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A morphogen is a substance whose non-uniform distribution governs the Natural patterns of tissue development in the process of morphogenesis or pattern formation, one of the core processes of developmental 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 unspecialised into different cell types, ultimately forming all the tissues and organs of the body. The control of morphogenesis is a central element in evolutionary developmental biology (evo-devo).
The concept of the morphogen has a long history in developmental biology, dating back to the work of the pioneering Drosophila (fruit fly) geneticist, Thomas Hunt Morgan, in the early 20th century. Lewis Wolpert refined the morphogen concept in the 1960s with the French flag model, which described how a morphogen could subdivide a tissue into domains of different target gene expression (corresponding to the colours of the French flag). This model was championed by the leading Drosophila biologist, Peter Lawrence. Christiane Nüsslein-Volhard was the first to identify a morphogen, Bicoid, one of the transcription factors present in a gradient in the Drosophila syncitial embryo. She was awarded the 1995 Nobel Prize in Physiology and Medicine for her work explaining the morphogenic embryology of the common fruit fly. Groups led by Gary Struhl and Stephen Cohen then demonstrated that a secreted signalling protein, decapentaplegic (the Drosophila homologue of transforming growth factor beta), acted as a morphogen during the later stages of Drosophila development.
Some of the earliest and best-studied morphogens are transcription factors that diffusion within early Drosophila melanogaster (fruit fly) embryos. However, most morphogens are secretion proteins that cell signalling.
During development, retinoic acid, a metabolite of vitamin A, is used to stimulate the growth of the posterior end of the organism. Retinoic acid binds to retinoic acid receptors that acts as transcription factors to regulate the expression of . Exposure of embryos to exogenous retinoids especially in the first trimester results in birth defects.
TGF-β family members are involved in dorsoventral patterning and the formation of some organs. Binding to TGF-β to type II TGF beta receptors recruits type I receptors causing the latter to be transphosphorylated. The type I receptors activate Smad proteins that in turn act as transcription factors that regulate gene transcription.
Sonic hedgehog (SHH) are morphogens that are essential to early patterning in the developing embryo. SHH binds to the Patched receptor which in the absence of SHH inhibits the Smoothened receptor. Activated smoothened in turn causes Gli1, Gli2, and Gli3 to be translocated into the nucleus where they activate target genes such at PTCH1 and Engrailed.
In most developmental systems, such as human embryos or later Drosophila 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 transmembrane receptor proteins, which use an elaborate process of signal 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 syncitial Drosophila 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 which transcription 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.
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