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研究生:黃盈誠
研究生(外文):Yin Cheng Huang
論文名稱:染色質重組因子Mll1對於出生後神經幹細胞新生之重要性
論文名稱(外文):Chromatin remodelling factor Mll1 is essential for neurogenesis from postnatal neural stem cells
指導教授:廖順奎廖順奎引用關係
指導教授(外文):S. K. Liao
學位類別:博士
校院名稱:長庚大學
系所名稱:臨床醫學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2009
畢業學年度:97
論文頁數:100
中文關鍵詞:神經幹細胞染色植重組混合型白血病基因腦室下區組蛋白甲基化
外文關鍵詞:neural stem cellchromatin remodellingmixed lineage leukemiasubventricular zonehistone methylation
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幹細胞可以進行自我更新,增殖及分化。在於哺乳類腦中,目前已有證據哺乳類之腦室下區之存在著神經幹細胞,每天產生數以千計之神經母細胞移行至嗅葉,並分化成為中間神經元。這樣的過程牽涉至許多之控管機制,而其中外遺傳之控管是一個相當重要之機制。
染色植重組是一個控管基因活化及抑制重要機制,對於幹細胞之控管及維持相當重要。但是對於神經幹細胞,染色質重組之重要性甚少在這一個領域被討論。Trithorax 以及 polycomb 這兩組基因就是對於胚胎發育相當重要之染色植重組基因。從已經發表之論文中,有幾種基因重組因子是同時在腦室下區及嗅葉表現量增加;其中Mll1(mixed lineage leukemia-1)是trithorax基因群中之一,已經證實對於人類白血病有著致癌之作用。神經幹細胞之自我新生扮演著重要之角色。運用反轉錄多鏈反應(reversed-transcription polymerase reaction), 原位雜交反應(in situ hybridization)及基因轉殖小鼠,我們可以確認Mll1 從胚胎時期便開始表現於腦室下區。
運用一個特殊之條件性基因剔除小鼠(conditional knockout),將此小鼠與另外一品系之小鼠(hGFAP-Cre)交配,我們可以觀察到在小鼠之子代有神經新生之缺損。表現DCX(double-cortin)之神經母細胞,無法移行至嗅葉進行下一步之分化,而聚積於腦室下區。此缺損僅限於神經細胞新生,但不影響寡樹突細胞之分化或星狀細胞之分化。將攜帶Cre之腺病毒(Ad-hGFAP-Cre),注射至基因轉殖鼠之腦室下區後,可以確認此表現性狀。
在體外,我們利用神經幹細胞培養之模型,可以將神經幹細胞在體外繁殖並分化。條件性基因剔除之小鼠,在體外之神經細胞新生僅有正常小鼠之四十分之一左右;同時星狀細胞及寡樹突細胞之分化反而有代償性之增加。
在此小鼠之腦部,Mll1從胚胎時期11.5至12.5天開始剔除;因此出生後小鼠之神經新生缺損,可能並非直接來自Mll1。我們再利用短別針核醣核酸抑制(short hairpin RNA inhibition)及攜帶Cre之腺病毒,在體外培養之環境,將Mll1剔除;以這兩種方式均可以觀察到神經新生抑制之現象。
在腦室下區神經母細胞之轉譯因子表現量並非同時受到Mll1之影響;MASH1表現量正常,但是Dlx2之表現量則顯著降低,因此Dlx2可能是Mll1之下游目標基因。將攜帶Dlx2之質體轉殖入剔除Mll1之細胞當中可以觀察到神經新生之缺損有著顯著之改善。
為了進一步了解Mll1之下游基因標的,我們利用MLL之抗體進行染色質免疫沉澱試驗(chromatin immunoprecipitation)。結果顯示大量之Mll直接結合於Dlx2之位置,甚至結合至起始點上游1000個鹼基之位置。
組蛋白離胺酸(H: histone, K: lysine)之甲基化是抑制基因之機制之一;我們以不同位置之甲基化抗體進行染色質沉殿試驗,在幾個轉譯因子之H3K4上甲基化之程度沒有顯著差別,然而在Dlx2之H3K27位置上,缺乏MLL細胞則有大量之甲基化現象。我們提出一個假說,在沒有MLL時,Dlx2 之位置受到甲基化之影響,呈現抑制狀況;當MLL存在時,Dlx2上之甲基則會被去甲基化,而啟動Dlx2之作用,開始神經分化之過程。
Stem cells are defined to have the capability of self-renewal, proliferation and differentiation. In mammals, subventricular zone (SVZ) is a neural stem niche where thousands of neuroblasts are born everyday and migrate to the olfactory bulb (OB). There are a few signals pathways reported to be involved in this neurogenic niche; epigenetic control is a one of the major mechanisms remained to be elucidate.
