Bài giảng Cơ sở phân tử tính tự làm mới

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Mời các bạn tham khảo bài giảng Cơ sở phân tử tính tự làm mới do TS. Trần Hồng Diễm biên soạn sau đây để nắm bắt được những kiến thức về phân bào đối xứng, phân bào bất đối xứng, quá trình phân bào bất đối xứng và một số kiến thức khác.

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Nội dung Text: Bài giảng Cơ sở phân tử tính tự làm mới

CƠ SỞ PHÂN TỬ TÍNH TỰ LÀM MỚI 10/10/2015 TS. Trần Hồng Diễm PTN Nghiên cứu và Ứng dụng Tế bào gốc Trường Đại học KHTN - Đại học Quốc Gia Tp. HCM
SELF-RENEWAL Sự tự làm mới (self-renewal) là quá trình tạo ra những bản sao tế bào gốc thông qua quá trình nguyên phân tạo ra Ít nhất 1 tế bào chị em vẫn giữ khả năng tự làm mới và biệt hoá •  Phân bào đối xứng (Symmetric cell division) •  Phân bào bất đối xứng (Asymmetric cell division)
PHÂN BÀO ĐỐI XỨNG •  Tạo ra 2 tế bào gốc •  Sự tự làm mới bởi quá trình phân bào đối xứng thường gặp ü  ở các tế bào gốc nhất thời, chúng xuất hiện trong quá trình phát triển của phôi ở GĐ sớm để gia tăng kích thước cơ thể ü  Trong quá trình tái sinh sau tổn thương
PHÂN BÀO BẤT ĐỐI XỨNG •  Tạo ra 1 tế bào gốc và 1 tế bào biệt hoá hoặc 1 tế bào gốc với khả năng biệt hoá có giới hạn •  Sự tự làm mới bởi quá trình phân bào bất đối xứng có thể thấy ở các tế bào gốc trong phôi ở giai đoạn phát triển muộn và trong cá thể trưởng thành để duy trì cân bằng nội mô
Spindle orientation and asymmetric division in neuronal stem cells Y.M. Yamashita et al. Drosophila A Apical Neuroectoderm Symmetric Asymmetric Symmetric mouse (mutant situation) B Apical Symmetric Asymmetric Figure 3. Spindle orientation and asymmetric division in Drosophila and mouse neuronal stem cells. (A) In
nants. Although each germline stem cell is marked by a cytoplasmic aorganelle called the ‘spectrosome’, the b function of this asymmetrically “Chiến lược” phân bào của tế bào gốc a Tế bào gốc b Phân bào bất đối xứng Self-renewal Generation of differentiated cells Self-renewal Generation of differentiated cells c Phân bào đối xứng d Sự kết hợp các quá trình phân bào Stem-cell population Stem-cell population c d Stem-cell population Stem-cell population •  “Chiến lược” tế bào gốc nhằm duy trì sự cân bằng tế bào gốc và Figure 1 | Stem-cell tế bào con biệt strategies. hoá a, Stem cells (orange) must accomplish the dual •  Sự kiểmtask of self-renewal soát andgiữa cân bằng động generation tế bào of differentiated gốc và tế bào đãcells biệt(green). hoá cần thiết cho sửa chữa sau khi tổn thương hoặc bệnh. b–d, Possible Figure stem-cell 1 | Stem-cell strategiesa,that strategies. Stemmaintain a balance cells (orange) mustofaccomplish stem cells and differentiated the dual task ofprogeny. b, Asymmetric self-renewal cell division: and generation each stemcells of differentiated cell(green). generates Morrison SJ, Kimble J. (2006) Asymmetric and symmetric stem-cell divisions in development and cancer. Nature, 29;441(7097):1068-74.
NATURE|Vol 441|29 June 2006 INSIGHT REVIEW NATURE INSIGHT REVIEW NATURE Tế bào gốc có thể linh hoạt phân bào cả Figure 5 | Stem cells can facultativelyINSIGHT INSIGHT REVIEW use both INSIGHT REVIEW REVIEW NATURE NATURE NATURE symmetric and asymmetric divisions. a, Division đối xứng và bất đối xứng a b Figure 5 | Stem cells can facult c in the plane of the epithelium generates a two b Figure 5 | Stem symmetric and cells can facult asymmetric div morphologically similar daughter cells that are both Symmetric Asymmetric symmetric in the plane and of asymmetric the epithelium div a Symmetric b Asymmetric Figure in the 5 | Stem plane of cells the can facultg epithelium g likely to be stem cells (orange). Grey aline, basement b Figure symmetric5 | Stem morphologically and cells can facult similar asymmetric daughdiv Figure 5 | Stem morphologically cells can similar facult daugh membrane. b, Division perpendiculara to the plane Symmetric b Asymmetric symmetric likely in the to be and plane stem asymmetric of the cells (orange) epithelium divg Symmetric Asymmetric symmetric likely to be and stem asymmetric cells (orange) div of the epithelium generates one stem cell and one Symmetric Asymmetric in the plane b, membrane. morphologically ofDivision thesimilar epithelium perpen daugh g in the plane membrane. of the b, Divisionepithelium perpen g differentiated daughter (green). Such asymmetric morphologically of the likely epithelium to be stem similar generates cells daugh (orange) on morphologically of the to epithelium similar generates daughon divisions by stem cells are thought to predominate likely be stem differentiated membrane. cells b, daughter Division (orange) (green perpen c likely to be stem differentiated cells (orange) daughter (green during late fetal development and adulthood c in the membrane. divisions of byb, the epithelium Division stem perpen cells are generates thou on membrane. divisions b, byfetalDivision stem perpen cells are thou basal layer of epithelia7,61 and in the ventricular zone Symmetric Expansion of the during epithelium late differentiated generates development daughter (green ona c Symmetric Expansion of the epithelium during late fetal generates development ona of the brain40,53. Although spindle orientation seems differentiated basal layerbyofstem divisions daughter epithelia (green 7,61 cells 7,61 are and thou i c differentiated basal layer of daughter epithelia (green and i to correlate with cell fate in this manner c in various Symmetric Expansion divisions of the during brain latebyfetal stem 40,53 . cells are spin Although development thou a Symmetric Expansion divisions of the brain by stem 40,53 cells . Although are thou spin systems, it is not an obligate relationship •  Phân bào