Molecular embryology part (2)


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In this PPT I completed that interesting topic In this PPT I completed that interesting topic , molecular embryology discussing this time molecular regulation of some other systems in the developing embryo, wishing that I could make this as simple as possible.

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Molecular embryology part (2)

  1. 1. By:Dr. Khaled El MasryAssistant Lecturer of Human Anatomy &EmbryologyMansoura Faculty of Medicine, Mansoura University,Mansoura , Egypt.Molecular Embryology20134/28/2013
  2. 2. 4/28/2013All Data and Diagrams includedin this presentation are basicallyderived from our highlyvaluable reference ofEmbryology(Langmans MedicalEmbryology 12th ed. - T.Sadler (Lippincott, 2012), recommending you all to referto it for more details….
  3. 3. 4/28/2013Introduction
  4. 4. Molecular Biology has opened the doors to new waysto study Embryology and to enhance ourunderstanding of Normal and Abnormal development.Sequencing the Human Genome, together withcreating techniques to investigate gene regulation atmany levels of complexity, has taken Embryology tothe next level.Thus, from Anatomical to Biochemical toMOLECULAR level, the story of Embryology hasprogressed, and each chapter has enhanced ourknowledge.4/28/2013
  5. 5.  Genes are contained in a complex of DNA and proteins called chromatin, andits basic unit of structure is the nucleosome. Chromatin appears tightly coiledas beads of nucleosomes on a string and is called heterochromatin. For transcription to occur, DNA must be uncoiled from the beads aseuchromatin. Genes reside within strands of DNA and contain regions that canbe translated into proteins, called exons, and untranslatable regions, calledintrons. A typical gene also contains :1. a promoter region that binds RNA polymerase for the initiation of transcription;2. a transcription initiation site, to designate the first amino acid in the protein;3. a translation termination codon; and4. a 3′ untranslated region that includes a sequence (the poly A addition site)that assists with stabilization of the mRNA.4/28/2013
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  7. 7.  The RNA polymerase binds to the promoter region that usuallycontains the sequence TATA, the TATA box. Binding requiresadditional proteins called transcription factors. Methylation ofcytosine bases in the promoter region silences genes andprevents transcription. Different proteins can be produced from a single gene by theprocess of alternative splicing that removes different intronsusing spliceosomes. Proteins derived in this manner are calledsplicing isoforms or splice variants. Also, proteins may bealtered by post- translational modifi cations, such asphosphorylation or cleavage.4/28/2013
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  9. 9.  Induction is the process whereby one group of cells or tissues (theinducer) causes another group (the responder) to change their fate.The capacity to respond is called competence and must be conferredby a competence factor. Many inductive phenomena involve epithelial– mesenchymalinteractions. Signal transduction pathways include a signaling molecule (theligand) and a receptor.The receptor usually spans the cell membraneand is activated by binding with its specific ligand. Activation usually involves the capacity to phosphorylate otherproteins, most often as a kinase. This activation establishes a cascadeof enzyme activity among proteins that ultimately activates atranscription factor for initiation of gene expression.4/28/2013
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  11. 11.  Cell-to-cell signaling may be paracrine, involving diffusablefactors, or juxtacrine, involving a variety of nondiffusable factors. Proteins responsible for paracrine signaling are called paracrinefactors or growth and differentiation factors (GDFs). There are four major families of GDFs:FGFs, WNTs, hedgehogs, and TGF-bs. In addition to proteins, neurotransmitters, such as serotonin (5HT)and norepinephrine, also act through paracrine signaling, serving asligands and binding to receptors to produce specific cellularresponses. Juxtacrine factors may include products of the extracellularmatrix, ligands bound to a cell’s surface, and direct cell-to-cellcommunications. 4/28/2013
  12. 12. Molecular Regulation ofGastrulation(Establishment of the Body Axes)4/28/2013
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  15. 15. 4/28/2013Establishment of the body axes;anteroposterior, dorsoventral, and left-right, takesplace before and during the period of gastrulation.Cells at the prospective cranial end ofthe embryo in the anterior visceralendoderm (AVE) express thetranscription factors OTX2, LIM1, andHESX1 and the secreted factorcerberus that contribute to headdevelopment and establish thecephalic region.Goosecoid, expressed in the node, regulates chordinexpression, and this gene product, together with noggin andfollistatin, antagonizes the activity of BMP4, dorsalizing mesoderminto notochord and paraxial mesoderm for the head region.Once the streak is formed and gastrulation is progressing, BMP4 issecreted throughout the bilaminar disc and acts with FGF toventralize mesoderm into intermediate and lateral plate mesoderm.Later, expression of the Brachyury (T) gene antagonizes BMP4 todorsalize mesoderm into notochord and paraxial mesoderm in caudalregions of the embryo.