Chromatin remodelling, a key process to activate or suppress gene function, is important for stem cell maintenance. However, for neural stem cells, the relationship with chromatin remodelling is still poorly understood. Trithorax (Trx) and polycomb (Pcb) groups are both important chromatin remodelling factors which modulating embryo development. From published expression profiles of SVZ and OB, several chromatin modifiers were identified. Mll, a trithorax member, is first identified as a leukemic oncogene. With the utilization of reversed-transcription polymerase reaction (RT-PCR), in situ hybridization and conditional knock-in mice, we are able to demonstrate and confirm the persistent expression of Mll in the SVZ, starting from embryo stage.
With an unique Mll1 conditional knockout mice, when crossed to an hGFAP-Cre strain, we observed a significant defective neurogenesis. The DCX-expressing neuroblasts accumulated in the SVZ without migration to the OB. The defect is limited to neurogenesis but not to gliogenesis; oligodrencytes and astrocytes are normally differentiated from the SVZ. This phenotype is re-confirmed by injecting the Cre-carrying adenovirus to the SVZ of conditional knockout mice.
To further demonstrate this ex vivo, with monolayer neural stem cell culture, we compared the neurogenesis from SVZ of conditional knock-out mice. In vitro, the neurogenesis was decreased by near 40 folds; while oligodendrocytes and astrocytes were compensatory increased.
Since in a conditional knockout model, the Mll1 is deleted since embryo stage day 11.5-12.5, it is possible that Mll1 may not affect neurogenesis directly. We utilized shRNAi and Cre-carrying virus to infect the monolayer SVZ stem cells and knockdown Mll1 immediately. In both methods, the neurogenesis decreased in vitro.
Neuroblasts transcription signals were not decreased symmetrically; Dlx2 was decreased while MASH1 was not. We designed a Dlx2-carrying plasmid to infect the Mll1-depleted cells and the neurogenesis was partially rescued.
To further explore the downstream targets, chromatin immunoprecipitation (CHIP) with MLL antibody was performed. Mll1 is directly binding on the Dlx2 promoter regions, also abundant at 1Kb upstream at the initiation site.
To investigate which histone methylation manipulates the activation of Dlx2, we performed another two CHIP experiments with H3K4me3 and H3K27me3 antibodies. We found that in Mll1-deleted SVZ, H3K4me3 is not different on Dlx2, MASH1 and Olig2 loci; whiles Dlx2 locus is strongly methylated on H3K27.
In conclusions, Mll1 is expressed in the mammals SVZ. Lacking Mll1 may lead to defective neurogenesis and failure to migration; it does not affect gliogenesis. Mll1 in the CNS does not act as H3K4 methyl-transferase; more possibly, it may recruit a demethylase to specifically remove the methylation on H3K27 of Dlx2 locus.
