Integrative genomic analysis of early neurogenesis reveals a temporal genetic program for differentiation and specification of preplate and Cajal-Retzius neurons

English version

Autoři: Jia Li ^aff001; Lei Sun ^aff004; Xue-Liang Peng ^aff003; Xiao-Ming Yu ^aff003; Shao-Jun Qi ^aff001; Zhi John Lu ^aff005; Jing-Dong J. Han ^aff006; Qin Shen ^aff001
Působiště autorů: Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Orthopaedic Department of Tongji Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, China ^aff001; PTN graduate program, School of Life Sciences, Peking University, Beijing, China ^aff002; School of Medicine, Tsinghua University, Beijing, China ^aff003; PTN graduate program, School of Life Sciences, Tsinghua University, Beijing, China ^aff004; MOE Key Laboratory of Bioinformatics, Center for Synthetic and Systems Biology, School of Life Sciences, Tsinghua University, Beijing, China ^aff005; Key Laboratory of Computational Biology, CAS Center for Excellence in Molecular Cell Science, Collaborative Innovation Center for Genetics and Developmental Biology, Chinese Academy of Sciences-Max Planck Partner Institute for Computational Biology, Sh... ^aff006; Frontier Science Center for Stem Cell Research, Ministry of Education, School of Life Sciences and Technology, Tongji University, Shanghai, China ^aff007; Brain and Spinal Cord Clinical Research Center, Tongji University, Shanghai, China ^aff008
Vyšlo v časopise: Integrative genomic analysis of early neurogenesis reveals a temporal genetic program for differentiation and specification of preplate and Cajal-Retzius neurons. PLoS Genet 17(3): e1009355. doi:10.1371/journal.pgen.1009355
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.pgen.1009355

Souhrn

Neurogenesis in the developing neocortex begins with the generation of the preplate, which consists of early-born neurons including Cajal-Retzius (CR) cells and subplate neurons. Here, utilizing the Ebf2-EGFP transgenic mouse in which EGFP initially labels the preplate neurons then persists in CR cells, we reveal the dynamic transcriptome profiles of early neurogenesis and CR cell differentiation. Genome-wide RNA-seq and ChIP-seq analyses at multiple early neurogenic stages have revealed the temporal gene expression dynamics of early neurogenesis and distinct histone modification patterns in early differentiating neurons. We have identified a new set of coding genes and lncRNAs involved in early neuronal differentiation and validated with functional assays in vitro and in vivo. In addition, at E15.5 when Ebf2-EGFP+ cells are mostly CR neurons, single-cell sequencing analysis of purified Ebf2-EGFP+ cells uncovers molecular heterogeneities in CR neurons, but without apparent clustering of cells with distinct regional origins. Along a pseudotemporal trajectory these cells are classified into three different developing states, revealing genetic cascades from early generic neuronal differentiation to late fate specification during the establishment of CR neuron identity and function. Our findings shed light on the molecular mechanisms governing the early differentiation steps during cortical development, especially CR neuron differentiation.

Klíčová slova:

Developmental neuroscience – Gene expression – Histone modification – Hyperexpression techniques – Long non-coding RNA – Neuronal differentiation – Neurons – Stem cells

Zdroje

1. Caviness VS. Neocortical Histogenesis in Normal and Reeler Mice: A Developmental Study Based Upon [3H]Thymidine Autoradiography. Developmental Brain Research. 1982;4:293–302.

2. Kriegstein A, Alvarez-Buylla A. The glial nature of embryonic and adult neural stem cells. Annu Rev Neurosci. 2009;32:149–84. doi: 10.1146/annurev.neuro.051508.135600 19555289.