  16. 16. 4/28/2013FGF8, secreted by the node andprimitive streak, establishesexpression of Nodal, a member ofthe TGF-b superfamily, and the nodalprotein then accumulates on the leftside near the node.Later, as the neural plate starts toform, FGF8 induces expression ofNodal and LEFTY-2 in the lateralplate mesoderm, whereas LEFTY-1is expressed on the left side of theventral aspect of the neural tube.
  17. 17. 4/28/2013These signals are dependent uponserotonin (5HT). Products from theBrachyury (T) gene, expressed in thenotochord, also participate in induction ofthese three genes.In turn, expression of Nodal andLEFTY-2 regulates expression of thetranscription factor PITX2, which, through further downstreameffectors, establishes left-sidedness.SHH, expressed in the notochord, mayserve as a midline barrier and alsorepresses expression of left-sided geneson the right. Expression of thetranscription factor Snail may regulatedownstream genes important forestablishing right-sidedness.
  18. 18. 4/28/2013Cells migrating more posteriorlythrough the node and most cranialaspect of the streak will formparaxial mesoderm (pm;somitomeres and somites);Fate map established duringgastrulationCells migrating at the mostcranial part of the node willform the notochord (n);Cells migrating through the next portionof the streak will form intermediatemesoderm (im; urogenital system);Cells migrating through the more caudalpart of the streak will form lateral platemesoderm (lpm; body wall);Cells migrating through the mostcaudal part will contribute toextraembryonic mesoderm (eem;chorion).
  19. 19. Molecular Regulation ofGenital DuctDevelopment4/28/2013
  20. 20. SOX94/28/2013
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  22. 22. Estrogrn4/28/2013
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  24. 24. Molecular Regulation ofPharyngeal ArchesDevelopment4/28/2013
  25. 25. Crest cells originating from Rhombomeres migrate to specificarchesPatterning of pharyngealarchesThis is regulatedby1st Arch 2nd to 6th ArchByOTX 2 geneMidbrainandForebrainExpressed inregions and migrate with crest cells to1st arch.ByHOX genesinHindbrainExpressed inspecific overlappingpatternThere may bean interactionwith HOXgenes in 1starchpatterning4/28/2013
  26. 26. HOXgenesCrest cells alone can’t maintain HOX genesexpression but require interaction withmesoderm of the pharyngeal archesHOX expression isregulated bySHHUpstream regulatorexpressed in thearchesRegulate HOX expression in concentrationRAREdependent manner viaRetinoic Acid: ( Retinoic Acid Response Elements)RAREBinding sites for retinoic acid in promoter regions of HOX genes4/28/2013
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  28. 28. 4/28/2013Patterns of HOX gene expression in thehindbrain. HOX genes are expressed in overlappingpatternsending at specifi c rhombomere boundaries. Genesatthe 3′ end of a cluster have the most anteriorboundaries,and paralogous genes have identical expressiondomains.These genes confer positional value along theanteriorposterioraxis of the hindbrain, determine the identity ofthe rhombomeres, and specify their derivatives.
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  30. 30. Molecular Regulation ofSpinal Cord&BrainDevelopment4/28/2013
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  32. 32. Forebrain&MidbrainInhibition of BMP 4ChordinNogginFollistatinByExpression of ( OTX 1,2 , EMX1, EMX2) genes in specific& overlapping patternDifferentiation of Forebrain & MidbrainRegionsOnce Boundaries of Forebrain & Midbrain Regions areestablished2 additional Organizing Centers appearANR( at the junction of cranial border ofneural plate & non- neuralectodermIsthmus( at the junction Midbrain &Hindbrain)4/28/2013
  33. 33. ANRFGF8BF1RegulateDevelopment ofTelencephalonInduce expression ofIshmusFGF8Induce expression ofWNT 1EN1EN2RegulateDevelopment ofTectum &CerebellumRegulateDevelopment ofCerebellum onlyInteract withEN1 & EN2to regulatedevelopmentof the region4/28/2013
  34. 34. IsthmusFGF8EN1EN2WNT 14/28/2013
  35. 35. HindbrainWNT 3a & FGFInduce differentiation ofHindbrain region into 8segments calledRhombomeresExpress HOXgenesExpressed in overlapping patternDetermine identity of these Rhombomeres & specify theirderivativesRetinoic Acid Organizes Craniocaudal Axis4/28/2013
  36. 36. 4/28/2013Patterns of HOX gene expression in theHindbrain:HOX genes are expressed in overlapping patternsending at specifi c rhombomere boundaries. Genes atthe 3′ end of a cluster have the most anterior boundaries,and paralogous genes have identical expression domains.These genes confer positional value along theanteriorposterioraxis of the hindbrain, determine the identity ofthe rhombomeres, and specify their derivatives.
