**Author details**

Atsushi Shimomura1 and Eri Hashino2\*

\*Address all correspondence to: ehashino@iupui.edu

1 Department of Anatomy I, Fujita Health University School of Medicine, Toyoake, Aichi, Japan

2 Department of Otolaryngology-Head and Neck Surgery, Stark Neurosciences Research In‐ stitute, Indiana University School of Medicine, Indianapolis, IN, USA

## **References**


[6] Kilpatrick TJ, Bartlett PF. Cloning and growth of multipotential neural precursors: re‐ quirements for proliferation and differentiation. Neuron 1993;10(2) 255-265.

remodeling, and non-coding RNAs. Each of these epigenetic events interacts with intrinsic (ex. transcription factors) and/or extrinsic factors (ex. developmental cues such as morpho‐ gens and cytokines). Studies so far have suggested that, during sequential transitions from pluripotent ESCs to terminally differentiated neurons, epigenetic mechanisms play critical roles in not only maintaining self-renewal capacity and pluripotency of ESCs, but also re‐ stricting cell lineage choices. Further investigation will therefore help clarifying the mecha‐ nisms that control pluripotency and neuronal/glial fate specification. Furthermore, the knowledge will be used in harnessing ESCs safely and effectively for clinical applications.

The authors wish to thank the financial support of JSPS KAKENHI Grant Number 24592567

1 Department of Anatomy I, Fujita Health University School of Medicine, Toyoake, Aichi,

2 Department of Otolaryngology-Head and Neck Surgery, Stark Neurosciences Research In‐

[1] Evans MJ, Kaufman MH. Establishment in culture of pluripotential cells from mouse

[2] Spivakov M, Fisher AG. Epigenetic signatures of stem-cell identity. Nat Rev Genet

[3] Chen L, Daley GQ. Molecular basis of pluripotency. Hum Mol Genet 2008;17(R1)

[5] Temple S. Division and differentiation of isolated CNS blast cells in microculture.

[4] Temple S. The development of neural stem cells. Nature 2001;414(6859) 112-117.

**Ackknowledgments**

**Author details**

Atsushi Shimomura1

Japan

**References**

2007;8(4) 263-271.

R23-27.

(to A. S.) and NIH RC1 DC010706 (to E.H.).

316 Trends in Cell Signaling Pathways in Neuronal Fate Decision

and Eri Hashino2\*

stitute, Indiana University School of Medicine, Indianapolis, IN, USA

\*Address all correspondence to: ehashino@iupui.edu

embryos. Nature 1981;292(5819) 154-156.

Nature 1989;340(6233) 471-473.


[19] Yuan GC, Liu YJ, Dion MF, Slack MD, Wu LF, Altschuler SJ, Rando OJ. Genomescale identification of nucleosome positions in S. cerevisiae. Science 2005;309(5734) 626-630.

[34] Wang Y, Jia S. Degrees make all the difference: the multifunctionality of histone H4

Epigenetic Regulation of Neural Differentiation from Embryonic Stem Cells

http://dx.doi.org/10.5772/53650

319

[35] Suzuki MM, Bird A. DNA methylation landscapes: provocative insights from epige‐

[36] Eden S, Cedar H. Role of DNA methylation in the regulation of transcription. Curr

[37] Law JA, Jacobsen SE. Establishing, maintaining and modifying DNA methylation

[38] Ballestar E, Wolffe AP. Methyl-CpG-binding proteins. Targeting specific gene repres‐

[39] Wade PA. Methyl CpG-binding proteins and transcriptional repression. Bioessays

[40] Jones PL, Veenstra GJ, Wade PA, Vermaak D, Kass SU, Landsberger N, Strouboulis J, Wolffe AP. Methylated DNA and MeCP2 recruit histone deacetylase to repress tran‐

[41] Nan X, Ng HH, Johnson CA, Laherty CD, Turner BM, Eisenman RN, Bird A. Tran‐ scriptional repression by the methyl-CpG-binding protein MeCP2 involves a histone

