fundamental example. Folding also operates at a smaller scale, for example in the formation of the cardiac loop from the initially straight primitive heart tube.

Fusion in its apoptosis-dependent mechanism joins separate tissue processes into a single continuous structure. It is required for normal formation of the face, palate, neural tube, ventral body wall, and cardiac septa, among other structures.

Rotation reorients a developing structure into its correct final anatomical position relative to the rest of the body.

The midgut undergoes a defined, precisely sequenced rotation, a total of 270 degrees counterclockwise. It occurs partly during physiological herniation into the umbilical cord and partly during its return to the abdominal cavity. This achieves the normal final arrangement of the small and large intestine.

The primitive heart tube similarly undergoes rightward looping as an essential step in establishing normal cardiac chamber arrangement.

Disruption of either rotational sequence produces a recognised and clinically significant category of malformation: malrotation of the gut, and a range of congenital cardiac looping and positional anomalies, respectively.