đối xứng -> tăng sinh nguồn TBG trong because Symmetric Expansion during to basal during to late correlate quá layer fetal ofwith late fetal correlate development cell epithelia with fate 7,61 in development cell and thi 7,61 in thia fate ia current data on progenitor identity and daughter basal layer systems, of thelayer it brain of is epithelia not 40,53 an obligate . Although 7,61 and spinre i basal of epithelia and rei cell fates are incomplete, and divisions in trình the plane phát triển phôi systems, of the current to it is brain data correlate not 40,53 on with 40,53 an obligate . progenitor Although cell fate inspin ide thi of the current brain data . Although on progenitor spin c of the epithelium can sometimes yield • dd progenitors Phân bào bất đối xứng -> tăng sinh số lượng cell to tếcorrelate fates systems, bàoare it iswith not cell incomplete, fate and an obligate in ide thi red to correlate cell fates are with cell incomplete, fate andin thi 54 that acquire different fates . c, During development, Asymmetric systems, of it is the epithelium current data not on an obligate can sometim progenitor red ide Steady systems, it is not an obligate re symmetric divisions expand the stem-cellbiệt pool. hoá trong thời Steady kì thai nghén Asymmetricgiữa và muộn of the current that cell epithelium data acquire fates are can on progenitor different incomplete, sometim fates 54 and ide . c,d d state current that data acquire on progenitor different fates 54ide c, . th d, In healthy adults, divisions perpendicular d to the state cell of fates symmetric the are incomplete, divisions epithelium canexpand and sometim d d Steady Asymmetric cell fates aredivisions symmetric incomplete, expand andth d epithelial plane typically maintain normal numbers Steady Asymmetric of d, the In that epithelium healthy acquire adults, different can sometim divisions fates 54 . c, Steady state Asymmetric of d, the epithelium Inacquire healthy adults, can sometim divisions 54 of stem cells and differentiated cells in the basal that epithelial symmetric different plane typically divisions expand c, 54. th fatesmain state that acquire epithelial different plane fatesmain typically . c, layer of epithelia and in the subventricular zone of state symmetric of d, stem In cells healthy divisions and expand differentiated adults, divisions th symmetric of stem cells divisions and expand th differentiated the brain. e, In healthy adults, cells can be lost d, In layer healthy of epithelial epithelia planeadults,and divisions in the typically main su d, In healthy layer of epitheliaadults,and divisions inadults, the su to injury (X). Symmetric divisions are proposed to epithelial the of brain. stem plane e, cells In and typically healthy main differentiated e epithelial plane typically main regenerate additional stem cells, and-> duy trì kích thước easymmetric the to brain. of stemof cells injury layer e, In (X). and epithelia healthy adults, differentiated Symmetric and in the divis su Injury Symmetric of stem to injury cells (X). and differentiated Symmetric divis divisions to regenerate differentiated daughters. Injury Symmetric layer of regenerate the brain. epithelia additional e,additionaland In healthy in stemthe adults, su cel e layer of epithelia regenerate and in stemthecelsu f, We speculate that defects in regulation of the and the brain. divisions to injury e, to (X). In healthy regenerate Symmetric adults, differe divis e and asymmetric the brain. divisions e, In healthy to regenerate adults, differe switch between symmetric and asymmetric e Injury Symmetric asymmetric to injury f, We (X). speculate regenerate Symmetric that defects additional stem divis in cel Injury Symmetric to f, injury We (X). speculate Symmetric that defects divis in divisions can be deleterious. Left, a defect favouring Injury Symmetric and regenerate switch between divisions additional symmetric toadditional regenerate stem differecel and asymmetric and regenerate switch between symmetric stem cel and symmetric divisions results in tumorigenesis. and divisions f, to canregenerate We speculate bethat differe deleterious. defects inL asymmetric asymmetric divisions divisions to can regenerate be differe deleterious. L Chú Right, thích: a defect favouring asymmetric divisions -> Hồi phục nguồn TBG bị mất đi do tổn thương, f, We speculate symmetric switch bệnh f, between We speculate that divisions defects results symmetric that defects in in and in results in decreased capacity for tissue symmetric divisions results in Reduced f repair. Both switch Right, divisions switch Right, abetween defect abetween defect symmetric can befavouring deleterious. symmetric favouring and asym and asym L :Tế bào chị and tumorigenesis em poor biệt f are typical hoá healing wound divisions results in can be decreased deleterious. capacity Lf repair Cancer Cancer Reduced symmetric divisions results candivisions be in decreased results deleterious. capacity inLf of ageing :Tế bào animals, gốc (TBG) raising the question of whether Defective Defective Reduced symmetric tumorigenesis Right, a divisions defect and favouringresults poor woun asym in f Defective or Defective repair symmetric tumorigenesis divisions and results poor woun in defects in switch :Basement mechanisms accumulate membrane f with age. repair Right, of ageing results aindefect animals, favouring decreased raising capacity asym thef f regulation Cancer or regulation Reduced Right, of ageinga defect animals, favouring raising asym thef regulation Cancer regulation results defects in in tumorigenesis decreased switch and capacity mechanisms poor woun Defective Cancer Defective Reduced repair results defects in decreased in switch capacity mechanisms f