[42] Cairns BR. Chromatin remodeling: insights and intrigue from single-molecule stud‐

[43] Hargreaves DC, Crabtree GR. ATP-dependent chromatin remodeling: genetics, ge‐

[44] Smith CL, Peterson CL. ATP-dependent chromatin remodeling. Curr Top Dev Biol

[45] Varga-Weisz PD, Blank TA, Becker PB. Energy-dependent chromatin accessibility and nucleosome mobility in a cell-free system. EMBO J 1995;14(10) 2209-2216.

[46] Ito T, Bulger M, Pazin MJ, Kobayashi R, Kadonaga JT. ACF, an ISWI-containing and ATP-utilizing chromatin assembly and remodeling factor. Cell 1997;90(1) 145-155.

[47] Zhang Y, Ng HH, Erdjument-Bromage H, Tempst P, Bird A, Reinberg D. Analysis of the NuRD subunits reveals a histone deacetylase core complex and a connection with

[48] Xie W, Ling T, Zhou Y, Feng W, Zhu Q, Stunnenberg HG, Grummt I, Tao W. The chromatin remodeling complex NuRD establishes the poised state of rRNA genes characterized by bivalent histone modifications and altered nucleosome positions.

patterns in plants and animals. Nat Rev Genet 2010;11(3) 204-220.

lysine 20 methylation. Epigenetics 2009;4(5) 273-276.

nomics. Nat Rev Genet 2008;9(6) 465-476.

Opin Genet Dev 1994;4(2) 255-259.

sion. Eur J Biochem 2001;268(1) 1-6.

scription. Nat Genet 1998;19(2) 187-191.

ies. Nat Struct Mol Biol 2007;14(11) 989-996.

deacetylase complex. Nature 1998;393(6683) 386-389.

nomics and mechanisms. Cell Res 2011;21(3) 396-420.

DNA methylation. Genes Dev 1999;13(15) 1924-1935.

Proc Natl Acad Sci U S A 2012;109(21) 8161-8166.

2001;23(12) 1131-1137.

2005;65 115-148.


[34] Wang Y, Jia S. Degrees make all the difference: the multifunctionality of histone H4 lysine 20 methylation. Epigenetics 2009;4(5) 273-276.

[19] Yuan GC, Liu YJ, Dion MF, Slack MD, Wu LF, Altschuler SJ, Rando OJ. Genomescale identification of nucleosome positions in S. cerevisiae. Science 2005;309(5734)

[20] Muthurajan UM, Bao Y, Forsberg LJ, Edayathumangalam RS, Dyer PN, White CL, Luger K. Crystal structures of histone Sin mutant nucleosomes reveal altered pro‐

[21] Lieb JD, Clarke ND. Control of transcription through intragenic patterns of nucleo‐

[22] Bell O, Tiwari VK, Thoma NH, Schubeler D. Determinants and dynamics of genome

[23] Bai L, Morozov AV. Gene regulation by nucleosome positioning. Trends Genet

[24] Anderson JD, Lowary PT, Widom J. Effects of histone acetylation on the equilibrium accessibility of nucleosomal DNA target sites. J Mol Biol 2001;307(4) 977-985.

[25] Strahl BD, Allis CD. The language of covalent histone modifications. Nature

[26] Lewis BP, Burge CB, Bartel DP. Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell 2005;120(1)

[27] Kouzarides T. Chromatin modifications and their function. Cell 2007;128(4) 693-705.

