AmandaLinkeBiol211Essay Prompt: Discuss the importance of intercellular signaling in development.EssayWord Count: TotalWord Count:Role of Intercellular SignalingDuring EmbryogenesisThe information needed tocreate a fully developed organism is stored within all cells, but duringdevelopment this information must be correctly translated and interpreted.Cells are constantly signaling each other during development through secretedsignals, communicating important information which allows cells to establishbody axes, layout a body plan, and differentiate in order to properly form theembryo. Mutation or misinterpretation of these signals translates intodevelopmental abnormalities which may kill the embryo or lead to phenotypicmalformations. The correct useand interpretation of intercellular signaling is therefore essential for thecorrect formation of the embryo during development. TRD1 Bodyaxes establishmentOneof the first and most important developmental steps during early embryogenesisis the process of gastrulation, which differentiates ofTRD2 the fertilized oocyte into the ectoderm, mesoderm, and endoderm germ layers.Fibroblast Growth Factor (FGF) signaling plays a central role in gastrulationand helps establish the dorsal/ventral and left/right axes of the developingembryo by specifying mesodermal cell fates through the Ras/MAPK cascade (Oki etal, 2010).
Thisstep establishes the first oriental axes in the developing embryo and organizesthe rest of the organism to form properly around these axes, making it acrucial developmental step towards the correct differentiation and growth ofthe embryo. TRD3 Mutationsof the FGF signaling pathway can cause major embryonic abnormalities and caninterfere with or arrest proper development. For example, in mouse embryosgrowth factor FGF8 and its receptor FGF1 have important roles in gastrulationand formation of left/right axes. ItTRD4 induces Snail expression, whichdownregulates ectodermal genes in the mesoderm by repressing E-cadherin, and induces TRD5 T and Tbx6 expression which specifies mesodermal fate and helps establishthe left/right axis via Notch signaling. In FGF8 negative mouse embryos, however,epiblast cells are able to move the TRD6 primitivestreak and undergo the epithelial-to-mesenchymal transition (EMT) but areunable to move away from the streak, preventing mesodermal and endodermaltissues from forming and greatly mutating the developing embryo (Sun et al,1999). The lack of intercellular FGF signaling causes EMT and mesodermalpatterning defects,greatly mutating the embryo and preventing it from properly developing.
TRD7 TheWnt signaling pathway is also crucial for establishing body axes, most notablyin the form of the dorsal/ventral axis by creating the Spemann organizer fromthe Nieuwkoop center, establishing the dorsal side of the embryo (Amerongen andNusse). The Spemann organizer instigates development of the central nervous systemby inducingcells into becoming neural TRD8 platecells, which will fold together to form the neural tube and eventually thespinal chord, forbrain, midbrain, and hindbrain. The Spemann organizer alsoestablishes the anterior/posterior axis in the neural tube via Wnt and BMPsignaling. Forexample, the Spemann organizer secretes Cerebus and insulin-like growth factorswhich inhibits Wnt and BMP signals in order to form the head region, while theposterior region is established by a Wnt and BMP signal gradient (Neurulationand the Notochord, 2010). TRD9 Bodyplan establishmentAfterthe body axes have been established cells can begin to transmit informationabout the body plan of the organism.
TRD10 TheHedgehog (hh) signaling pathway is one of the key methods by which this occurs.TRD11 Inthe Hedgehog signaling pathway the hh TRD12 proteinis produced and processed in the cytoplasm, creating an active protein and twolipids, which help transport and attach the protein to the cell membrane. Thecell can then generate a protein gradient in the extracellular space so thatother cells can respond to the proteins through Patched (Ptch), a transmembranereceptor protein. When Ptch is inactive it inhibits Smoothened (Smo), anothertransmembrane protein which inhibits the transcription of certain genes. Ptchbecomes activated upon hh ligand binding, activating the Smo protein andcausing an hh signal cascade which finally initiates transcription of specificgenes (Mohler, 1998?). TRD13 Mutationsor abnormalities in the hh signaling pathway cause major phenotypic changes;for example, in some hh mutant drosophila the embryo will grow to be short andstubby compared to wild type embryos, and can grow “lawns” of denticles insteadof rows, making the embryo look short and hairy like its namesake (Mohler, 1988).TRD14 Mutationsin hh signaling are typically embryonic lethal, demonstrating the clearimportance of efficient intercellular signaling in development.
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TRD15 Intercellularsignaling plays a crucial role in both body axis formation and body planinitiation. Mutations of FGF or Wnt signaling, which both contribute to bodyaxis formation, prevent normal development and lead to extreme phenotypicabnormalities or embryonic termination. Mutations of hh genes, which establishes TRD16 embryonicbody segments, also causes TRD17 extremephenotypic irregularities. Successful embryonic development depends on theaccurate intercellular signaling which determines cell fates.