  37. 37. SpinalCordInduced byWNT 3a &FGFNeural plate in spinal cord regionexpresses the followingTranscription Factors(PAX3, PAX7, MSX1, MSX2)This expression iscontrolled bySHH (secreted by prochordalplate)Inhibit theirexpressionVentralize the Neural plateMotor Neurons formationBMP4,7(secreted by Non-neuralEctoderm)Upregulate PAX3,7Dorsalize the Neural plateSensory Neuronsformationneeded forNeuralCrest cellsformation4/28/2013
  38. 38. Molecular Regulation ofLIMBDevelopment4/28/2013
  39. 39. Limb outgrowth is initiated by FGF10 secreted bylateral plate mesoderm in the limb-forming regionsOnce outgrowth is initiated, the AER is induced byBMPs and restricted in its location by the geneRadical fringe expressed in dorsal ectoderm. Inturn, this expression induces that of SER2 in cellsdestined to form the AER.After the ridge is established, itexpresses FGF4 and FGF8 to maintainthe progress zone, the rapidlyproliferating mesenchyme cells adjacentto the ridge.4/28/2013
  40. 40. Anteroposterior patterning of the limb is controlledby cells in the ZPA at the posterior border.These cells produce retinoic acid (vitamin A), whichinitiates expression of SHH, regulating patterning.The dorsoventral limb axis is directed byWNT7a, which is expressed in the dorsalectoderm.This gene induces expression of thetranscription factor LMX1 in the dorsalmesenchyme, specifying these cells asdorsal.4/28/2013
  41. 41. 4/28/2013Longitudinal section through thelimb bud of a chickembryo, showing a core ofmesenchyme cover by a layer ofectoderm that thickens at the distalborder of the limb to form the AER.In humans, this occurs during thefifth week of development.External view of a chick limb athigh magnification showing theectoderm and the specializedregion at the tip of the limb calledthe AER
  42. 42. Bone type and shape are regulated by HOX genes, whoseexpression is determined by the combinatorial expression ofSHH, FGFs, and WNT7a.HOXA and HOXD clusters are the primary determinants of bonemorphology.4/28/2013
  43. 43. Molecular Regulation ofEYEDevelopment4/28/2013
  44. 44.  The eyes begin to develop as a pair of outpocketings that willbecome the optic vesicles on each side of the forebrain at the endof the fourth week of development . The optic vesicles contact the surface ectoderm and induce lensformation. When the optic vesicle begins to invaginate to form the pigmentand neural layers of the retina, the lens placode invaginates to formthe lens vesicle. Through a groove at the inferior aspect of the optic vesicle, thechoroid fissure, the hyaloid artery (later the central artery of theretina) enters the eye . Nerve fibers of the eye also occupy this groove to reach the opticareas of the brain. The cornea is formed by:(a) a layer of surface ectoderm,(b) the stroma, which is continuous with the sclera, and 4/28/2013
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  47. 47. The master gene forEye DevelopmentPAX6Expressed in the single eye field at the neuralplate stage.SHHSeparate theeye field intotwo opticprimordia.upregulatesPAX2 expression inthe optic stalkswhiledownregulatingPAX6.Restricting(PAX6)expression to the optic cupand lensEpithelial–mesenchymal interactions between prospective lensectoderm, optic vesicle, and surrounding mesenchyme thenregulate lens and optic cup differentiation.4/28/2013
  48. 48. Molecular Regulation ofTOOTHDevelopment4/28/2013
  49. 49.  Teeth develop from epithelial–mesenchymal interactionsbetween oral epithelium and neural crest–derivedmesenchyme. Enamel is made by ameloblasts. It lies on a thick layer of dentin produced byodontoblasts,a neural crest derivative. Cementum is formed by cementoblasts, anothermesenchymal derivative found in the root of the tooth.4/28/2013
  50. 50. Enamel Knot(CircumscribedRegion of dentalepith. at tips oftoothbudsThe organizer for theTOOTHDevelopment isExpressFGF 4 BMP 4Regulateoutgrowth of thecap.Regulate timing ofapoptosis in Knotcells 4/28/2013
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