Table of contents
指導教授推薦書…………………………………………………………ii
口試委員會審定書……………………………………………………iii
授權書……………………………………………………………………iv
誌謝………………………………………………………………………v
中文摘要…………………………………………………………………vi
英文摘要………………………………………………………………viii
Abbreviations…………………………………………………………x
Introduction …………………………………………………………01
1. Background …………………………………………………………01
2. Specific Aims of This Project ………………………………04
Materials and Methods ………………………………………………06
1. In Vitro Models of SVZ Monolayer Culture …………………06
1.1 Preparation of Neural Stem Cell- monolayer Culture System……………………………………………………………………06
1.2 Maintenance of SVZ Cells under a Proliferation Condition or Differentiation Condition ………………………06
1.3 Preparation of Adenovirus and Dlx2 Plasmid ……………06
1.4 Analysis of Stem Cell Differentiation …………………07
1.5 Analysis of Cell Proliferation, Cell Death and Apoptosis ………………………………………………………………08
1.6 Preparation of RNAi-lentivirus ……………………………08
1.7 RNA Preparation and Reverse Transcription ………………09
1.8 Reverse Transcription PCR and Real-time PCR ……………09
1.9 Chromatin Immunoprecipitation ………………………………09
2. In Vivo Conditional Mll-knockout Model …………………10
2.1 Transgenic Mouse Generation and Genetic Background …11
2.2 Genotyping Method ………………………………………………11
2.3 Phenotypes of Conditional Knockout Mice After Recombination …………………………………………………………11
2.4 Perfusion and Fixation ………………………………………12
2.5Immunohistochemistry and Histology …………………………12
2.6 In Situ Hybridization …………………………………………13
2.7 In Vivo BrdU-incorporation Assay …………………………13
2.8 Migration Assay …………………………………………………13
2.9 Direct Injection of Ad5-hGFAP-Cre Virus into Adult Mouse SVZ ………………………………………………………………13
RESULTS
a. SVZ Cells Express Mll …………………………………………15
a.1 Expressions of Mll in Embryo Brain………………………15
a.2 Expression of Mll in the Adult SVZ ………………………15
a.3 Relative Expression of Mll Comparing to Other Regions
of Brain …………………………………………………………16
a.4 Expression of Mll1 by in situ Hybridization …………16
a.5 SVZ of Mll-LacZ Knock-in Animal-X-gal Stainings ……16
a.6 Ultrastructure of Mll Expression in SVZ ………………17
b. Mll1 is Required for SVZ-Ob Neurogenesis in vivo ………18
b.1. Conditional Knockout of Mll1 in the Mouse Brain ……18
b.2 In vivo Phenotype of Mll1-deletion ………………………18
b.3 SVZ-OB Neurogenesis Defect in Mll1-deleted Mutants …19
b.4 Mll1-deleted SVZ is Less Proliferative …………………19
b.5 The Mll1-deleted SVZ Neuroblasts Accumulate
Post-natally ……………………………………………………20
b.6 Neurogenesis Defects in Hippocampus and Cerebellum …20
b.7 Induced Cre-recombination by Direct Injection of
Ad5-hGFAP-Cre Virus………………………………………… 21
c. Mll1 is Essential in SVZ Stem Cells Proliferation,
Differentiation, and Neuroblasts Migration ………………23
c.1 In vitro Model of Neural Stem Cell Culture ……………23
c.2 Lentiviral-Mll1-shRNAi Inhibited Neurogenesis in vitro
……………………………………………………………………23
c.3 Defective Neurogenesis in Conditional Mll1-knockout in
SVZ Culture ……………………………………………………24
c.4 Impaired Neurogenesis in Acute Mll1-deleted SVZ
Culture …………………………………………………………24
c.5 Over-expression of Dlx2 Partially Rescues
Neurogenesis……………………………………………………25
c.6 Neuroblasts Migration Defect in Mll1-deleted SVZ in
vivo and ex vivo ………………………………………………25
d. Mll1 Regulates Neurogenesis through Histone Methylation-
downstream Target, Dlx2 ………………………………………27
d.1 Expression of Dlx2, Mash1 and Olig2 in SVZ ……………27
d.2 Chromatin Immunoprecipitation with MLL Antibody ……27
d.3 Chromatin Immunoprecipitation with H3K4me3 and
H4K27me3 Antibody ……………………………………………27
Discussion ……………………………………………………………29
Conclusions ……………………………………………………………32
Future perspectives …………………………………………………33
References ……………………………………………………………………………35
Publications Publications (during my PhD years)……………………………………………………………………67

Figure contents
Fig. 1 Expression profiles of mouse SVZ and OB ……………44
