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Amorphogen is a substance whose non-uniform distribution governs thepattern of tissue development in the process ofmorphogenesis orpattern formation, one of the core processes ofdevelopmental biology, establishing positions of the various specialized cell types within a tissue. More specifically, a morphogen is a signaling molecule that acts directly on cells to produce specific cellular responses depending on its local concentration.
Typically, morphogens are produced by source cells and diffuse through surrounding tissues in an embryo during early development, such that concentration gradients are set up. These gradients drive the process of differentiation of unspecialisedstem cells into different cell types, ultimately forming all the tissues and organs of the body. The control of morphogenesis is a central element inevolutionary developmental biology (evo-devo).
The term was coined byAlan Turing in the paper "The Chemical Basis of Morphogenesis", where he predicted a chemical mechanism for biologicalpattern formation,[1] decades before the formation of such patterns was demonstrated.[2]
The concept of the morphogen has a long history in developmental biology, dating back to the work of the pioneeringDrosophila (fruit fly)geneticist,Thomas Hunt Morgan, in the early 20th century.Lewis Wolpert refined the morphogen concept in the 1960s with theFrench flag model, which described how a morphogen could subdivide a tissue into domains of different targetgene expression (corresponding to the colours of the French flag). This model was championed by the leadingDrosophila biologist,Peter Lawrence.Christiane Nüsslein-Volhard was the first to identify a morphogen,Bicoid, one of thetranscription factors present in a gradient in theDrosophilasyncitial embryo. She was awarded the 1995Nobel Prize in Physiology and Medicine for her work explaining the morphogenicembryology of the common fruit fly.[3][4][5][6] Groups led by Gary Struhl and Stephen Cohen then demonstrated that a secreted signalling protein,decapentaplegic (theDrosophila homologue oftransforming growth factor beta), acted as a morphogen during the later stages ofDrosophila development.
During early development, morphogen gradients result in the differentiation of specificcell types in a distinct spatial order. The morphogen provides spatial information by forming aconcentration gradient that subdivides a field of cells by inducing or maintaining theexpression of different targetgenes at distinct concentration thresholds. Thus, cells far from the source of the morphogen will receive low levels of morphogen and express only low-threshold targetgenes. In contrast, cells close to the source of morphogen will receive high levels of morphogen and will express both low- and high-threshold target genes. Distinct cell types emerge as a consequence of the different combination of target gene expression. In this way, the field of cells is subdivided into different types according to their position relative to the source of the morphogen. This model is assumed to be a general mechanism by which cell type diversity can be generated inembryonic development in animals.
Some of the earliest and best-studied morphogens aretranscription factors thatdiffuse within earlyDrosophila melanogaster (fruit fly) embryos. However, most morphogens aresecreted proteins thatsignal between cells.
A morphogen spreads from a localized source and forms a concentration gradient across a developing tissue.[7] In developmental biology, 'morphogen' is rigorously used to mean a signalling molecule that acts directly on cells (not through serial induction) to produce specific cellular responses that depend on morphogen concentration. This definition concerns the mechanism, not any specific chemical formula, so simple compounds such asretinoic acid (the active metabolite ofretinol orvitamin A) may also act as morphogens. The model is not universally accepted due to specific issues with setting up a gradient in the tissue outlined in theFrench flag model[8] and subsequent work showing that the morphogen gradient of the Drosophila embryo is more complex than the simple gradient model would indicate.[9]
Proposed mammalian morphogens includeretinoic acid, sonic hedgehog (SHH), transforming growth factor beta (TGF-β)/bone morphogenic protein (BMP), andWnt/beta-catenin.[10][11] Morphogens inDrosophila includedecapentaplegic andhedgehog.[10]
During development,retinoic acid, a metabolite ofvitamin A, is used to stimulate the growth of theposterior end of the organism.[12] Retinoic acid binds toretinoic acid receptors that act astranscription factors to regulate the expression ofHox genes. Exposure ofembryos toexogenous retinoids, especially in the first trimester, results in birth defects due to deregulation of gene expression.[11]
TGF-β family members are involved indorsoventral patterning and the formation of someorgans. Binding of TGF-β to type IITGF beta receptors recruits type I receptors, thereby causing the latter to be transphosphorylated. The type I receptors activateSmad proteins that in turn act as transcription factors that regulate gene transcription.[11]
Sonic hedgehog (SHH) are morphogens that are essential to early patterning in the developing embryo. SHH binds to thePatched receptor which in the absence of SHH inhibits theSmoothened receptor. Activated Smoothened in turn causesGli1,Gli2, andGli3 to be translocated into the nucleus where they activate target genes such atPTCH1 andEngrailed.[11]
Drosophila melanogaster has an unusual developmental system, in which the first thirteen cell divisions of the embryo occur within asyncytium prior to cellularization. Essentially the embryo remains a single cell with over 8000 nuclei evenly spaced near the membrane until the fourteenth cell division, when independent membranes furrow between the nuclei, separating them into independent cells. As a result, in fly embryostranscription factors such asBicoid or Hunchback can act as morphogens because they can freely diffuse between nuclei to produce smooth gradients of concentration without relying on specialized intercellular signalling mechanisms. Although there is some evidence thathomeoboxtranscription factors similar to these can pass directly through cell membranes,[13] this mechanism is not believed to contribute greatly to morphogenesis in cellularized[clarification needed] systems.
In most developmental systems, such as human embryos or laterDrosophila development, syncytia occur only rarely (such as in skeletal muscle), and morphogens are generally secreted signalling proteins. These proteins bind to the extracellular domains of transmembranereceptor proteins, which use an elaborate process ofsignal transduction to communicate the level of morphogen to the nucleus. The nuclear targets of signal transduction pathways are usually transcription factors, whose activity is regulated in a manner that reflects the level of morphogen received at the cell surface. Thus, secreted morphogens act to generate gradients of transcription factor activity just like those that are generated in the syncitialDrosophila embryo.
Discrete target genes respond to different thresholds of morphogen activity. The expression of target genes is controlled by segments of DNA called 'enhancers' to whichtranscription factors bind directly. Once bound, the transcription factor then stimulates or inhibits the transcription of the gene and thus controls the level of expression of the gene product (usually a protein). 'Low-threshold' target genes require only low levels of morphogen activity to be regulated and feature enhancers that contain many high-affinity binding sites for the transcription factor. 'High-threshold' target genes have relatively fewer binding sites or low-affinity binding sites that require much greater levels of transcription factor activity to be regulated.
The general mechanism by which the morphogen model works, can explain the subdivision of tissues into patterns of distinct cell types, assuming it is possible to create and maintain a gradient. However, the morphogen model is often invoked for additional activities such as controlling the growth of the tissue or orienting the polarity of cells within it (for example, the hairs on your forearm point in one direction) which cannot be explained by model.
The organizing role that morphogens play during animal development was acknowledged in the 2014 naming of a new beetle genus,Morphogenia. The type species,Morphogenia struhli, was named in honour of Gary Struhl, the US developmental biologist who was instrumental in demonstrating that thedecapentaplegic andwingless genes encode proteins that function as morphogens duringDrosophila development.[14]