3. Marin-Padilla M. Ontogenesis of the Pyramidal Cell of the Mammalian Neocortex and Developmental Cytoarchitectonics: A Unifying Theory. J Comp Neurol. 1992;321:321–3. doi: 10.1002/cne.903210205 1500541

4. Hevner RF, Neogi T, Englund C, Daza RA, Fink A. Cajal–Retzius cells in the mouse: transcription factors, neurotransmitters, and birthdays suggest a pallial origin. Developmental Brain Research. 2003;141(1–2):39–53. doi: 10.1016/s0165-3806(02)00641-7 12644247

5. Bayer SA, Altman J. Development of the Endopiriform Nucleus and the Claustrum in the Rat Brain. Neuroscience. 1991;45:391–412. doi: 10.1016/0306-4522(91)90236-h 1762685

6. Takahashi T, Goto T, Miyama S, Nowakowski RS, Caviness VS Jr. Sequence of Neuron Origin and Neocortical Laminar Fate: Relation to Cell Cycle of Origin in the Developing Murine Cerebral Wall. J Neurosci. 1999;19(23):10357–71. doi: 10.1523/JNEUROSCI.19-23-10357.1999 10575033

7. Bystron I, Blakemore C, Rakic P. Development of the human cerebral cortex: Boulder Committee revisited. Nat Rev Neurosci. 2008;9(2):110–22. doi: 10.1038/nrn2252 18209730.

8. Olson EC. Analysis of preplate splitting and early cortical development illuminates the biology of neurological disease. Front Pediatr. 2014;2:1–9. doi: 10.3389/fped.2014.00001 24459665.

9. Ghosh A, Antonini A, McConnell SK, Shatz CJ. Requirement of Subplate Neurons in the Formation of Thalamocortical Connections. Nature. 1990;347:179–81. doi: 10.1038/347179a0 2395469

10. Molnar Z, Adams R, Blakemore C. Mechanisms Underlying the Early Establishment of Thalamocortical Connections in the Rat. J Neurosci. 1998;18(5):5723–45. doi: 10.1523/JNEUROSCI.18-15-05723.1998 9671663

11. del Rio JA, Martinez A, Fonseca M, Auladell C, Soriano E. Glutamate-like Immunoreactivity and Fate of Cajal-Retzius Cells in the Murine Cortex as Identified with Calretinin Antibody. Cereb Cortex. 1995;5:13–21. doi: 10.1093/cercor/5.1.13 7719127

12. Kirischuk S, Luhmann HJ, Kilb W. Cajal-Retzius cells: update on structural and functional properties of these mystic neurons that bridged the 20th century. Neuroscience. 2014;275:33–46. doi: 10.1016/j.neuroscience.2014.06.009 24931764.

13. Hong SE, Shugart YY, Huang DT, Shahwan SA, Grant PE, Hourihane JOB, et al. Autosomal recessive lissencephaly with cerebellar hypoplasia is associated with human RELN mutations. Nature Genetics. 2000;26:93–6. doi: 10.1038/79246 10973257

14. Nakagawa N, Yagi H, Kato K, Takematsu H, Oka S. Ectopic clustering of Cajal-Retzius and subplate cells is an initial pathological feature in Pomgnt2-knockout mice, a model of dystroglycanopathy. Sci Rep. 2015;5:11163. doi: 10.1038/srep11163 26060116.

15. Osheroff H, Hatten ME. Gene expression profiling of preplate neurons destined for the subplate: genes involved in transcription, axon extension, neurotransmitter regulation, steroid hormone signaling, and neuronal survival. Cereb Cortex. 2009;19 Suppl 1:i126–34. doi: 10.1093/cercor/bhp034 19398467.

16. Belgard TG, Marques AC, Oliver PL, Abaan HO, Sirey TM, Hoerder-Suabedissen A, et al. A transcriptomic atlas of mouse neocortical layers. Neuron. 2011;71(4):605–16. doi: 10.1016/j.neuron.2011.06.039 21867878.

17. Oeschger FM, Wang WZ, Lee S, Garcia-Moreno F, Goffinet AM, Arbones ML, et al. Gene expression analysis of the embryonic subplate. Cereb Cortex. 2012;22(6):1343–59. doi: 10.1093/cercor/bhr197 21862448.

18. Hoerder-Suabedissen A, Oeschger FM, Krishnan ML, Belgard TG, Wang WZ, Lee S, et al. Expression profiling of mouse subplate reveals a dynamic gene network and disease association with autism and schizophrenia. Proc Natl Acad Sci U S A. 2013;110(9):3555–60. doi: 10.1073/pnas.1218510110 23401504.