[28] Zhang Y, Reinberg D. Transcription regulation by histone methylation: interplay be‐ tween different covalent modifications of the core histone tails. Genes Dev

[29] Peterson CL, Laniel MA. Histones and histone modifications. Curr Biol 2004;14(14)

[30] Nishioka K, Rice JC, Sarma K, Erdjument-Bromage H, Werner J, Wang Y, Chuikov S, Valenzuela P, Tempst P, Steward R, Lis JT, Allis CD, Reinberg D. PR-Set7 is a nucleo‐ some-specific methyltransferase that modifies lysine 20 of histone H4 and is associat‐

[31] Schotta G, Lachner M, Sarma K, Ebert A, Sengupta R, Reuter G, Reinberg D, Jenu‐ wein T. A silencing pathway to induce H3-K9 and H4-K20 trimethylation at constitu‐

[32] Kouzarides T. Histone methylation in transcriptional control. Curr Opin Genet Dev

[33] Martin C, Zhang Y. The diverse functions of histone lysine methylation. Nat Rev Mol

ed with silent chromatin. Mol Cell 2002;9(6) 1201-1213.

tive heterochromatin. Genes Dev 2004;18(11) 1251-1262.

tein-DNA interactions. EMBO J 2004;23(2) 260-271.

some composition. Cell 2005;123(7) 1187-1190.

accessibility. Nat Rev Genet 2011;12(8) 554-564.

626-630.

318 Trends in Cell Signaling Pathways in Neuronal Fate Decision

2010;26(11) 476-483.

2000;403(6765) 41-45.

2001;15(18) 2343-2360.

2002;12(2) 198-209.

Cell Biol 2005;6(11) 838-849.

15-20.

R546-551.


[49] Brosnan CA, Voinnet O. The long and the short of noncoding RNAs. Curr Opin Cell Biol 2009;21(3) 416-425.

[61] Cao R, Wang L, Wang H, Xia L, Erdjument-Bromage H, Tempst P, Jones RS, Zhang Y. Role of histone H3 lysine 27 methylation in Polycomb-group silencing. Science

Epigenetic Regulation of Neural Differentiation from Embryonic Stem Cells

http://dx.doi.org/10.5772/53650

321

[62] Schwartz YB, Pirrotta V. Polycomb silencing mechanisms and the management of ge‐

[63] Jiang H, Shukla A, Wang X, Chen WY, Bernstein BE, Roeder RG. Role for Dpy-30 in ES cell-fate specification by regulation of H3K4 methylation within bivalent domains.

[64] Burgold T, Spreafico F, De Santa F, Totaro MG, Prosperini E, Natoli G, Testa G. The histone H3 lysine 27-specific demethylase Jmjd3 is required for neural commitment.

[65] Schmitz SU, Albert M, Malatesta M, Morey L, Johansen JV, Bak M, Tommerup N, Abarrategui I, Helin K. Jarid1b targets genes regulating development and is involved

[66] Meshorer E, Yellajoshula D, George E, Scambler PJ, Brown DT, Misteli T. Hyperdy‐ namic plasticity of chromatin proteins in pluripotent embryonic stem cells. Dev Cell

[67] Song MR, Ghosh A. FGF2-induced chromatin remodeling regulates CNTF-mediated gene expression and astrocyte differentiation. Nat Neurosci 2004;7(3) 229-235.

[68] Meshorer E, Misteli T. Chromatin in pluripotent embryonic stem cells and differen‐

[69] Hayakawa T, Nakayama J. Physiological roles of class I HDAC complex and histone

[70] Sapountzi V, Logan IR, Robson CN. Cellular functions of TIP60. Int J Biochem Cell

[71] Fazzio TG, Huff JT, Panning B. An RNAi screen of chromatin proteins identifies Tip60-p400 as a regulator of embryonic stem cell identity. Cell 2008;134(1) 162-174.

