Morphogen

Amorphogenis a substance whose non-uniform distribution governs thepatternof tissue development in the process ofmorphogenesisorpattern 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 cellsinto 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).

History[edit]

The term was coined byAlan Turingin 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 Wolpertrefined 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 leadingDrosophilabiologist,Peter Lawrence.Christiane Nüsslein-Volhardwas the first to identify a morphogen,Bicoid,one of thetranscription factorspresent in a gradient in theDrosophilasyncitialembryo. She was awarded the 1995Nobel Prize in Physiology and Medicinefor her work explaining the morphogenicembryologyof the common fruit fly.^[3]^[4]^[5]^[6]Groups led by Gary Struhl and Stephen Cohen then demonstrated that a secreted signalling protein,decapentaplegic(theDrosophilahomologue oftransforming growth factor beta), acted as a morphogen during the later stages ofDrosophiladevelopment.

Mechanism[edit]

During early development, morphogen gradients result in the differentiation of specificcell typesin a distinct spatial order. The morphogen provides spatial information by forming aconcentration gradientthat subdivides a field of cells by inducing or maintaining theexpressionof different targetgenesat 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 developmentin animals.

Some of the earliest and best-studied morphogens aretranscription factorsthatdiffusewithin earlyDrosophila melanogaster(fruit fly) embryos. However, most morphogens aresecretedproteins thatsignal between cells.

Genes and signals[edit]

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 ofretinolorvitamin 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]

Examples[edit]

Proposed mammalian morphogens includeretinoic acid,sonic hedgehog (SHH), transforming growth factor beta (TGF-β)/bone morphogenic protein (BMP), andWnt/beta-catenin.^[10]^[11]Morphogens inDrosophilaincludedecapentaplegicandhedgehog.^[10]

During development,retinoic acid,a metabolite ofvitamin A,is used to stimulate the growth of theposteriorend of the organism.^[12]Retinoic acid binds toretinoic acid receptorsthat acts as transcription factors to regulate the expression ofHox genes.Exposure of embryos to exogenous retinoids especially in the first trimester results in birth defects.^[11]

TGF-βfamily members are involved indorsoventral patterningand the formation of some organs. Binding to TGF-β to type IITGF beta receptorsrecruits type I receptors causing the latter to be transphosphorylated. The type I receptors activateSmadproteins 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 thePatchedreceptor which in the absence of SHH inhibits theSmoothenedreceptor. Activated smoothened in turn causesGli1,Gli2,andGli3to be translocated into the nucleus where they activate target genes such atPTCH1andEngrailed.^[11]

Fruit fly[edit]

Drosophila melanogasterhas an unusual developmental system, in which the first thirteen cell divisions of the embryo occur within asyncytiumprior 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 factorssuch asBicoidor 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 thathomeobox transcription factorssimilar 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 laterDrosophiladevelopment, syncytia occur only rarely (such as in skeletal muscle), and morphogens are generally secreted signalling proteins. These proteins bind to the extracellular domains of transmembranereceptorproteins, which use an elaborate process ofsignal transductionto 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 syncitialDrosophilaembryo.

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 factorsbind 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.

Eponyms[edit]

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 thedecapentaplegicandwinglessgenes encode proteins that function as morphogens duringDrosophiladevelopment.^[14]

References[edit]

^Turing, A. M. (1952). "The chemical basis of morphogenesis".Philosophical Transactions of the Royal Society of London B.237(641): 37–72.Bibcode:1952RSPTB.237...37T.doi:10.1098/rstb.1952.0012.
^Hiscock, Tom W.; Megason, Sean G. (2015)."Orientation of Turing-like Patterns by Morphogen Gradients and Tissue Anisotropies".Cell Systems.1(6): 408–416.doi:10.1016/j.cels.2015.12.001.PMC4707970.PMID 26771020.
^Nüsslein-Volhard, C.; Wieschaus, E. (October 1980). "Mutations affecting segment number and polarity inDrosophila".Nature.287(5785): 795–801.Bibcode:1980Natur.287..795N.doi:10.1038/287795a0.PMID 6776413.S2CID 4337658.
^Arthur, Wallace (14 February 2002). "The emerging conceptual framework of evolutionary developmental biology".Nature.415(6873): 757–764.doi:10.1038/415757a.PMID 11845200.S2CID 4432164.
^Winchester, Guil (2004)."Edward B. Lewis 1918-2004"(PDF).Current Biology.14(18) (published Sep 21, 2004): R740–742.doi:10.1016/j.cub.2004.09.007.PMID 15380080.S2CID 32648995.
^"Eric Wieschaus and Christiane Nüsslein-Volhard: Collaborating to Find Developmental Genes".iBiology. Archived fromthe originalon 13 October 2016.Retrieved13 October2016.
^Russell, Peter (2010).iGenetics: a molecular approach.San Francisco, CA: Pearson Benjamin Cummings. p. 566.ISBN 978-0-321-56976-9.
^Gordon, Natalie K.; Gordon, Richard (2016)."The organelle of differentiation in embryos: The cell state splitter".Theoretical Biology and Medical Modelling.13:11.doi:10.1186/s12976-016-0037-2.PMC4785624.PMID 26965444.
^Roth S., Lynch JDoes the Bicoid Gradient Matter?Cell, Volume 149, Issue 3, p511–512, 27 April 2012.
^^a ^bKam RK, Deng Y, Chen Y, Zhao H (2012)."Retinoic acid synthesis and functions in early embryonic development".Cell & Bioscience.2(1): 11.doi:10.1186/2045-3701-2-11.PMC3325842.PMID 22439772.
^^a ^b ^c ^dMoore KL, Persaud TV, Torchia MG (2013)."Common signaling pathways used during development: morphogens".The developing human: clinically oriented embryology(9th ed.). Philadelphia, PA: Saunders/Elsevier. pp. 506–509.ISBN 978-1437720020.
^Cunningham, T.J.; Duester, G. (2015)."Mechanisms of retinoic acid signalling and its roles in organ and limb development".Nat. Rev. Mol. Cell Biol.16(2): 110–123.doi:10.1038/nrm3932.PMC4636111.PMID 25560970.
^Derossi D, Joliot AH, Chassaing G, Prochiantz A (April 1994)."The third helix of the Antennapedia homeodomain translocates through biological membranes".J. Biol. Chem.269(14): 10444–50.doi:10.1016/S0021-9258(17)34080-2.PMID 8144628.
^Parker J (23 January 2014)."Morphogenia: a new genus of the Neotropical tribe Jubini (Coleoptera, Staphylinidae, Pselaphinae) from the Brazilian Amazon".ZooKeys(373): 57–66.doi:10.3897/zookeys.373.6788.PMC3909807.PMID 24493960.