普度大学发育生物学.pptx

BIOL 595Developmental BiologyFall 2010 8-24-10IntroductionCourse Overview1)Pre-requests2)Textbooks3)Exam dates4)Grading5)School PolicyThe goal of this course is tostudy the regulation of zygote developmentZygote-Fertilized egg-Diploidy-contains chromosomes of both male and female parentsHow does a single cell(zygote)transform into a complex organism?2)Pluripotent Potential of a cell to generate all cell types except extraembryonic tissue-Examples:embryonic stem cells and induced pluripotent stem(ips)cells1)Totipotent Ability of a single cell to divide and produce all the differentiated cells in an organism,including extraembryonic tissuesCell Plasticity-developmental potential3)Multipotent Potential of a cell to form several lineages within a tissue-Examples:Haematopietic stem cells and mesodermCell Plasticity-developmental Potential4)Progenitor Cell with the capacity to differentiate and divide but with limited self-renewal potentialCell Determination Commitment to a lineageCommitment Stable activation of a gene expression program characteristic of a lineageCell Differentiation Process by which cells become more specialized acquiring new identities-Cells of the same developmental origin sharing a similar phenotype/functionSpecification of Distinct Cell Lineages Involve cell-extrinsic signals Involve cell-Intrinsic transcriptional activitiesTranscription FactorTranscriptionMany binary junctures during development seem to be governed by cross-antagonistic transcription factor interactionsCell Fates by Cross-antagonisms using Transcription Factors Binary Model of PU.1 and Gata 1 antagonism1)To activate a target gene in erythroid cells,Gata1 recruits the histone acetylase CREB-binding protein2)Overexpression of PU.1 -displaces CBP by binding to Gata1 and recruits Rb as well as Suv39 protein-results in methylation of lysine 9 in histone H3-Leads to the recruitment of HP1a-causes repression of the target gene of Gata1Lineage Outcome by Sequential Participation of Transcription FactorsSwitching Cell Lineage1)Lineage reprogramming Conversion of cells from one lineage to another-Term covers both transdifferentiation and transdetermination2)Transdifferentiation Reprogramming of one specialized cell type into another,without reversion to pluripotent cells-Also called“lineage switching”or“lineage conversion”3)Transdetermination Reprogramming of a committed,but not yet fully differentiated,cell type into anotherSwitching Cell LineagesiPS(induced pluripotent stem)cellDiscovered by Takahashi and Yamanaka,2006Reprogramming Quartet:-Oct3/4-Sox2-Klf4(Kruppel-like factor4)-c-Myc(myelocytomatosis oncogene)induced conversion of somatic cells into pluripotent stem cellsiPS(induced pluripotent stem)cellProperly reprogrammed iPS cells exhibit:1)Loss of somatic cell-specific markers,expression of the appropriate stage-specific embryonic antigens2)X chromosome reactivation(in female cells)3)Reactivation of endogenous genes essential for pluripotency and self renewal(e.g.Sox2,Oct4,and Nanog)iPS(induced pluripotent stem)cellProperly reprogrammed iPS cells exhibit:4)Fully reprogrammed mouse iPS cells are germline competent Cancer Stem TheoryAdult tissues contain dormant embryonic remnants,but maintained the potential to become cancerousCancer arises from embryonic-like cellsCancer arises from a subpopulation of tumour stem cellsHuman Embryonic Stem Cell Microenvironment Model1)Compact colonies of Human embryonic stem cell(hESCs)are seeded onto a 3-D matrix fro 3-4 days2)hESCs are removed,resulting in a conditioned 3-D matrix(CMTX)3)Human metastatic melanoma cells are seeded onto the conditioned CMTX and incubated for 3-4 days4)The changes in cell morphology,gene expression as well as the behavioral functions of the tumor cell can be examinedHuman Embryonic Stem Cell Microenvironment ModelResults:1)Alteration in cell morphology(panel b)2)Induced expression of MLANA,melanocyte marker,in metastatic nmelanoma cells on an hESC CMTX(panel c)3)Cultured in two different conditions,showing reduction(42%)in the invasiveness of cultured cells(panel d)4)In vivo tumor formation was reduced in nude mice that received orthotopic injection of metastatic melanoma cells cultured on an hESC CMTX compared with the injection of metastatic melanoma cells cultured on an unconditioned matrix(panel e).Transplantation of Metastatic Melanoma Cells into the Zebrafish EmbryoNodal Signaling PathwayFGF Signaling Pathway1)Limb Development(chick and mouse)2)Somite Development(chick,mouse and zebrafish)Wnt Signaling Pathway1)Cell lineage determination(worm)2)Mesoderm patterning(Frog)3)Limb bud development(chick and mouse)4)Somite Development(mouse)Bmp Signaling1)Body axis formation(Drosophila and frog)2)Mesoderm patterning(Drosophila and frog)3)Neural and non-neural ectoderm formation(Drosophila and frog)4)Cardiac Development(chick,mouse and zebrafish)Nodal Signaling1)Mesoderm pattern(Frog)2)Cardiac Development(chick,mouse and zebrafish)Notch Signaling pathway1)Cell lineage determination(Drosophila and Frog)2)Vulva Development(worm)3)Somite Development(chick,mouse and zebrafish)