[72] Meissner A, Mikkelsen TS, Gu H, Wernig M, Hanna J, Sivachenko A, Zhang X, Bern‐ stein BE, Nusbaum C, Jaffe DB, Gnirke A, Jaenisch R, Lander ES. Genome-scale DNA methylation maps of pluripotent and differentiated cells. Nature 2008;454(7205)

[73] Isagawa T, Nagae G, Shiraki N, Fujita T, Sato N, Ishikawa S, Kume S, Aburatani H. DNA methylation profiling of embryonic stem cell differentiation into the three germ

[74] Mohn F, Weber M, Rebhan M, Roloff TC, Richter J, Stadler MB, Bibel M, Schubeler D. Lineage-specific polycomb targets and *de novo* DNA methylation define restriction

and potential of neuronal progenitors. Mol Cell 2008;30(6) 755-766.

2002;298(5595) 1039-1043.

Cell 2011;144(4) 513-525.

PLoS One 2008;3(8) e3034.

2006;10(1) 105-116.

Biol 2006;38(9) 1496-1509.

layers. PLoS One;6(10) e26052.

766-770.

nomic programmes. Nat Rev Genet 2007;8(1) 9-22.

in neural differentiation. EMBO J 2011;30(22) 4586-4600.

tiation. Nat Rev Mol Cell Biol 2006;7(7) 540-546.

demethylase. J Biomed Biotechnol 2011;2011 129383.


[61] Cao R, Wang L, Wang H, Xia L, Erdjument-Bromage H, Tempst P, Jones RS, Zhang Y. Role of histone H3 lysine 27 methylation in Polycomb-group silencing. Science 2002;298(5595) 1039-1043.

[49] Brosnan CA, Voinnet O. The long and the short of noncoding RNAs. Curr Opin Cell

[50] Cannell IG, Kong YW, Bushell M. How do microRNAs regulate gene expression? Bi‐

[51] Lagos-Quintana M, Rauhut R, Lendeckel W, Tuschl T. Identification of novel genes

[52] Lee Y, Jeon K, Lee JT, Kim S, Kim VN. MicroRNA maturation: stepwise processing

[53] He L, Thomson JM, Hemann MT, Hernando-Monge E, Mu D, Goodson S, Powers S, Cordon-Cardo C, Lowe SW, Hannon GJ, Hammond SM. A microRNA polycistron as

[54] Azuara V, Perry P, Sauer S, Spivakov M, Jorgensen HF, John RM, Gouti M, Casanova M, Warnes G, Merkenschlager M, Fisher AG. Chromatin signatures of pluripotent

[55] Bernstein BE, Mikkelsen TS, Xie X, Kamal M, Huebert DJ, Cuff J, Fry B, Meissner A, Wernig M, Plath K, Jaenisch R, Wagschal A, Feil R, Schreiber SL, Lander ES. A biva‐ lent chromatin structure marks key developmental genes in embryonic stem cells.

[56] Mikkelsen TS, Ku M, Jaffe DB, Issac B, Lieberman E, Giannoukos G, Alvarez P, Brockman W, Kim TK, Koche RP, Lee W, Mendenhall E, O'Donovan A, Presser A, Russ C, Xie X, Meissner A, Wernig M, Jaenisch R, Nusbaum C, Lander ES, Bernstein BE. Genome-wide maps of chromatin state in pluripotent and lineage-committed

[57] Ringrose L, Paro R. Epigenetic regulation of cellular memory by the Polycomb and

[58] Lee TI, Jenner RG, Boyer LA, Guenther MG, Levine SS, Kumar RM, Chevalier B, Johnstone SE, Cole MF, Isono K, Koseki H, Fuchikami T, Abe K, Murray HL, Zucker JP, Yuan B, Bell GW, Herbolsheimer E, Hannett NM, Sun K, Odom DT, Otte AP, Vol‐ kert TL, Bartel DP, Melton DA, Gifford DK, Jaenisch R, Young RA. Control of devel‐ opmental regulators by Polycomb in human embryonic stem cells. Cell 2006;125(2)

[59] Boyer LA, Plath K, Zeitlinger J, Brambrink T, Medeiros LA, Lee TI, Levine SS, Wer‐ nig M, Tajonar A, Ray MK, Bell GW, Otte AP, Vidal M, Gifford DK, Young RA, Jae‐ nisch R. Polycomb complexes repress developmental regulators in murine

[60] Cao R, Zhang Y. The functions of E(Z)/EZH2-mediated methylation of lysine 27 in

coding for small expressed RNAs. Science 2001;294(5543) 853-858.

and subcellular localization. EMBO J 2002;21(17) 4663-4670.

a potential human oncogene. Nature 2005;435(7043) 828-833.