Fig. 2 Expression profile analysis ……………………………45
Fig. 3 Adenovirus illustration …………………………………46
Fig. 4 Map of pSicoR ………………………………………………47
Fig. 5 Mll expression in CNS ……………………………………48
Fig. 6 Expression of Mll in adult and embryo animals by in
situ hybridization,EM and knocking transgenic
animal…………………………………………………………49
Fig. 7 hGFAP-Cre;Mll1flox/flox crossing phenotype …………50
Fig. 8 Mll1 is required for normal SVZ-olfactory bulb
neurogenesis …………………………………………………51
Fig. 9 Neuroblasts accumulate in SVZ of hGFAP-
Cre;Mll1flox/flox mice postnatally ……………………53
Fig. 10 The cerebellar internal granular layer and
hippocampal dentate gyrus show evidence of reduced
neurogenesis in hGFAP-Cre;Mll1F/F mice ……………54
Fig. 11 Ad5-Cre virus injection to conditional
Mll1flox/flox SVZ …………………………………………55
Fig. 12 SVZ monolayer layer NSC culture system ……………56
Fig. 13 shRNAi is targeting the exon 3 of Mll1 ……………57
Fig. 14 Lentiviral-Mll1-shRNAi inhibits neurogenesis in
vitro …………………………………………………………58
Fig. 15 Mll1-depleted SVZ has defective neurogenesis in
vitro …………………………………………………………60
Fig. 16 In vitro deleteion of Mll1 resulted neurogenesis
defect ………………………………………………………61
Fig. 17 Overexpression of Dlx2 partially rescued
neurogenesis in vitro ……………………………………62
Fig. 18 Migration defects in Mll1-deleted SVZ, ex vivo and
in vivo ………………………………………………………63
Fig. 19 qCHIP analysis of chromatin and MLL interactions…64
References
Adachi K., Mirzadeh Z., Sakaguchi M., et al. Beta-catenin signaling promotes proliferation of progenitor cells in the adult mouse subventricular zone. Stem Cells 25: 2827-36, 2007
Alcock J., Lowe J., England T., et al. Expression of Sox1, Sox2 and Sox9 is maintained in adult human cerebellar cortex. Neurosci Lett 450: 114-6, 2009
Alexanian A. R., Maiman D. J., Kurpad S. N., et al. In vitro and in vivo characterization of neurally modified mesenchymal stem cells induced by epigenetic modifiers and neural stem cell environment. Stem Cells Dev 17: 1123-30, 2008
Allegrucci C., Denning C., Priddle H., et al. Stem-cell consequences of embryo epigenetic defects. Lancet 364: 206-8, 2004
Alvarez-Buylla A. Commitment and migration of young neurons in the vertebrate brain. Experientia 46: 879-82, 1990
Alvarez-Buylla A. Mechanism of neurogenesis in adult avian brain. Experientia 46: 948-55, 1990
Alvarez-Buylla A. Mechanism of migration of olfactory bulb interneurons. Semin Cell Dev Biol 8: 207-13, 1997
Alvarez-Buylla A. and Garcia-Verdugo J. M. Neurogenesis in adult subventricular zone. J Neurosci 22: 629-34, 2002
Alvarez-Buylla A. and Kirn J. R. Birth, migration, incorporation, and death of vocal control neurons in adult songbirds. J Neurobiol 33: 585-601, 1997
Alvarez-Buylla A., Kirn J. R. and Nottebohm F. Birth of projection neurons in adult avian brain may be related to perceptual or motor learning. Science 249: 1444-6, 1990
Alvarez-Buylla A., Kohwi M., Nguyen T. M., et al. The Heterogeneity of Adult Neural Stem Cells and the Emerging Complexity of Their Niche. Cold Spring Harb Symp Quant Biol, 2008
Alvarez-Buylla A. and Lim D. A. For the long run: maintaining germinal niches in the adult brain. Neuron 41: 683-6, 2004
Alvarez-Buylla A. and Lois C. Neuronal stem cells in the brain of adult vertebrates. Stem Cells 13: 263-72, 1995
Alvarez-Buylla A., Theelen M. and Nottebohm F. Proliferation "hot spots" in adult avian ventricular zone reveal radial cell division. Neuron 5: 101-9, 1990
Ayton P. M. and Cleary M. L. Molecular mechanisms of leukemogenesis mediated by MLL fusion proteins. Oncogene 20: 5695-707, 2001
Bonaguidi M. A., Peng C. Y., McGuire T., et al. Noggin expands neural stem cells in the adult hippocampus. J Neurosci 28: 9194-204, 2008
