Morphogenesis (from theGreekmorphê shape andgenesis creation, literally "the generation of form") is thebiological process that causes acell,tissue ororganism to develop its shape. It is one of three fundamental aspects ofdevelopmental biology along with the control oftissue growth andpatterning ofcellular differentiation.
The process controls the organized spatial distribution of cells during theembryonic development of anorganism. Morphogenesis can take place also in a mature organism, such as in the normalmaintenance of tissue bystem cells or inregeneration of tissues after damage.Cancer is an example of highly abnormal and pathological tissue morphogenesis. Morphogenesis also describes the development ofunicellular life forms that do not have an embryonic stage in their life cycle. Morphogenesis is essential for theevolution of new forms.
Morphogenesis is a mechanical process involving forces that generate mechanical stress, strain, and movement of cells,[1] and can be induced by genetic programs according to the spatial patterning of cells within tissues. Abnormal morphogenesis is calleddysmorphogenesis.
Some of the earliest ideas and mathematical descriptions on how physical processes and constraints affect biological growth, and hencenatural patterns such as thespirals ofphyllotaxis, were written byD'Arcy Wentworth Thompson in his 1917 bookOn Growth and Form[2][3][note 1] andAlan Turing in hisThe Chemical Basis of Morphogenesis (1952).[6] Where Thompson explained animal body shapes as being created by varying rates of growth in different directions, for instance to create thespiral shell of asnail, Turing correctly predicted a mechanism of morphogenesis, the diffusion of two different chemical signals, one activating and one deactivating growth, to set up patterns of development, decades before the formation of such patterns was observed.[7] The fuller understanding of the mechanisms involved in actual organisms required the discovery of the structure ofDNA in 1953, and the development ofmolecular biology andbiochemistry.[citation needed]
Several types of molecules are important in morphogenesis.Morphogens are soluble molecules that can diffuse and carry signals that control cell differentiation via concentration gradients. Morphogens typically act through binding to specific proteinreceptors. An important class of molecules involved in morphogenesis aretranscription factor proteins that determine the fate of cells by interacting withDNA. These can be coded for by master regulatorygenes, and either activate or deactivate thetranscription of other genes; in turn, these secondary gene products can regulate the expression of still other genes in a regulatory cascade ofgene regulatory networks. At the end of this cascade are classes of molecules that control cellular behaviors such ascell migration, or, more generally, their properties, such ascell adhesion or cell contractility. For example, duringgastrulation, clumps ofstem 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. Developmental signaling pathways implicated in morphogenesis includeWnt,Hedgehog, andephrins.[8]
At a tissue level, ignoring the means of control, morphogenesis arises because of cellular proliferation and motility.[9] Morphogenesis also involves changes in the cellular structure[10] or how cells interact in tissues. These changes can result in tissue elongation, thinning, folding, invasion or separation of one tissue into distinct layers. The latter case is often referred ascell sorting. Cell "sorting out" consists of cells moving so as to sort into clusters that maximize contact between cells of the same type. The ability of cells to do this has been proposed to arise from differential cell adhesion byMalcolm Steinberg through hisdifferential adhesion hypothesis. Tissue separation can also occur via more dramaticcellular differentiation events during which epithelial cells become mesenchymal (seeEpithelial–mesenchymal transition). Mesenchymal cells typically leave the epithelial tissue as a consequence of changes in cell adhesive and contractile properties. Following epithelial-mesenchymal transition, cells can migrate away from an epithelium and then associate with other similar cells in a new location.[11] In plants, cellular morphogenesis is tightly linked to the chemical composition and the mechanical properties of the cell wall.[12][13]
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. Incell culture cells that have the strongest adhesion move to the center of a mixed aggregates of cells. Moreover, cell-cell adhesion is often modulated by cell contractility, which can exert forces on the cell-cell contacts so that two cell populations with equal levels of the same adhesion molecule can sort out. 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 arecadherins. 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.[14][15]
Theextracellular matrix (ECM) is involved in keeping tissues separated, providing structural support or providing a structure for cells to migrate on.Collagen,laminin, andfibronectin are major ECM molecules that are secreted and assembled into sheets, fibers, and gels. Multisubunit transmembrane receptors calledintegrins are used to bind to the ECM. Integrins bind extracellularly to fibronectin, laminin, or other ECM components, and intracellularly tomicrofilament-binding proteinsα-actinin andtalin to link thecytoskeleton with the outside. Integrins also serve as receptors to triggersignal transduction cascades when binding to the ECM. A well-studied example of morphogenesis that involves ECM ismammary gland ductal branching.[16][17]
Tissues can change their shape and separate into distinct layers via cell contractility. Just as in muscle cells,myosin can contract different parts of the cytoplasm to change its shape or structure. Myosin-driven contractility in embryonic tissue morphogenesis is seen during the separation ofgerm layers in themodel organismsCaenorhabditis elegans,Drosophila andzebrafish. There are often periodic pulses of contraction in embryonic morphogenesis. A model called the cell state splitter involves alternating cell contraction and expansion, initiated by a bistable organelle at the apical end of each cell. The organelle consists ofmicrotubules andmicrofilaments in mechanical opposition. It responds to local mechanical perturbations caused by morphogenetic movements. These then trigger travelingembryonic differentiation waves of contraction or expansion over presumptive tissues that determine cell type and is followed by cell differentiation. The cell state splitter was first proposed to explainneural plate morphogenesis duringgastrulation of theaxolotl[18] and the model was later generalized to all of morphogenesis.[19][20]
In the development of thelung a bronchus branches into bronchioles forming therespiratory tree.[21] The branching is a result of the tip of each bronchiolar tube bifurcating, and the process of branching morphogenesis forms the bronchi, bronchioles, and ultimately the alveoli.[22]
Branching morphogenesis is also evident in theductal formation of themammary gland.[23][17] Primitive duct formation begins indevelopment, but the branching formation of the duct system begins later in response toestrogen during puberty and is further refined in line with mammary gland development.[17][24][25]
Cancer can result from disruption of normal morphogenesis, including both tumor formation and tumormetastasis.[26]Mitochondrial dysfunction can result in increased cancer risk due to disturbed morphogen signaling.[26]
During assembly of thebacteriophage (phage) T4virion, the morphogenetic proteins encoded by the phagegenes interact with each other in a characteristic sequence. Maintaining an appropriate balance in the amounts of each of these proteins produced during viral infection appears to be critical for normal phage T4 morphogenesis.[27] Phage T4 encoded proteins that determine virion structure include major structural components, minor structural components and non-structural proteins that catalyze specific steps in the morphogenesis sequence.[28] Phage T4 morphogenesis is divided into three independent pathways: the head, the tail and the long tail fibres as detailed by Yap and Rossman.[29]
An approach to model morphogenesis incomputer science ormathematics can be traced toAlan Turing's 1952 paper, "The chemical basis of morphogenesis",[30] a model now known as theTuring pattern.
Another famous model is the so-calledFrench flag model, developed in the sixties.[31]
Improvements incomputer performance in the twenty-first century enabled the simulation of relatively complex morphogenesis models. In 2020, such a model was proposed where cell growth and differentiation is that of acellular automaton with parametrized rules. As the rules' parameters are differentiable, they can be trained withgradient descent, a technique which has been highly optimized in recent years due to its use inmachine learning.[32] This model was limited to the generation of pictures, and is thus bi-dimensional.
A similar model to the one described above was subsequently extended to generate three-dimensional structures, and was demonstrated in the video gameMinecraft, whose block-based nature made it particularly expedient for the simulation of 3D cellular automatons.[33]