Defective or Defective Reduced repair tumorigenesis of ageing animals, and poor woun raising the Defective Defective repair tumorigenesis and poor woun is also frequently deleted Morrison SJ, in cancer Kimble 77,78 J. (2006), and deletion Asymmetric -> Rối loạn and of the corresponding regulation regulation điều hoà phân or or bào có regulation thể dẫn đến ung regulation of ageing defects of ageingthư inanimals, raising the switch mechanisms animals, raising the gene in mice leads to a loss of polarity and dysplasia in Stem-cell the central nervous regulation divisions and cancer regulation defects in switch77,78mechanisms symmetric stem-cell divisions in development and cancer. Nature, 29;441(7097):1068-74. hoặc suy giảm khả năng sửa chữa mô Stem-cell divisions and cancer is also frequently deleted in defects cancer in switch77,78 , and deletion mechanisms is also frequently deleted in cancer , and deletion system79. Loss of Numb may be involved in the hyperactivation of Notch The capacity for symmetric stem-cell self-renewal may confer devel- gene in mice leads to a loss of polarity and dysplasia The capacity Stem-cell for symmetric divisions stem-cell self-renewal may confer devel- and cancer gene is alsoinfrequently mice leadsdeleted to a lossinofcancer polarity 77,78and dysplasia pathway signalling observed in breast cancers80,81. Although these plasticity, opmental gene increased growth and enhanced regenerative system 79 79. Loss of Numb may be involved 77,78 , and indeletion the hyp
(Tế bào gốc tạo máu) Blank U, Karlsson G, Karlsson S.(2008). Signaling pathways governing stem-cell fate. Blood.,111(2):492-503.
C. elegans C. elegans life cycle at 22˚C (artwork by Altun and Hall, © Wormatlas)
current data on progenitor identity and daughter d cell fates are incomplete, and divisions in the plane Steady Asymmetric of the epithelium can sometimes yield progenitors Phân bào đối xứng của tế bào mầm C. elegans state that acquire different fates54. c, During development, symmetric divisions expand the stem-cell pool. d, In healthy adults, divisions perpendicular to the trong giai đoạn phát triển epithelial plane typically maintain normal numbers of stem cells and differentiated cells in the basal layer of epithelia and in the subventricular zone of the brain. e, In healthy adults, cells can be lost e INSIGHT REVIEW to injury (X). Symmetric divisions are proposed to Injury Symmetric regenerate additional stem cells, and asymmetric and divisions to regenerate differentiated daughters. asymmetric f, We speculate that defects in regulation of the INSIGHTswitch REVIEW between symmetric and asymmetric a b divisions can be deleterious. Left,that seem a defect to be un favouring a zone wherethatstem symmetric divisionsbresults in tumorigenesis. seem to bec Right, a defect favouring asymmetric divisionszone where ste f Cancer Reduced Chú results thích: in decreased capacity for epidermis seemseem tissue repair. Both epidermis to tumorigenesis and poor wound healing are equivalent und typical Defective or Defective repair :Tế bào chị em biệt hoáequivalentepidermis undiffe whe regulation regulation of ageing :Tế bào animals, gốc (TBG)raising the question of whetherhowever, that m epidermis defects in switch mechanisms accumulate where withlocations age. know s :Ổ tế bào gốc mental potentia however, that potentialmor or fat divisions of ste Stem-cell divisions and cancer is also frequently c deleted in cancer77,78, and d deletionlocations known considered prot of the corresponding The capacity for symmetric stem-cell self-renewal may confer devel- gene in mice leads to a loss of polarity and dysplasia mental potentials. in the central nervous Symmetric di Morrison SJ, Kimble J. (2006) Asymmetric and symmetric stem-cell opmental plasticity, increased growth and enhanced regenerative system79. Loss of Numb may be involved in the hyperactivation of Notch Symmetric stem divisions in development and cancer. Nature, 29;441(7097):1068-74. 80,81 potential or fate, i capacity; however, it may also confer an inherent risk of cancer. Nor- pathway signalling observed in breast cancers . Although thesethey genecan also be ovary. As descr mally, Drosophila neuroblasts divide asymmetrically3 as a result of the products could inhibit tumorigenesis through various divisions mechanisms ofmally stem that c divide asy asymmetric localization of cortical cell polarity determinants (such as are independent of their effects on cell polarity, the fact that these genes cells can be ind Partner of Inscuteable (PINS) and aPKC) and cell fate determinants consistently function as tumour suppressors suggests considered provis tional that asymmetric stem cell c d cell is removed -> Ấu trùng nở ra từ trứng với chỉ 2 tế bào gốc mầm duy (for example, Numb and Prospero), and regulated alignment of the division itself may protect against cancer. stem cells are re Recent exper mitotic spindle (Fig. 2). When the machinery that regulates asymmet- Further evidence for the link between symmetric Symmetric cell divisions anddivis nhất, nhưng trong giai đoạn phát triển ấu trùng về sau, germline stem ric divisions is disrupted, however, these neuroblasts begin dividing cancer is the observation Figure that some 3 | Symmetric divisions gene products in the developing C. elegans germ can line. both inducetheir distinct c symmetrically and form tumours42,70,71. symmetric a,cell divisions C. elegans germlineand function divisions as oncogenes during development Symmetric are symmetric inwith mammalian stem-c germline stem những tế bào mầm này tăng sinh để tạo ra khoảng 2000 tế Cell clones lacking PINS are tumorigenic42,71, and double mutant respect to size and morphology of daughter cells, cleavage plane and