Breiling A., Sessa L. and Orlando V. Biology of polycomb and trithorax group proteins. Int Rev Cytol 258: 83-136, 2007
Bruggeman S. W., Hulsman D., Tanger E., et al. Bmi1 controls tumor development in an Ink4a/Arf-independent manner in a mouse model for glioma. Cancer Cell 12: 328-41, 2007
Burmeister T., Meyer C., Thiel G., et al. A MLL-KIAA0284 fusion gene in a patient with secondary acute myeloid leukemia and t(11;14)(q23;q32). Blood Cells Mol Dis 41: 210-4, 2008
Busson-Le Coniat M., Salomon-Nguyen F., Hillion J., et al. MLL-AF1q fusion resulting from t(1;11) in acute leukemia. Leukemia 13: 302-6, 1999
Butler L. H., Slany R., Cui X., et al. The HRX proto-oncogene product is widely expressed in human tissues and localizes to nuclear structures. Blood 89: 3361-70, 1997
Cerveira N., Correia C., Bizarro S., et al. SEPT2 is a new fusion partner of MLL in acute myeloid leukemia with t(2;11)(q37;q23). Oncogene 25: 6147-52, 2006
Chaumeil J., Okamoto I. and Heard E. X-chromosome inactivation in mouse embryonic stem cells: analysis of histone modifications and transcriptional activity using immunofluorescence and FISH. Methods Enzymol 376: 405-19, 2004
Clark S. J., Cynx J., Alvarez-Buylla A., et al. On variables that affect estimates of the true sizes and densities of radioactively labeled cell nuclei. J Comp Neurol 301: 114-22, 1990
Cobos I., Borello U. and Rubenstein J. L. Dlx transcription factors promote migration through repression of axon and dendrite growth. Neuron 54: 873-88, 2007
Coles-Takabe B. L., Brain I., Purpura K. A., et al. Don't look: growing clonal versus nonclonal neural stem cell colonies. Stem Cells 26: 2938-44, 2008
Cordey M., Limacher M., Kobel S., et al. Enhancing the reliability and throughput of neurosphere culture on hydrogel microwell arrays. Stem Cells 26: 2586-94, 2008
Davidson K. C., Jamshidi P., Daly R., et al. Wnt3a regulates survival, expansion, and maintenance of neural progenitors derived from human embryonic stem cells. Mol Cell Neurosci 36: 408-15, 2007
De Braekeleer M., Morel F., Le Bris M. J., et al. The MLL gene and translocations involving chromosomal band 11q23 in acute leukemia. Anticancer Res 25: 1931-44, 2005
Doetsch F., Caille I., Lim D. A., et al. Subventricular zone astrocytes are neural stem cells in the adult mammalian brain. Cell 97: 703-16, 1999
Doetsch F., Petreanu L., Caille I., et al. EGF converts transit-amplifying neurogenic precursors in the adult brain into multipotent stem cells. Neuron 36: 1021-34, 2002
Duan X., Kang E., Liu C. Y., et al. Development of neural stem cell in the adult brain. Curr Opin Neurobiol 18: 108-15, 2008
Ernst P., Mabon M., Davidson A. J., et al. An Mll-dependent Hox program drives hematopoietic progenitor expansion. Curr Biol 14: 2063-9, 2004
Fang M., Ren H., Liu J., et al. Drosophila ptip is essential for anterior/posterior patterning in development and interacts with the PcG and trxG pathways. Development 136: 1929-38, 2009
Garcia-Verdugo J. M., Doetsch F., Wichterle H., et al. Architecture and cell types of the adult subventricular zone: in search of the stem cells. J Neurobiol 36: 234-48, 1998
Glaser S., Lubitz S., Loveland K. L., et al. The histone 3 lysine 4 methyltransferase, Mll2, is only required briefly in development and spermatogenesis. Epigenetics Chromatin 2: 5, 2009
Griesinger F., Elfers H., Ludwig W. D., et al. Detection of HRX-FEL fusion transcripts in pre-pre-B-ALL with and without cytogenetic demonstration of t(4;11). Leukemia 8: 542-8, 1994
Hagg T. Endogenous regulators of adult CNS neurogenesis. Curr Pharm Des 13: 1829-40, 2007
Hanson R. D., Hess J. L., Yu B. D., et al. Mammalian Trithorax and polycomb-group homologues are antagonistic regulators of homeotic development. Proc Natl Acad Sci U S A 96: 14372-7, 1999
