Morphogenesis

Morphogenesis (from the Greek morphê shape and genesis creation, literally, "beginning of the shape"), is the biological process that causes an organism to develop its shape. It is one of three fundamental aspects of developmental biology along with the control of cell growth and cellular differentiation.

The process controls the organized spatial distribution of cells during the embryonic development of an organism. Morphogenesis can take place also in a mature organism, in cell culture or inside tumor cell masses. Morphogenesis also describes the development of unicellular life forms that do not have an embryonic stage in their life cycle, or describes the evolution of a body structure within a taxonomic group.

Morphogenetic responses may be induced in organisms by hormones, by environmental chemicals ranging from substances produced by other organisms to toxic chemicals or radionuclides released as pollutants, and other plants, or by mechanical stresses induced by spatial patterning of the cells.

History
Some of the earliest ideas on how physical and mathematical processes and constraints affect biological growth were written by D'Arcy Wentworth Thompson and Alan Turing. These works postulated the presence of chemical signals and physico-chemical processes such as diffusion, activation, and deactivation in cellular and organismic growth. The fuller understanding of the mechanisms involved in actual organisms required the discovery of DNA and the development of molecular biology and biochemistry. The term Histomorphogenesis was coined by Ricqlès et al. (2001) for the same process in the bone histology.

Molecular basis
Several types of molecules are particularly important during morphogenesis. Morphogens are soluble molecules that can diffuse and carry signals that control cell differentiation decisions in a concentration-dependent fashion. Morphogens typically act through binding to specific protein receptors. An important class of molecules involved in morphogenesis are transcription factor proteins that determine the fate of cells by interacting with DNA. These can be coded for by master regulatory genes and either activate or deactivate the transcription of other genes; in turn, these secondary gene products can regulate the expression of still other genes in a regulatory cascade. Another class of molecules involved in morphogenesis are molecules that control cell adhesion. For example, during gastrulation, clumps of stem cells switch off their cell-to-cell adhesion, become migratory, and take up new positions within an embryo where they again activate specific cell adhesion proteins and form new tissues and organs. Several examples that illustrate the roles of morphogens, transcription factors and cell adhesion molecules in morphogenesis are discussed below.

Cellular basis
Morphogenesis arises because of changes in the cellular structure or how cells interact in tissues. Certain cell types "sort out". Cell "sorting out" means that when the cells physically interact they move so as to sort into clusters that maximize contact between cells of the same type. The ability of cells to do this comes from differential cell adhesion. Two well-studied types of cells that sort out are epithelial cells and mesenchymal cells. During embryonic development there are some cellular differentiation events during which mesenchymal cells become epithelial cells and at other times epithelial cells differentiate into mesenchymal cells (see Epithelial-mesenchymal transition). Following epithelial-mesenchymal transition, cells can migrate away from an epithelium and then associate with other similar cells in a new location.

Adhesion
During embryonic development, cells are restricted to different layers due to differential affinities. One of the ways this can occur is when cells share the same cell-to-cell adhesion molecules. For instance, homotypic cell adhesion can maintain boundaries between groups of cells that have different adhesion molecules. Furthermore, cells can sort based upon differences in adhesion between the cells, so even two populations of cells with different levels of the same adhesion molecule can sort out. In cell culture cells that have the strongest adhesion move to the center of a mixed aggregates of cells.

The molecules responsible for adhesion are called cell adhesion molecules (CAMs). Several types of cell adhesion molecules are known and one major class of these molecules are cadherins. There are dozens of different cadherins that are expressed on different cell types. Cadherins bind to other cadherins in a like-to-like manner: E-cadherin (found on many epithelial cells) binds preferentially to other E-cadherin molecules. Mesenchymal cells usually express other cadherin types such as N-cadherin.

Extracellular matrix
The extracellular matrix (ECM) is involved with separating tissues, providing structural support or providing a structure for cells to migrate on. Collagen, laminin, and fibronectin are major ECM molecules that are secreted and assembled into sheets, fibers, and gels. Multisubunit transmembrane receptors called integrins are used to bind to the ECM. Integrins bind extracellularly to fibronectin, laminin, or other ECM components, and intracellularly to microfilament-binding proteins α-actinin and talin to link the cytoskeleton with the outside. Integrins also serve as receptors to trigger signal transduction cascades when binding to the ECM. A well-studied example of morphogenesis that involves ECM is mammary gland ductal branching.