Trithorax group proteins. Annu Rev Genet 2004;38 413-443.

embryonic stem cells. Nature 2006;441(7091) 349-353.

histone H3. Curr Opin Genet Dev 2004;14(2) 155-164.

Biol 2009;21(3) 416-425.

320 Trends in Cell Signaling Pathways in Neuronal Fate Decision

ochem Soc Trans 2008;36(Pt 6) 1224-1231.

cell lines. Nat Cell Biol 2006;8(5) 532-538.

cells. Nature 2007;448(7153) 553-560.

Cell 2006;125(2) 315-326.

301-313.


[75] Fouse SD, Shen Y, Pellegrini M, Cole S, Meissner A, Van Neste L, Jaenisch R, Fan G. Promoter CpG methylation contributes to ES cell gene regulation in parallel with Oct4/Nanog, PcG complex, and histone H3 K4/K27 trimethylation. Cell Stem Cell 2008;2(2) 160-169.

[86] Gao FB. Context-dependent functions of specific microRNAs in neuronal develop‐

Epigenetic Regulation of Neural Differentiation from Embryonic Stem Cells

http://dx.doi.org/10.5772/53650

323

[87] Hirabayashi Y, Itoh Y, Tabata H, Nakajima K, Akiyama T, Masuyama N, Gotoh Y. The Wnt/beta-catenin pathway directs neuronal differentiation of cortical neural pre‐

[88] Hirabayashi Y, Suzki N, Tsuboi M, Endo TA, Toyoda T, Shinga J, Koseki H, Vidal M, Gotoh Y. Polycomb limits the neurogenic competence of neural precursor cells to

[89] Lee S, Lee B, Lee JW, Lee SK. Retinoid signaling and neurogenin2 function are cou‐ pled for the specification of spinal motor neurons through a chromatin modifier CBP.

[90] Marin-Husstege M, Muggironi M, Liu A, Casaccia-Bonnefil P. Histone deacetylase activity is necessary for oligodendrocyte lineage progression. J Neurosci 2002;22(23)

[91] Balasubramaniyan V, Boddeke E, Bakels R, Kust B, Kooistra S, Veneman A, Copray S. Effects of histone deacetylation inhibition on neuronal differentiation of embryonic

[92] Hsieh J, Nakashima K, Kuwabara T, Mejia E, Gage FH. Histone deacetylase inhibi‐ tion-mediated neuronal differentiation of multipotent adult neural progenitor cells.

[93] Rossler R, Boddeke E, Copray S. Differentiation of non-mesencephalic neural stem

[94] Humphrey GW, Wang YH, Hirai T, Padmanabhan R, Panchision DM, Newell LF, McKay RD, Howard BH. Complementary roles for histone deacetylases 1, 2, and 3 in

[95] Chong JA, Tapia-Ramirez J, Kim S, Toledo-Aral JJ, Zheng Y, Boutros MC, Altshuller YM, Frohman MA, Kraner SD, Mandel G. REST: a mammalian silencer protein that

[96] choenherr CJ, Paquette AJ, Anderson DJ. Identification of potential target genes for the neuron-restrictive silencer factor. Proc Natl Acad Sci U S A 1996;93(18) 9881-9886.