Jackson E. L., Garcia-Verdugo J. M., Gil-Perotin S., et al. PDGFR alpha-positive B cells are neural stem cells in the adult SVZ that form glioma-like growths in response to increased PDGF signaling. Neuron 51: 187-99, 2006
Jude C. D., Climer L., Xu D., et al. Unique and independent roles for MLL in adult hematopoietic stem cells and progenitors. Cell Stem Cell 1: 324-37, 2007
Katsimpardi L., Gaitanou M., Malnou C. E., et al. BM88/Cend1 expression levels are critical for proliferation and differentiation of subventricular zone-derived neural precursor cells. Stem Cells 26: 1796-807, 2008
Kohyama J., Kojima T., Takatsuka E., et al. Epigenetic regulation of neural cell differentiation plasticity in the adult mammalian brain. Proc Natl Acad Sci U S A 105: 18012-7, 2008
Krivtsov A. V. and Armstrong S. A. MLL translocations, histone modifications and leukaemia stem-cell development. Nat Rev Cancer 7: 823-33, 2007
Kuge A., Takemura S., Kokubo Y., et al. Temporal profile of neurogenesis in the subventricular zone, dentate gyrus and cerebral cortex following transient focal cerebral ischemia. Neurol Res, 2009
Lappin T. R., Grier D. G., Thompson A., et al. HOX genes: seductive science, mysterious mechanisms. Ulster Med J 75: 23-31, 2006
Lee J., Son M. J., Woolard K., et al. Epigenetic-mediated dysfunction of the bone morphogenetic protein pathway inhibits differentiation of glioblastoma-initiating cells. Cancer Cell 13: 69-80, 2008
Li X., Barkho B. Z., Luo Y., et al. Epigenetic regulation of the stem cell mitogen Fgf-2 by Mbd1 in adult neural stem/progenitor cells. J Biol Chem 283: 27644-52, 2008
Lim D. A., Huang Y. C. and Alvarez-Buylla A. The adult neural stem cell niche: lessons for future neural cell replacement strategies. Neurosurg Clin N Am 18: 81-92, ix, 2007
Lim D. A., Suarez-Farinas M., Naef F., et al. In vivo transcriptional profile analysis reveals RNA splicing and chromatin remodeling as prominent processes for adult neurogenesis. Mol Cell Neurosci 31: 131-48, 2006
Mehler M. F. Epigenetics and the nervous system. Ann Neurol 64: 602-17, 2008
Merkle F. T., Mirzadeh Z. and Alvarez-Buylla A. Mosaic organization of neural stem cells in the adult brain. Science 317: 381-4, 2007
Meyer C., Schneider B., Jakob S., et al. The MLL recombinome of acute leukemias. Leukemia 20: 777-84, 2006
Michaelidis T. M. and Lie D. C. Wnt signaling and neural stem cells: caught in the Wnt web. Cell Tissue Res 331: 193-210, 2008
Milne T. A., Martin M. E., Brock H. W., et al. Leukemogenic MLL fusion proteins bind across a broad region of the Hox a9 locus, promoting transcription and multiple histone modifications. Cancer Res 65: 11367-74, 2005
Morrissey J., Tkachuk D. C., Milatovich A., et al. A serine/proline-rich protein is fused to HRX in t(4;11) acute leukemias. Blood 81: 1124-31, 1993
Nie Z., Yan Z., Chen E. H., et al. Novel SWI/SNF chromatin-remodeling complexes contain a mixed-lineage leukemia chromosomal translocation partner. Mol Cell Biol 23: 2942-52, 2003
Nottebohm F., Alvarez-Buylla A., Cynx J., et al. Song learning in birds: the relation between perception and production. Philos Trans R Soc Lond B Biol Sci 329: 115-24, 1990
Ono R., Nosaka T. and Hayashi Y. Roles of a trithorax group gene, MLL, in hematopoiesis. Int J Hematol 81: 288-93, 2005
Petryniak M. A., Potter G. B., Rowitch D. H., et al. Dlx1 and Dlx2 control neuronal versus oligodendroglial cell fate acquisition in the developing forebrain. Neuron 55: 417-33, 2007
Philbert M. A., Beiswanger C. M., Roscoe T. L., et al. Enhanced resolution of histochemical distribution of glucose-6-phosphate dehydrogenase activity in rat neural tissue by use of a semipermeable membrane. J Histochem Cytochem 39: 937-43, 1991