DifferentiationWhilethe body axes and body plan are being established cells can begin todifferentiate within their germ layers via induction, the process by whichcells determine other cell’s fates through intercellular signaling. There are 6major signaling pathways by which differentiation occurs: FGF, SHH, BMP, Notch,canonical Wnt, and noncanonical Wnt. TRD18 Eachsignaling pathway influences the differentiation of embryonic stem cells intoparticular tissues depending on its location according to the established bodyplan. However, an embryo can only successfully develop when these signalingpathways are used appropriately and interpreted correctly. Notchsignaling allows for differentiation between adjacent cells via lateralinhibition giving rise to asymmetric cell division, whereby one daughter cellhas a different cell fate than the original cell. Initially cells in a clusterexpress both Delta and Notch, but a random change in gene expression changesthe balance of ligands and receptors on a cell such that a cell expresses moreDelta. The asymmetry is generated when the cell can stably express Delta,becoming the signal sender and activating Notch signaling so that the adjacentcells can adopt their cell fates (Perrimon, 2001). Notch signaling is activatedwhen the Notch receptor extracellular domain binds to Delta and DSL ligands onan adjacent cell, inducing a conformational change in Notch, exposing anADAM10/TACE cleavage site.
This site is cleaved by y-secretase, releasing theNotch intracellular domain (NICD) which then travels to the nucleus andcomplexes with coactivators (CoA) and Mastermind (Mam) to replace corepressors(CoR) which occupy CLS bound Notch target gene promoters like Hes genes. Hesinhibits expression of genes like Mash1, whereas cells which do not receiveNotch signals express Mash1, upregulating expression of Notch ligand DSL(Brasson, 2012). TRD19 Mutationsin the Notch signaling pathway can affect cell fate decisions and prevent cellsfrom properly differentiating. For example, the Notch signaling pathway plays alarge part in differentiating cells in the gut of Zebrafish. In Zebrafish witha defective Delta ligand Notch signaling was unable to take place and theepithelial cells defaulted into secretory cells, overproducing secretory cellsand producing no absorptive cells (Crosnier et al, 2005). This shows TRD20 thatthe Notch pathway is crucial to the correct differentiation between adjacenttissues and that mutations in this type of intercellular signaling causesextreme developmental problems. Developmentof complex structures like limbs require much intercellular signaling.
TRD21 Stimulationof limb bud development is caused by expression of Tbx5 in the forelimb andTbx4 in the hindlimb. Both T-box transcription factors stimulate the expressionof FGF10 by the mesodermal cells, which in turn stimulates the ectodermal cellsto produce FGF8, establishing a feedback loop which initiates limb development(Zuniga, 2015). The correct expression of Tbx5, and consequentially FGF10signal pathway, is crucial to proper limb development. For example, in FGF10knockout mice the limbs and lungs fail to form, while if a bead soaked in FGF10is implanted into a mouse embryo an extra limb will develop at that spot.
Thebirth defect Amelia is also an outcome of mutations in FGF signaling, resultingin the underdevelopment or lack of one or more limbs (Limb Development, 2015). Brachydactyly,an inherited human hand malformation syndrome causing shortness in the fingers,is another defect caused by mutations of intercellular signaling. However,brachydactyly is caused by mutations of BMP signaling pathways resulting in thefailure to receive or misinterpretation of the signals (Bernatik, 2017). Mutationsin intercellular signaling pathways such as the FGF or BMP pathway can resultin huge phenotypic abnormalities which, if not embryonic lethal, could greatlyimpair the developing organism and prevent it from growing and developingnormally.
Cellsignaling is responsible for the differentiation of cells so that limbs and organscan properly develop. FGF, Notch, and BMP are among the most prevalentintercellular signaling pathways and facilitate the correct development of theembryo when used and interpreted accurately. However, mutations of thesesignaling pathways can lead to drastic phenotypic changes like the Amelia birthdefect or Brachydactyly syndrome, which can greatly impair the organism andprevent it from living normally. Conclusion: Embryogenesisis a complex process which depends on intercellular signaling to convey bodyaxes, establish a body plan, and differentiate cells so that they can begin todevelop the limbs and organs necessary for normal development. TRD22 Signalingpathways such as Notch, BMP, FGF, SHH, and Wnt play a crucial role in conveyingthis information, while mutations of these pathways can be embryonic lethal orinflict debilitating defects on the organism. Development depends on theaccurate transmission and interpretation of intercellular signals, withoutwhich embryogenesis would be impossible to complete.