[97] Ballas N, Mandel G. The many faces of REST oversee epigenetic programming of

[98] Sun YM, Greenway DJ, Johnson R, Street M, Belyaev ND, Deuchars J, Bee T, Wilde S, Buckley NJ. Distinct profiles of REST interactions with its target genes at different

[99] Abrajano JJ, Qureshi IA, Gokhan S, Zheng D, Bergman A, Mehler MF. REST and CoREST modulate neuronal subtype specification, maturation and maintenance.

stages of neuronal development. Mol Biol Cell 2005;16(12) 5630-5638.

restricts sodium channel gene expression to neurons. Cell 1995;80(6) 949-957.

cells towards dopaminergic neurons. Neuroscience 2010;170(2) 417-428.

differentiation of pluripotent stem cells. Differentiation 2008;76(4) 348-356.

ment. Neural Dev 2010;5 25.

Neuron 2009;62(5) 641-654.

10333-10345.

cursor cells. Development 2004;131(12) 2791-2801.

promote astrogenic fate transition. Neuron 2009;63(5) 600-613.

mouse neural stem cells. Neuroscience 2006;143(4) 939-951.

Proc Natl Acad Sci U S A 2004;101(47) 16659-16664.

neuronal genes. Curr Opin Neurobiol 2005;15(5) 500-506.


[86] Gao FB. Context-dependent functions of specific microRNAs in neuronal develop‐ ment. Neural Dev 2010;5 25.

[75] Fouse SD, Shen Y, Pellegrini M, Cole S, Meissner A, Van Neste L, Jaenisch R, Fan G. Promoter CpG methylation contributes to ES cell gene regulation in parallel with Oct4/Nanog, PcG complex, and histone H3 K4/K27 trimethylation. Cell Stem Cell

[76] Brinkman AB, Gu H, Bartels SJ, Zhang Y, Matarese F, Simmer F, Marks H, Bock C, Gnirke A, Meissner A, Stunnenberg HG. Sequential ChIP-bisulfite sequencing ena‐ bles direct genome-scale investigation of chromatin and DNA methylation cross-talk.

[77] Kaji K, Caballero IM, MacLeod R, Nichols J, Wilson VA, Hendrich B. The NuRD component Mbd3 is required for pluripotency of embryonic stem cells. Nat Cell Biol

[78] Kaji K, Nichols J, Hendrich B. Mbd3, a component of the NuRD co-repressor com‐ plex, is required for development of pluripotent cells. Development 2007;134(6)

[79] Ho L, Ronan JL, Wu J, Staahl BT, Chen L, Kuo A, Lessard J, Nesvizhskii AI, Ranish J, Crabtree GR. An embryonic stem cell chromatin remodeling complex, esBAF, is es‐ sential for embryonic stem cell self-renewal and pluripotency. Proc Natl Acad Sci U S

[80] Lessard J, Wu JI, Ranish JA, Wan M, Winslow MM, Staahl BT, Wu H, Aebersold R, Graef IA, Crabtree GR. An essential switch in subunit composition of a chromatin re‐

[81] Marson A, Levine SS, Cole MF, Frampton GM, Brambrink T, Johnstone S, Guenther MG, Johnston WK, Wernig M, Newman J, Calabrese JM, Dennis LM, Volkert TL, Gupta S, Love J, Hannett N, Sharp PA, Bartel DP, Jaenisch R, Young RA. Connecting microRNA genes to the core transcriptional regulatory circuitry of embryonic stem

[82] Wang Y, Baskerville S, Shenoy A, Babiarz JE, Baehner L, Blelloch R. Embryonic stem cell-specific microRNAs regulate the G1-S transition and promote rapid prolifera‐

[83] Sinkkonen L, Hugenschmidt T, Berninger P, Gaidatzis D, Mohn F, Artus-Revel CG, Zavolan M, Svoboda P, Filipowicz W. MicroRNAs control *de novo* DNA methylation through regulation of transcriptional repressors in mouse embryonic stem cells. Nat

[84] Delaloy C, Liu L, Lee JA, Su H, Shen F, Yang GY, Young WL, Ivey KN, Gao FB. Mi‐ croRNA-9 coordinates proliferation and migration of human embryonic stem cell-de‐

[85] Krichevsky AM, Sonntag KC, Isacson O, Kosik KS. Specific microRNAs modulate embryonic stem cell-derived neurogenesis. Stem Cells 2006;24(4) 857-864.

rived neural progenitors. Cell Stem Cell 2010;6(4) 323-335.

modeling complex during neural development. Neuron 2007;55(2) 201-215.