Richter G. H., Plehm S., Fasan A., et al. EZH2 is a mediator of EWS/FLI1 driven tumor growth and metastasis blocking endothelial and neuro-ectodermal differentiation. Proc Natl Acad Sci U S A 106: 5324-9, 2009
Ringrose L. and Paro R. Epigenetic regulation of cellular memory by the Polycomb and Trithorax group proteins. Annu Rev Genet 38: 413-43, 2004
Sanai N., Tramontin A. D., Quinones-Hinojosa A., et al. Unique astrocyte ribbon in adult human brain contains neural stem cells but lacks chain migration. Nature 427: 740-4, 2004
Sangiorgi E. and Capecchi M. R. Bmi1 is expressed in vivo in intestinal stem cells. Nat Genet 40: 915-20, 2008
Sanosaka T., Namihira M. and Nakashima K. Epigenetic mechanisms in sequential differentiation of neural stem cells. Epigenetics 4: 89-92, 2009
Scheffler B., Walton N. M., Lin D. D., et al. Phenotypic and functional characterization of adult brain neuropoiesis. Proc Natl Acad Sci U S A 102: 9353-8, 2005
Schmidt C., McGonnell I. M., Allen S., et al. Wnt6 controls amniote neural crest induction through the non-canonical signaling pathway. Dev Dyn 236: 2502-11, 2007
Tillib S., Petruk S., Sedkov Y., et al. Trithorax- and Polycomb-group response elements within an Ultrabithorax transcription maintenance unit consist of closely situated but separable sequences. Mol Cell Biol 19: 5189-202, 1999
Uda M., Ishido M. and Kami K. Features and a possible role of Mash1-immunoreactive cells in the dentate gyrus of the hippocampus in the adult rat. Brain Res 1171: 9-17, 2007
van der Lugt N. M., Alkema M., Berns A., et al. The Polycomb-group homolog Bmi-1 is a regulator of murine Hox gene expression. Mech Dev 58: 153-64, 1996
van Lohuizen M. Functional analysis of mouse Polycomb group genes. Cell Mol Life Sci 54: 71-9, 1998
Vescovi A. L., Parati E. A., Gritti A., et al. Isolation and cloning of multipotential stem cells from the embryonic human CNS and establishment of transplantable human neural stem cell lines by epigenetic stimulation. Exp Neurol 156: 71-83, 1999
Wang T. W., Stromberg G. P., Whitney J. T., et al. Sox3 expression identifies neural progenitors in persistent neonatal and adult mouse forebrain germinative zones. J Comp Neurol 497: 88-100, 2006
Wilkinson R., Tscharke D. and Simmons A. Golfalpha is expressed in primary sensory neurons outside of the olfactory neuroepithelium. Brain Res 831: 311-4, 1999
Wynder C., Hakimi M. A., Epstein J. A., et al. Recruitment of MLL by HMG-domain protein iBRAF promotes neural differentiation. Nat Cell Biol 7: 1113-7, 2005
Yamamoto K., Shibata F., Yamaguchi M., et al. Fusion of MLL and MSF in adult de novo acute myelomonocytic leukemia (M4) with t(11;17)(q23;q25). Int J Hematol 75: 503-7, 2002
Yu B. D., Hanson R. D., Hess J. L., et al. MLL, a mammalian trithorax-group gene, functions as a transcriptional maintenance factor in morphogenesis. Proc Natl Acad Sci U S A 95: 10632-6, 1998
Yu B. D., Hess J. L., Horning S. E., et al. Altered Hox expression and segmental identity in Mll-mutant mice. Nature 378: 505-8, 1995
Zardo G., Cimino G. and Nervi C. Epigenetic plasticity of chromatin in embryonic and hematopoietic stem/progenitor cells: therapeutic potential of cell reprogramming. Leukemia 22: 1503-18, 2008
Zeisig B. B., Schreiner S., Garcia-Cuellar M. P., et al. Transcriptional activation is a key function encoded by MLL fusion partners. Leukemia 17: 359-65, 2003
Zencak D., Lingbeek M., Kostic C., et al. Bmi1 loss produces an increase in astroglial cells and a decrease in neural stem cell population and proliferation. J Neurosci 25: 5774-83, 2005
Zhuo L., Theis M., Alvarez-Maya I., et al. hGFAP-cre transgenic mice for manipulation of glial and neuronal function in vivo. Genesis 31: 85-94, 2001
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