19. Chuang SM, Wang Y, Wang Q, Liu KM, Shen Q. Ebf2 marks early cortical neurogenesis and regulates the generation of cajal-retzius neurons in the developing cerebral cortex. Dev Neurosci. 2011;33(6):479–93. doi: 10.1159/000330582 22042145.

20. Gong S, Zheng C, Doughty ML, Losos K, Didkovsky N, Schambra UB, et al. A gene expression atlas of the central nervous system based on bacterial artificial chromosomes. Nature. 2003;425:917–25. doi: 10.1038/nature02033 14586460

21. Chowdhury TG, Jimenez JC, Bomar JM, Cruz-Martin A, Cantle JP, Portera-Cailliau C. Fate of cajal-retzius neurons in the postnatal mouse neocortex. Front Neuroanat. 2010;4:1–8. doi: 10.3389/neuro.05.001.2010 20161990.

22. Chiara F, Badaloni A, Croci L, Yeh ML, Cariboni A, Hoerder-Suabedissen A, et al. Early B-cell factors 2 and 3 (EBF2/3) regulate early migration of Cajal-Retzius cells from the cortical hem. Dev Biol. 2012;365(1):277–89. doi: 10.1016/j.ydbio.2012.02.034 22421355.

23. Yamazaki H, Sekiguchi M, Takamatsu M, Tanabe Y, Nakanishi S. Distinct ontogenic and regional expressions of newly identified Cajal–Retzius cell-specific genes during neocorticogenesis. PNAS. 2004;101(40):14509–14. doi: 10.1073/pnas.0406295101 15452350

24. Bielle F, Griveau A, Narboux-Neme N, Vigneau S, Sigrist M, Arber S, et al. Multiple origins of Cajal-Retzius cells at the borders of the developing pallium. Nat Neurosci. 2005;8(8):1002–12. doi: 10.1038/nn1511 16041369.

25. Macosko EZ, Basu A, Satija R, Nemesh J, Shekhar K, Goldman M, et al. Highly Parallel Genome-wide Expression Profiling of Individual Cells Using Nanoliter Droplets. Cell. 2015;161(5):1202–14. doi: 10.1016/j.cell.2015.05.002 26000488.

26. Zeisel A, Muñoz-Manchado AB, Codeluppi S, Lönnerberg P, La Manno G, Juréus A, et al. Cell types in the mouse cortex and hippocampus revealed by single-cell RNA-seq. Science. 2015;347(6226):1138–42. doi: 10.1126/science.aaa1934 25700174

27. Shin J, Berg DA, Zhu Y, Shin JY, Song J, Bonaguidi MA, et al. Single-Cell RNA-Seq with Waterfall Reveals Molecular Cascades underlying Adult Neurogenesis. Cell Stem Cell. 2015;17(3):360–72. doi: 10.1016/j.stem.2015.07.013 26299571.

28. Hanashima C, Li SC, Shen L, Lai E, Fishell G. Foxg1 Suppresses Early Cortical Cell Fate. Science. 2004;303:56–9. doi: 10.1126/science.1090674 14704420

29. Shen Q, Wang Y, Dimos JT, Fasano CA, Phoenix TN, Lemischka IR, et al. The timing of cortical neurogenesis is encoded within lineages of individual progenitor cells. Nat Neurosci. 2006;9(6):743–51. doi: 10.1038/nn1694 16680166.

30. Hevner RF, Shi L, Justice N, Hsueh YP, Sheng M, Smiga S, et al. Tbr1 Regulates Differentiation of the Preplate and Layer 6. Neuron. 2001;29:353–66. doi: 10.1016/s0896-6273(01)00211-2 11239428

31. Lein ES, Hawrylycz MJ, Ao N, Ayres M, Bensinger A, Bernard A, et al. Genome-wide atlas of gene expression in the adult mouse brain. Nature. 2007;445(7124):168–76. Epub 2006/12/08. doi: 10.1038/nature05453 17151600.