cells. One example is aPKC, 46 position . Continued thedivisions mitotic atypical protein rely on they signallingkinase can also that normally from the stem-cell regulators: in th was be obs ectopically cells lacking both PINS and Lethal giant larvae (LGL) generate a localizes to the nicheapical cortex cells are of the neuroblast cellsas arepart green;of thethe PAR–aPKC 5,46,87 . Stem orange; differentiated stem- tis, the stat92E bào con trong tuyến sinh dục trưởng thành gồm các tế brain composed largely of symmetrically dividing and self-renewing complex. Neural-specific (marked with a cross)expression of a constitutively during early (shown) ovary. activeAs cell niche is red. b, Elimination of one or more germ cells by laser ablation or later larval development describe ture-sensitive m variant of of th expression neuroblasts42. Cell clones lacking the cell fate determinants Numb or bào mầm chưa biệt hoá và các tế bào con đang biệt hoá. aPKC causes a large 5 increase in symmetrically mally divide asym does not affect the ability to generate pools of stem cells and differentiated dividing cells . Mitotic germ cells are therefore developmentally equivalent. neuroblasts 42 germline . stem c Prospero are tumorigenic and can be propagated after transplantation Consistent c,with this tumorigenic potential in Drosophila, at the new positionaPKC and has ce adopted cells stem-cellcan pool. be induce 5 Repositioning the niche induces germline stem cells . d, Niche duplication results in duplication of the germline (Fig. 4c). When into new hosts71. Moreover, these tumour cells have been shown to been also identified Niche duplication as has anbeen oncogene accomplished inbyhuman alterations lung in eithercancers the cell- 82,83 . We the differentiati become aneuploid within 40 days of adopting a symmetric mode of speculate that cycleasymmetric machinery or division 47,48,50 mayspecification regulators of niche suppress tional 49,51 stema stem-cell carcinogenesis, . cellin aftfate The simplest division71. This finding indicates that invertebrate cells are capable of addition to itsSeveral rolelinesin maintaining a balance between of evidence show that C. elegans germcell isstem cells divide cells and stem c removed sym- germlinefrom rapid neoplastic transformation. An intriguing possibility is that the differentiated progeny. metrically during larval development. First, these divisions produce them in differe capacity to divide symmetrically may be a prerequisite for neoplastic Symmetric daughters modes of of equal size and morphology, division may not only and they stem are variable promote cells the with are regu (Fig. 4d). expansion Thes
NATURE|Vol 441|29 June 2006 Phân bào đối xứng INSIGHTcủa tế bào mầm C. elegans REVIEW INSIGHT REVIEW trong giai đoạn phát triển (tt) Figure 5 | Stem cells can facultatively use both symmetric and asymmetric divisions. a, Division c in the plane of the epithelium generates two morphologically similar daughter cells that are both a b that see likely to be stem cells (orange). Grey line, basement a b that zonesee wh membrane. b, Division perpendicular to the plane of the epithelium generates one stem cell and one zone wh epiderm differentiated daughter (green). Such asymmetric divisions by stem cells are thought to predominate epiderm equivale Trong giai đoạn phát triển dòng during late fetal development and adulthood in the equivale epiderm basal layer of epithelia7,61 and in the ventricular zone mầm,tế bào mầm C. elegans tạo ra of the brain40,53. Although spindle orientation seems epiderm howeve to correlate with cell fate in this manner in various howeve location tế bào con tương đương về tiềm systems, it is not an obligate relationship because location current data on progenitor identity and daughter năng phát triển, những tế bào con mental p cell fates are incomplete, and divisions in the plane mental potentiap c of the epithelium can sometimes yield progenitors này có số phận riêng tuỳ vào vị that acquire different fates54. c, During development, potentia division trí và số lượng ổ tế bào. symmetric divisions expand the stem-cell pool. d, In healthy adults, divisions perpendicular to the division conside epithelial plane typically maintain normal numbersc d conside c of stem cells and differentiated cells in the basal d layer of epithelia and in the subventricular zone of Symme the brain. e, In healthy adults, cells can be lost Symme Symmet to injury (X). Symmetric divisions are proposed to c regenerate additional stem cells, and asymmetric Symmet they can c divisions to regenerate differentiated daughters. they ovary.canA f, We speculate that defects in regulation of the INSIGHTswitch REVIEW between symmetric and asymmetric NATURE|Vol 441|29 June 2006 ovary. mally di A divisions can be deleterious. Left, a defect favouring symmetric divisionsbresults in tumorigenesis. that seem to be undifferentiated and lie side by side in the ventricular mally di cells can a Right, a defect favouring asymmetric divisionszone where stem cells are located. Similarly, cell divisions in the fetal Chú results thích: cells tionalcanst in decreased capacity for tissue repair. Both Reduced tumorigenesis and poor wound healing are epidermis seem to be largely symmetric, generating morphologically equivalent undifferentiated cells in the plane of the basal layer of the typical tional st cell is re repair :Tế bào chị em biệt hoá n of ageing :Tế bào animals, gốc (TBG) epidermis where stem cells are present7. It remains formally possible, raising the question of whether however, that morphologically and positionally equivalent progeny in cell stemiscel re defects in switch mechanisms accumulate withlocationsage. known to contain stem cells could