2008;2(2) 160-169.

322 Trends in Cell Signaling Pathways in Neuronal Fate Decision

2006;8(3) 285-292.

A 2009;106(13) 5181-5186.

cells. Cell 2008;134(3) 521-533.

tion. Nat Genet 2008;40(12) 1478-1483.

Struct Mol Biol 2008;15(3) 259-267.

1123-1132.

Genome Res 2012;22(6) 1128-1138.


PLoS One 2009;4(12) e7936. http://www.plosone.org/article/info%3Adoi %2F10.1371%2Fjournal.pone.0007936 (accessed 7 December 2009)

[112] Yoo AS, Staahl BT, Chen L, Crabtree GR. MicroRNA-mediated switching of chroma‐ tin-remodelling complexes in neural development. Nature 2009;460(7255) 642-646.

Epigenetic Regulation of Neural Differentiation from Embryonic Stem Cells

http://dx.doi.org/10.5772/53650

325

[113] Smirnova L, Grafe A, Seiler A, Schumacher S, Nitsch R, Wulczyn FG. Regulation of miRNA expression during neural cell specification. Eur J Neurosci 2005;21(6)

[114] Conaco C, Otto S, Han JJ, Mandel G. Reciprocal actions of REST and a microRNA promote neuronal identity. Proc Natl Acad Sci U S A 2006;103(7) 2422-2427.

[115] Yeo M, Lee SK, Lee B, Ruiz EC, Pfaff SL, Gill GN. Small CTD phosphatases function

[116] Wu H, Xu J, Pang ZP, Ge W, Kim KJ, Blanchi B, Chen C, Sudhof TC, Sun YE. Integra‐ tive genomic and functional analyses reveal neuronal subtype differentiation bias in human embryonic stem cell lines. Proc Natl Acad Sci U S A 2007;104(34) 13821-13826.

in silencing neuronal gene expression. Science 2005;307(5709) 596-600.

1469-1477.


[112] Yoo AS, Staahl BT, Chen L, Crabtree GR. MicroRNA-mediated switching of chroma‐ tin-remodelling complexes in neural development. Nature 2009;460(7255) 642-646.

PLoS One 2009;4(12) e7936. http://www.plosone.org/article/info%3Adoi

[100] Takizawa T, Nakashima K, Namihira M, Ochiai W, Uemura A, Yanagisawa M, Fujita N, Nakao M, Taga T. DNA methylation is a critical cell-intrinsic determinant of as‐

[101] Fan G, Martinowich K, Chin MH, He F, Fouse SD, Hutnick L, Hattori D, Ge W, Shen Y, Wu H, ten Hoeve J, Shuai K, Sun YE. DNA methylation controls the timing of as‐ trogliogenesis through regulation of JAK-STAT signaling. Development 2005;132(15)

[102] Martins-Taylor K, Schroeder DI, Lasalle JM, Lalande M, Xu RH. Role of DNMT3B in the regulation of early neural and neural crest specifiers. Epigenetics 2012;7(1) 71-82.

[103] Yoo AS, Crabtree GR. ATP-dependent chromatin remodeling in neural development.