32. Hoerder-Suabedissen A, Wang WZ, Lee S, Davies KE, Goffinet AM, Rakic S, et al. Novel markers reveal subpopulations of subplate neurons in the murine cerebral cortex. Cereb Cortex. 2009;19(8):1738–50. doi: 10.1093/cercor/bhn195 19008461.

33. Winner B, Regensburger M, Schreglmann S, Boyer L, Prots I, Rockenstein E, et al. Role of alpha-synuclein in adult neurogenesis and neuronal maturation in the dentate gyrus. J Neurosci. 2012;32(47):16906–16. Epub 2012/11/24. doi: 10.1523/JNEUROSCI.2723-12.2012 23175842.

34. Fan H, Lv P, Mu T, Zhao X, Liu Y, Feng Y, et al. LncRNA n335586/miR-924/CKMT1A axis contributes to cell migration and invasion in hepatocellular carcinoma cells. Cancer Lett. 2018;429:89–99. Epub 2018/05/14. doi: 10.1016/j.canlet.2018.05.010 29753758.

35. Kruger M, Ruschke K, Braun T. NSCL-1 and NSCL-2 synergistically determine the fate of GnRH-1 neurons and control necdin gene expression. EMBO J. 2004;23(21):4353–64. Epub 2004/10/08. doi: 10.1038/sj.emboj.7600431 15470499.

36. Albrieux M, Platel JC, Dupuis A, Villaz M, Moody WJ. Early expression of sodium channel transcripts and sodium current by cajal-retzius cells in the preplate of the embryonic mouse neocortex. J Neurosci. 2004;24(7):1719–25. doi: 10.1523/JNEUROSCI.3548-02.2004 14973256.

37. Nguyen-Ba-Charvet KT, Picard-Riera N, Tessier-Lavigne M, Baron-Van Evercooren A, Sotelo C, Chedotal A. Multiple roles for slits in the control of cell migration in the rostral migratory stream. J Neurosci. 2004;24(6):1497–506. Epub 2004/02/13. doi: 10.1523/JNEUROSCI.4729-03.2004 14960623.

38. Yagi H, Yanagisawa M, Suzuki Y, Nakatani Y, Ariga T, Kato K, et al. HNK-1 epitope-carrying tenascin-C spliced variant regulates the proliferation of mouse embryonic neural stem cells. J Biol Chem. 2010;285(48):37293–301. Epub 2010/09/22. doi: 10.1074/jbc.M110.157081 20855890.

39. Meyer G. Building a human cortex: the evolutionary differentiation of Cajal-Retzius cells and the cortical hem. J Anat. 2010;217(4):334–43. doi: 10.1111/j.1469-7580.2010.01266.x 20626498.

40. Corradi A, Croci L, Broccoli V, Zecchini S, Previtali S, Wurst W, et al. Hypogonadotropic hypogonadism and peripheral neuropathy in Ebf2-null mice. Development. 2003;130(2):401–10. doi: 10.1242/dev.00215 12466206

41. Miquelajauregui A, Varela-Echavarria A, Ceci ML, Garcia-Moreno F, Ricano I, Hoang K, et al. LIM-homeobox gene Lhx5 is required for normal development of Cajal-Retzius cells. J Neurosci. 2010;30(31):10551–62. doi: 10.1523/JNEUROSCI.5563-09.2010 20685998.

42. Tedeschi A, Dupraz S, Laskowski CJ, Xue J, Ulas T, Beyer M, et al. The Calcium Channel Subunit Alpha2delta2 Suppresses Axon Regeneration in the Adult CNS. Neuron. 2016;92(2):419–34. doi: 10.1016/j.neuron.2016.09.026 27720483.

43. Ohtsuka T, Sakamoto M, Guillemot F, Kageyama R. Roles of the basic helix-loop-helix genes Hes1 and Hes5 in expansion of neural stem cells of the developing brain. J Biol Chem. 2001;276(32):30467–74. Epub 2001/06/16. doi: 10.1074/jbc.M102420200 11399758.