have different develop- :Ổ tế bào gốc mental potentials. Thus, without direct information on developmental stem cel Recen potential or fate, inferences regarding symmetric versus asymmetric divisions of stem cells are based on incomplete criteria and should be Recen germlin is also frequently deleted in cancer77,78, and deletion of the corresponding c d considered Morrison provisional. SJ, Kimble J. (2006) Asymmetric and symmetric stem-cell divisions in development and cancer. Nature, 29;441(7097):1068-74. germlin gene in mice leads to a loss of polarity and dysplasia in the centralFigure nervous3 | Symmetric Symmetric divisions can persistdivisions in the developing C. elegans germ line. into adulthood their di system . Loss of Numb may be involved in the hyperactivationFigure 79 of Notch3 |stem-cell Symmetric Symmetric divisions aredivisions in the common in developing developing tissues, but C. elegans germ line. their di
regulation change make a development current data on progenitor identity and d d to predominantly asy cell fates are incomplete, and divisions in of the epithelium can sometimes yield pr d Steady Asymmetric Phân bào đối xứng của tế bào mầm trong caveat, however, is tha that acquire different fates54. c, During d state symmetric divisions expand the stem-ce Symmetric Asymmetric from other progenito d, In healthy adults, divisions perpendic C.divisionelegans trưởng thành (tt) epithelial plane typically maintain norm fate so it remains possible of stem cells and differentiated cells in th layer of epithelia and in the subventricu e divisions of stem cells the brain. e, In healthy adults, cells can b to injury (X). Symmetric divisions are p undifferentiated cells Injury Symmetric regenerate additional stem cells, and asy e and divisions to regenerate differentiated da DTC (Nhân dòng mầm trong giai đoạn sớm của giảm phân có hình liềm) asymmetric INSIGHTswitch Only limited data ar f, We speculate that defects in regulation REVIEW between symmetric and asymme Expression of regulators mammalian stem cel divisions can be deleterious. Left, a defe symmetric divisionsbresults in tumorige f promoting differentiation a escent most of the tim Right, a defect favouring asymmetric di results in decreased capacity for tissue r makes them technicall Cancer Reduced Chú tumorigenesis thích: Defective Defective repair and poor wound healing or of ageing animals, raising the question o Mitotically dividing cells regulation Early meiotic prophaseregulation whether homeostasis i :Tế bào gốc (TBG) defects in switch mechanisms accumula f chịu trách nhiệm gcho tính tự làm h khi rời khỏi ổ tế bào gốc, sự by a population strate :Ổ tế bào gốc DTC Stem-cell DTC tế divisions mới và làm giàu nguồn bào mầmand cancer biệt hoá thành tế bào con is The capacity for symmetric stem-cell self-renewal may confer devel- also frequently xảy ra cells DTCdeleted :Distal c and in cancer , differentiate tip cell 77,78 and deletion of the co gene in mice leads to a loss of polarity and dysplasia in the cen d opmental plasticity, increased growth and enhanced regenerative 79 system . Loss of Numb starting may be involved to indicate in the hyperactivat tha * * capacity; however, it may also confer an inherent risk of cancer. Nor- pathway signalling observed in breast cancers . Althoug 80,81 mally, Drosophila neuroblasts divide asymmetrically as a result of the 3 products could inhibit cally under tumorigenesis steady-stat through various mech -> Phân bào asymmetric đối xứng localizationcũng gặp phổ biến (such ở as C. elegans trưởng of cortical cell polarity determinants Partner of Inscuteable (PINS) and aPKC) and cell fate determinants are independent In the of their effects subventricular on cell polarity, the fact that consistently function as tumour suppressors suggests that thành (for example, Numb and Prospero), and regulated alignment of the metric division itself may protect against divisions cancer. pred -> Trong giai đọan phát triển ấu trùng và trưởng thành, tế bào mitotic spindle (Fig. 2). When the machinery that regulates asymmet- Further evidence for the link between symmetric cell d Figure 4 | Symmetricricstem-cell gốc mầm C. elegans divisions in the adult germ divisions is disrupted, however, these neuroblasts begin dividing được duy trì line. bởi tín hiệu cancer a–d, Adult từ is ổ some apparently the observation that some gene products can b sym celltế bào gốc.as oncogenes in m Figure 3 | Symmetric divisions in the developing C. elegans germ line. Drosophila germline stem cells. a, Germline stem-cell divisions in the ovary 42,70,71 symmetrically and form tumours . symmetric divisions and function is aPKC, the analyses clonal atypical proteinbased a, C. elegans germline divisions during development are symmetric wi respect to size and morphology of daughter cells, cleavage plane and Ổ DTC sử dụngCell tíncloneshiệu lacking PINS are tumorigenic Notch để kiểm 42,71 , and double soát mutant tế bàocells. One example gốc mầm. kinase th position46. Continued mitotic divisions rely on signalling from the stem are normally asymmetric. Theboth cells lacking niche PINS (red) and Lethalcontains giant larvae 2–3 germline (LGL) generate a stem cells localizes to the apicalsupport the cortex of the neuroblast idea as partthat of the niche5,46,87. Stem cells are orange; differentiated cells are green; the stem cell niche is red. b, Elimination of one or more germ cells by laser abla brain composed largely of symmetrically dividing and self-renewing complex. Neural-specific expression of a constitutively acti (orange). Each divides with a mitotic spindle oriented toward the niche, 42 neuroblasts . Cell clones lacking the cell fate determinants Numb or (marked with a cross) during