[104] Wu JI, Lessard J, Olave IA, Qiu Z, Ghosh A, Graef IA, Crabtree GR. Regulation of dendritic development by neuron-specific chromatin remodeling complexes. Neuron

[105] Wang W, Chi T, Xue Y, Zhou S, Kuo A, Crabtree GR. Architectural DNA binding by a high-mobility-group/kinesin-like subunit in mammalian SWI/SNF-related com‐

[106] Yun M, Wu J, Workman JL, Li B. Readers of histone modifications. Cell Res

[107] Deo M, Yu JY, Chung KH, Tippens M, Turner DL. Detection of mammalian micro‐ RNA expression by in situ hybridization with RNA oligonucleotides. Dev Dyn

[108] Kapsimali M, Kloosterman WP, de Bruijn E, Rosa F, Plasterk RH, Wilson SW. Micro‐ RNAs show a wide diversity of expression profiles in the developing and mature

[109] Shi Y, Chichung Lie D, Taupin P, Nakashima K, Ray J, Yu RT, Gage FH, Evans RM. Expression and function of orphan nuclear receptor TLX in adult neural stem cells.

[110] Li W, Sun G, Yang S, Qu Q, Nakashima K, Shi Y. Nuclear receptor TLX regulates cell cycle progression in neural stem cells of the developing brain. Mol Endocrinol

[111] Zhao C, Sun G, Li S, Shi Y. A feedback regulatory loop involving microRNA-9 and nuclear receptor TLX in neural stem cell fate determination. Nat Struct Mol Biol

%2F10.1371%2Fjournal.pone.0007936 (accessed 7 December 2009)

trocyte differentiation in the fetal brain. Dev Cell 2001;1(6) 749-758.

3345-3356.

324 Trends in Cell Signaling Pathways in Neuronal Fate Decision

2007;56(1) 94-108.

2011;21(4) 564-578.

2006;235(9) 2538-2548.

Nature 2004;427(6969) 78-83.

2008;22(1) 56-64.

2009;16(4) 365-371.

Curr Opin Neurobiol 2009;19(2) 120-126.

plexes. Proc Natl Acad Sci U S A 1998;95(2) 492-498.

central nervous system. Genome Biol 2007;8(8) R173.


**Chapter 13**

**Neural Fate of Mesenchymal Stem Cells**

**and Neural Crest Stem Cells: Which Ways**

**to Get Neurons for Cell Therapy Purpose?**

The treatment of neurological disorders represents a critical issue in clinical research, since no complete recovery of patients can be achieved with actual therapeutic means, despite symptomatic improvements. Indeed, whereas restricted brain areas still house cells compe‐ tent to generate newborn neurons in adulthood, those neural stem cells are present in re‐ stricted amounts. Moreover, this limited neurogenesis does not seem to be sufficient to enable neuronal regeneration in cases of traumatic, ischemic or degenerative lesions of the central nervous system. Therefore, other sources of neural cells have to be considered in a

Stem cells are characterized as cells endowed with continuous self-renewal ability and pluri- or multipotentiality, and could consequently give rise to a wide panel of cell types. Non-germinal stem cells are classified into different categories: (1) Embryonic stem cells (ES) are found in the inner cell mass of blastocyst and are pluripotent stem cells that can generate any mature cell of each of the three germ layers; (2) Induced pluripotent stem cells (iPS) are adult somatic cells that are reprogrammed into pluripotent cells with ESlike abilities; (3) Somatic stem cells are tissue-specific and more restricted than ES cells in terms of differentiation capabilities. They can be isolated from various fetal and adult tis‐ sues, which make them an attractive supply of material for cell therapy. Indeed, while neurons have already been successfully generated from ES cells [1] or iPS cells [2, 3], the use of adult somatic stem cells definitely remain of significant interest regarding technical, ethical and immunological issues concerning cell transplantation for brain diseases. In this

> © 2013 Neirinckx et al.; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© 2013 Neirinckx et al.; licensee InTech. This is a paper distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Bernard Rogister and Sabine Wislet-Gendebien

Additional information is available at the end of the chapter

Virginie Neirinckx, Cécile Coste,

http://dx.doi.org/10.5772/53260

**1. Introduction**

cell therapy objective.