44. Larysa Pevny, Placzek Marysia. SOX genes and neural progenitor identity. Curr Opin Neurobiol. 2005;15(1):7–13. doi: 10.1016/j.conb.2005.01.016 15721738

45. Buscarlet M, Perin A, Laing A, Brickman JM, Stifani S. Inhibition of Cortical Neuron Differentiation by Groucho/TLE1 Requires Interaction with WRPW, but Not Eh1, Repressor Peptides. Journal of Biological Chemistry. 2008;283(36):24881–8. doi: 10.1074/jbc.M800722200 18611861

46. Heng JI, Nguyen L, Castro DS, Zimmer C, Wildner H, Armant O, et al. Neurogenin 2 controls cortical neuron migration through regulation of Rnd2. Nature. 2008;455(7209):114–8. doi: 10.1038/nature07198 18690213.

47. Paap RH, Oosterbroek S, Wagemans Cmrj, von Oerthel L, Schellevis RD, Vastenhouw-van der Linden AJA, et al. FoxO6 affects Plxna4-mediated neuronal migration during mouse cortical development. Proc Natl Acad Sci U S A. 2016;113(45):E7087–E96. doi: 10.1073/pnas.1609111113 27791111.

48. Inoue T, Ogawa M, Mikoshiba K, Aruga J. Zic deficiency in the cortical marginal zone and meninges results in cortical lamination defects resembling those in type II lissencephaly. J Neurosci. 2008;28(18):4712–25. doi: 10.1523/JNEUROSCI.5735-07.2008 18448648.

49. Segklia A, Seuntjens E, Elkouris M, Tsalavos S, Stappers E, Mitsiadis TA, et al. Bmp7 regulates the survival, proliferation, and neurogenic properties of neural progenitor cells during corticogenesis in the mouse. PLoS One. 2012;7(3):e34088. doi: 10.1371/journal.pone.0034088 22461901.

50. Tiberi L, van den Ameele J, Dimidschstein J, Piccirilli J, Gall D, Herpoel A, et al. BCL6 controls neurogenesis through Sirt1-dependent epigenetic repression of selective Notch targets. Nat Neurosci. 2012;15(12):1627–35. doi: 10.1038/nn.3264 23160044.

51. Aprea J, Prenninger S, Dori M, Ghosh T, Monasor LS, Wessendorf E, et al. Transcriptome sequencing during mouse brain development identifies long non-coding RNAs functionally involved in neurogenic commitment. EMBO J. 2013;32(24):3145–60. doi: 10.1038/emboj.2013.245 24240175.

52. Nishi T, Forgac M. The vacuolar (H+)-ATPases-nature’s most versatile proton pumps. Nat Rev Mol Cell Biol. 2002;3(2):94–103. doi: 10.1038/nrm729 11836511.

53. Ueda T, Ugawa S, Shimada S. A novel putative M9.2 isoform of V-ATPase expressed in the nervous system. Neuroreport. 2003;14(1):25–30. doi: 10.1097/00001756-200301200-00005 12544825.

54. Boal F, Hodgson LR, Reed SE, Yarwood SE, Just VJ, Stephens DJ, et al. Insulin promotes Rip11 accumulation at the plasma membrane by inhibiting a dynamin- and PI3-kinase-dependent, but Akt-independent, internalisation event. Cell Signal. 2016;28(1):74–82. doi: 10.1016/j.cellsig.2015.10.014 26515129.

55. Sun L, Chen RG, Bai Y, Li J, Wu Q, Shen Q, et al. Morphological and Physiological Characteristics of Ebf2-EGFP-Expressing Cajal-Retzius Cells in Developing Mouse Neocortex. Cereb Cortex. 2018;29(9):1–15. doi: 10.1093/cercor/bhy265 30307495

56. Borrell V, Marin O. Meninges control tangential migration of hem-derived Cajal-Retzius cells via CXCL12/CXCR4 signaling. Nat Neurosci. 2006;9(10):1284–93. doi: 10.1038/nn1764 16964252.

57. Shinozaki K, Miyagi T, Yoshida M, Miyata T, Ogawa M, Aizawa S, et al. Absence of Cajal-Retzius cells and subplate neurons associated with defects of tangential cell migration from ganglionic eminence in Emx1/2double mutant cerebral cortex. Development. 2002;129:3479–92. 12091317

58. Trapnell C, Cacchiarelli D, Grimsby J, Pokharel P, Li S, Morse M, et al. The dynamics and regulators of cell fate decisions are revealed by pseudotemporal ordering of single cells. Nat Biotechnol. 2014;32(4):381–6. doi: 10.1038/nbt.2859 24658644.