early (shown) or later larval developmen aPKC causes a large metrically increase in symmetrically 65,66 . Homeo does not affect the ability to generate pools of stem cells and differenti dividing ne cells5. Mitotic germ cells are therefore developmentally equivalent. retaining one daughter in the Prospero niche and are tumorigenic placing and can the other be propagated outside theConsistent after transplantation niche with this tumorigenic potential in Drosophila been also identifiedapparently as an oncogene inasymmetri c, Repositioning the niche induces germline stem cells at the new posi 71 d, Niche duplication results in duplication of the germline stem-cell po into new hosts . Moreover, these tumour cells have been shown to human lung can (green). b, Elimination of one germline stem cell (marked with a cross) leads Niche duplication has been accomplished by alterations in either the c become aneuploid within 40 days of adopting a symmetric mode of to symmetric stem-cell division of the other germline stem cell . addition to itsSeveral Morrison SJ, Kimble J. 71 division . This finding indicates that invertebrate cells are 19of capable rolelines Although speculate that asymmetric division may suppress carcin (2006) Asymmetric and symmetric stem-cell divisions in development and cancer. Nature, 29;441(7097):1068-74. in maintaining a balance some between adu cycle machinery47,48,50 or regulators of niche specification49,51. ste of evidence show that C. elegans germ cells divide c, Daughters of germline rapid neoplastic transformation. An intriguing possibility is that the capacitystem-cell divisionmay to divide symmetrically have equivalent be a prerequisite for neoplastic differentiated developmentalSymmetric progeny. metrically daughters modes steady-state during of of equal size and morphology, division may not only condition larval development. First, these divisions pro and they are variable promote th
e division the brain. e, In healthy adults, cells can be lost to injury (X). Symmetric divisions are proposed t Injury Symmetric undiffe regenerate additional stem cells, and asymmetric e and Phân bào đối xứng của tế bào mầm trong asymmetric divisions to regenerate differentiated daughters. DTC INSIGHTswitch REVIEW Only f, We speculate that defects in regulation of the between symmetric and asymmetric C. elegans trưởng thành Expression(tt) mamm divisions can be deleterious. Left, a defect favouri of regulators a symmetric divisionsbresults in tumorigenesis. tha f Cancer promoting differentiation Reduced Chú tumorigenesis thích: escent m Right, a defect favouring asymmetric divisionszon results in decreased capacity for tissue repair. Bot epi equ Defective regulation or Defective regulation repair of ageing :Tế bào animals, makes t and poor wound healing are typica raising the question of whethe gốc (TBG) epi how defects in switch mechanisms accumulate withloc ag Mitotically dividing cells Early meiotic prophase :Ổ tế bào gốc whethe me pot f Stem-cell divisions g and cancer h DTCdeleted is also frequently :Distal c tip cell in cancer 77,78 bycorrespond , and deletion of the d a po div con The capacity for symmetric stem-cell self-renewal may confer devel- gene in mice leads to:Distal-most a loss of polarity and dysplasia in the central nerv DTC opmental plasticity, increased growth and enhanced regenerative system . Loss of*Numb may be involved in the hyperactivation DTC 79 germ cells cellsofan 80,81 No Sym Sym capacity; however, it may also confer an inherent risk of cancer. Nor- pathway signalling observed in breast cancers . Although these ge the products could inhibit tumorigenesis through variousstarting ova * 3 mally, Drosophila neuroblasts divide asymmetrically as a result of the mechanisms t ma * Partner of Inscuteable (PINS) and aPKC) and cell fate determinants consistently function as tumour suppressors suggestscally asymmetric localization of cortical cell polarity determinants (such as are independent of their effects on cell polarity, the fact un that these ge that asymmet cell tion cell (for example, Numb and Prospero), and regulated alignment of the mitotic spindle (Fig. 2). When the machinery that regulates asymmet- division itself may protect against cancer. Further evidence for the link between symmetric cell Indivisions the sa stem ger R symmetric cell divisions and function as oncogenesmetric ric divisions is disrupted, however, these neuroblasts begin dividing cancer is the observation that some gene products can both indu Figure 3 | Symmetric divisions in the developing C. elegans germ line. the 42,70,71 symmetrically and form tumours . in mammal a, C. elegans germline divisions during development are symmetric with ger •  Figure 20% sự phân bào TBGDM C. elegans duy trì cả những tế bào con respect to size and morphology of daughter cells, cleavage plane and reg 4 |cells Symmetric stem-cell divisions in the adult germ line. a–d, Adult some ap 42,71 Cell clones lacking PINS are tumorigenic , and double mutant cells. One example is aPKC, the atypical protein kinase that norma position46. Continued mitotic divisions rely on signalling from the stem-cell was trong ổ TBG lacking both PINS and Lethal giant larvae (LGL) generate a localizes to the apical cortex of the neuroblast as part of the PAR–aP niche5,46,87. Stem cells are orange; differentiated cells are green; the stem- tis, Drosophila germline stem cells.C. a,dividing Germline stem-cell divisions inở thenhững ovary cell niche is red. b, Elimination of one or more germ cells by laser ablation brain •  80% sự neuroblasts composed largely phân .bào 42 of symmetrically TBGDM elegans and self-renewing Cell clones lacking the cell fate determinants Numb or đặt complex. tế bào Neural-specific con expression aPKC causes a large increase in symmetrically clonal of a constitutively active varian (marked with a cross) during early (shown) or later larval development vịdividing a does not affect the ability to generate pools of stem cells and differentiated neuroblast tur exp ger are trínormally asymmetric. The nicheổ(red) contains Consistent 2–3 germline stem cells 5 cells . Mitotic germ cells are therefore developmentally equivalent. khácProspero nhau are tumorigenic theo and 71 tíncan behiệu propagated after into new hosts . Moreover, these tumour cells have been shown to transplantation TBG with this tumorigenic suppor potential in Drosophila, aPKC h c, Repositioning the niche induces germline stem cells at the new position5. d, Niche duplication results in duplication of the germline stem-cell pool. 82,83 been also identified as an oncogene in human lung cancers . and (Fig •  (orange). Eachaneuploiddivides with akhông mitotic a spindle oriented toward the cứ niche, Niche duplication has been accomplished by alterations in either the cell- the Tế bào become mầm C. elegans within 40 days of adopting phân symmetric chia mode of dọc theo speculate bất that asymmetric trục division metrica cụ carcinogenesis may suppress cycle machinery47,48,50 or regulators of niche specification49,51. a st retaining oneneoplastic daughter in the niche and placing the differentiated other outside the niche 71 T division thể nàorapid . This finding indicates that invertebrate cells are capable of addition to its role in maintaining a balance between stem cells a apparen Several lines of evidence show that C. elegans germ cells divide sym- ger transformation. An intriguing possibility is that the progeny. metrically during larval development. First, these divisions produce the (green). b,capacity Elimination of one to divide symmetrically maygermline be a prerequisite stem cell (marked for neoplastic Symmetricwith modes a cross) of division may leads daughters of equal size and morphology, and they are variable with (Fi not only promote the expans for secondaryAltho respect to both plane of cleavage and daughter cell position46. Second, dep Khác với transformation to symmetric C. elegans stem-cell and that cancer may reflect, at least in part, the capacity division , sự to adopt a symmetric mode of cell division. phân of the bàoother củagermline TBGDM of stem-cell numbers, stemở cell 19but also be permissive Drosophila . được events le one or more germ cells can be removed by laser ablation without elimi- (Fi ing to aneuploidy. Consistent with this possibility, the machinery t nating the capacity of the stem cells for both self-renewal and generation rev định hướng c, Daughters theo The machinery of tín germline hiệu that promotes stem-cellổ asymmetric TBG. cell divisions has an evolu- 2,72division tionarily conserved role in tumour suppression . The adenomatous poly- have controls asymmetric division also regulates the orientation equivalent 29,41,42 spindles developmental steady- of gametes5 (Fig. 3b). Third, experimental repositioning of the stem- nic of mito cell niche during early development — a time when all germ cells are stem . A potential source of aneuploidy in symmetrically div proliferating — results in maintenance of the stem-cell fate by whatever cou potential:spermatogonial germlinestem stem cells in the niche can posis coli (APC) gene is required for the asymmetric division of Drosophila 29 cells and is an important tumour suppressor in be induced to express cellular to resto germ cells happen to be located near the new niche position5 (Fig. 3c). cal ing fly neuroblasts is a defective centrosome — either abnormal in shape — that presumably leads to errors in chromoso duplicated Last, duplication of the niche results in duplication of germline stem- S been ob 47–51 Morrison SJ, Kimble J. (2006) Asymmetric and symmetric stem-cell divisions in development and cell pools cancer. (Fig. 3d). Thus, Nature, during the expansion phase of germline ger 29;441(7097):1068-74. 52,56 function by tumour su markers of the differentiation mammalian intestinal epithelium (green) 73–75 . It isby manipulating not known whether APC stem-cell 71 segregation . Theregulators development, regulation of centrosome . C. elegans germ cells generate daughters with equivalent hav developmental potential, and these daughter cells ultimately acquire ing regulates asymmetric division by stem cells in the intestinal epithelium, pressors is also important distinct fates dependingto avoid genomic on the position instability and number incells. of niche mammal A ren
Phân bào đối xứng và bất đối xứng trong dòng mầm Drosophila trưởng thành NATURE|Vol 441|29 June 2006 •  Phân bào đối xứng xảy ra chủ yếu trong giai đoạn phát triển mô, NATURE|Vol nhưng cũng 441|29 có June thấy ở cơ thể trưởng thành, chẳng hạn thể2006 như ở buồng trứng Drosophila trưởng thành. a symmetric or asym Asymmetric cells retain the po Asymmetric a symmetric or asy As layers of dif Asymmetric Asymmetric cells retain the p increasingly under As layers of d -> Thông thường, dòng tế bào mầm trong Drosophila trưởng in the ventricular b increasingly und thành phân bào bất đối xứng cell migrates into Symmetric Asymmetric in the ventricula b ing formation of a cell migrates int Symmetric Asymmetric predominate at em ing formation of cell that remains i predominate at e c second cell that m cell that remains -> Dòng tế bào mầm trong Drosophila Change trưởng thành được điềusecond Reverse tors that are fated c cell that m hoà để phân bào đối xứng hay bất đối xứng before differentia stem-cell regulation tors that are fated Change regulation Reverse change make a developm before differenti stem-cell regulation to predominantly d regulation change make a developm caveat, however, is Symmetric Asymmetric to predominantl from other progen Nature, Morrison SJ, Kimble J. (2006) Asymmetric and symmetric stem-cell divisions in development and cancer. 29;441(7097):1068-74. d caveat, however, division fate so it remains possi
b cell migrates into o Symmetric Asymmetric ing formation of a Phân bào đối xứng và bất đối xứng trong dòng a symmetric predominate or asym cells retain theatpos em Asymmetric Asymmetric mầm Drosophila trưởng thành (tt) cell Asthat second remains layers of diff cell that mi in c increasingly under Change Reverse tors in thethat are fated t ventricular b before differentiat stem-cell regulation cell migrates into o regulation Symmetric changeAsymmetric make a developme ing formation of a •  Tế bào con của tế bào gốc dòng mầm (TBGDM) Drosophila to predominantly predominate tương at em a d đương nhau về tiềm năng phát triển, mặc dù chúng có hình thái caveat, cell tế however, that remains isin Symmetric Asymmetric bào khác nhau. c from second other progen cell that mi hình thái TBG và chuyểnso it that remains possit division fate -> TBGDM trong Change ổ TBG được cảm ứng mấtReverse tors sang are fated đặc tính của những divisions of stem c before differentiat stem-cell tế bào biệt hoá bởi những chất điều hoà chuyên regulation biệt. Khi undifferentiated maketếa developme ce e hoạtregulation tính của những chất điều change hoà bị đảo ngược, các bào biệtDTC hoá có thể chuyển sang hình thái TBG to Only limited data predominantly d mammalian stem Expression of regulators caveat, however, is Symmetric Asymmetric promoting differentiation escent from othermostprogen of the division fate makes them techni so it remains possi Mitotically dividing cells Early meiotic prophase •  Phân bào bất đối xứng TBGDM Drosophila tạo ra những tế bào whether divisions homeosta con of stem c có tiềmfe năng phát gtriển tương h đương nhưng đặt chúng trong by a population str undifferentiated những ce DTC vị tríDTCkhác nhau đối DTCvới tín hiệu từ ổ TBG. cells Onlyandlimited different dat •  Những tế bào con có tiềm năng phát triển tương đương này sau starting đó to indicate mammalian stem * * Expression of regulators sẽ sở hữu đặc tính riêng tuỳ theo sự hiện diệndifferentiation promoting hay vắng mặt cally các escent under moststeady- of the tín hiệu từ ổ TBG. In the subventricu makes them techni Mitotically dividing cells Early meiotic prophase Nature, metric whetherdivisions homeosta Morrison SJ, Kimble J. (2006) Asymmetric and symmetric stem-cell divisions in development and cancer. pr 29;441(7097):1068-74. Figure 4 | Symmetric stem-cell divisions in the adult germ line. a–d, Adult some apparentlystr by a population sy
•  Những tế bào con có tiềm năng phát triển như nhau được tạo ra từ phân bào đối xứng của tế bào mầm C. elegans giai đoạn ấu trùng sớm, hoặc từ phân bào bất đối xứng TBGDM Drosophila
Kiểm soát quá trình phân bào bất đối xứng Tín hiệu nội sinh Tín hiệu ngoại sinh điều hoà INSIGHT REVIEW tuỳ thuộc vào vị trí trong ổ TBG, sự sắp xếp yếu tố sự chia tách các yếu tố xác các tế bào con sẽ phân cực tế bào định số phận tế bào có những số phận khác nhau a b c Phân bào bất đối xứng với số phận của những tế bào cho dù phân bào đối xứng nội sinh, bước đầu tạo nên 2 tế bào con có tiềm năng phát triển Figure tương 2 | Controls đương. of asymmetric stem-cell division. Three simple mechanisms Đối với are phânshown, bào bất but others đối xứng, are plausible. hướng thoi vô sắc For đượcmolecular điều hoà bởidetails, tín see 1–4,12,17,31 recent hiệu reviews . a, Asymmetric nội sinh lẫn ngoại sinh localization of cell polarity regulators (red) initiates the asymmetric division. Shown is asymmetric assembly Morrison SJ, Kimble J. (2006) Asymmetric and symmetric stem-cell divisions in development and cancer. Nature, 29;441(7097):1068-74.
ĐIỀU HOÀ CÂN BẰNG GIỮA PHÂN BÀO ĐỐI XỨNG VÀ BẤT ĐỐI XỨNG CỦA TBG TRONG QUÁ TRÌNH PHÁT TRIỂN NÃO RUỒI GIẤM
Drosophila Medulla neuroblast Cell cortices labled for aded by [14.161.4.38] at 23:16 06 October 2015 OL neuroepithelial cells Optic lobe neuroblasts Ü-BOEFT#JPTDJFODF Central brain neuroblasts VNC: Ventral nerve cord OPC: Outer proliferation center Figure 1. (A) TheIPC: Inner proliferation Drosophila larval nervouscenter system is composed of the ventral nerve cord (VNC), the central brain (CB) and the optic lobes (OL). At the medial edge of the me: Medulla optic cortex lobe neuroepithelium Egger B, Gold KS, Brand AH (2011). Regulating the balance cells transform sequentially into neuroblasts (red box). (B)between Pseudostratified symmetric andneuroepithelial cells division asymmetric stem cell trans- in the A: Anterior form into round neuroblasts. A single confocal section through the outer proliferation center shows immuno-labelling for Discs large, which labels cell developing brain, Fly (Austin)., 5(3):237-41. P: Posterior cortices (red). Medulla neuroblasts express the adaptor protein Miranda (green), which is segregated to the basal daughter cell upon asymmetric cell division. DNA is stained in blue. (C) The transition from neuroepithelial cells to neuroblasts involves a switch from symmetric to asymmetric division, the downregulation of adherens junctions and a change in division orientation. The neuroepithelium expands laterally with a planar spindle axis, whereas neuroblasts re-orient their division along the apicobasal axis to position their progeny towards the medulla cortex. OPC: outer proliferation center, IPC: inner proliferation center, me: medulla cortex, VNC: ventral nerve cord, A: anterior, P: posterior retina and neural tube, neuroepithelial brain centers. Each lobe is composed of hemisphere and remains closely attached to 14