59. Hevner RF, Hodge RD, Daza RA, Englund C. Transcription factors in glutamatergic neurogenesis: conserved programs in neocortex, cerebellum, and adult hippocampus. Neurosci Res. 2006;55(3):223–33. doi: 10.1016/j.neures.2006.03.004 16621079.

60. Aydin B, Kakumanu A, Rossillo M, Moreno-Estellés M, Garipler G, Ringstad N, et al. Proneural factors Ascl1 and Neurog2 contribute to neuronal subtype identities by establishing distinct chromatin landscapes. Nat Neurosci. 2019;22(6):897–908. doi: 10.1038/s41593-019-0399-y 31086315

61. Luo Z, Gao X, Lin C, Smith ER, Marshall SA, Swanson SK, et al. Zic2 Is an Enhancer-Binding Factor Required for Embryonic Stem Cell Specification. Mol Cell. 2015;57(4):685–94. doi: 10.1016/j.molcel.2015.01.007 25699711

62. Hanashima C, Fernandes M, Hebert JM, Fishell G. The role of Foxg1 and dorsal midline signaling in the generation of Cajal-Retzius subtypes. J Neurosci. 2007;27(41):11103–11. doi: 10.1523/JNEUROSCI.1066-07.2007 17928452.

63. Lodato S, Molyneaux BJ, Zuccaro E, Goff LA, Chen HH, Yuan W, et al. Gene co-regulation by Fezf2 selects neurotransmitter identity and connectivity of corticospinal neurons. Nat Neurosci. 2014;17(8):1046–54. doi: 10.1038/nn.3757 24997765

64. Jenuwein T, Allis CD. Translating the Histone Code. Science. 2001;293:1074–80. doi: 10.1126/science.1063127 11498575

65. Attanasio C, Nord AS, Zhu Y, Blow MJ, Biddie SC, Mendenhall EM, et al. Tissue-specific SMARCA4 binding at active and repressed regulatory elements during embryogenesis. Genome Res. 2014;24(6):920–9. doi: 10.1101/gr.168930.113 24752179.

66. Bernstein BE, Mikkelsen TS, Xie X, Kamal M, Huebert DJ, Cuff J, et al. A bivalent chromatin structure marks key developmental genes in embryonic stem cells. Cell. 2006;125(2):315–26. doi: 10.1016/j.cell.2006.02.041 16630819.

67. Albert M, Kalebic N, Florio M, Lakshmanaperumal N, Haffner C, Brandl H, et al. Epigenome profiling and editing of neocortical progenitor cells during development. EMBO J. 2017;36(17):2642–58. doi: 10.15252/embj.201796764 28765163.

68. Creyghton MP, Cheng AW, Welstead GG, Kooistra T, Carey BW, Steine EJ, et al. Histone H3K27ac separates active from poised enhancers and predicts developmental state. Proc Natl Acad Sci U S A. 2010;107(50):21931–6. doi: 10.1073/pnas.1016071107 21106759.

69. Ye Y, Li M, Gu L, Chen X, Shi J, Zhang X, et al. Chromatin remodeling during in vivo neural stem cells differentiating to neurons in early Drosophila embryos. Cell Death Differ. 2017;24(3):409–20. doi: 10.1038/cdd.2016.135 27858939.

70. Mienville JM, Barker JL. Potassium Current Expression during Prenatal Corticogenesis in the Rat. Neuroscience. 1997;81:163–72. doi: 10.1016/s0306-4522(97)00171-1 9300409

71. Kirmse K, Grantyn R, Kirischuk S. Developmental downregulation of low-voltage-activated Ca2+ channels in Cajal-Retzius cells of the mouse visual cortex. Eur J Neurosci. 2005;21(12):3269–76. doi: 10.1111/j.1460-9568.2005.04171.x 16026465.

72. Moore AR, Filipovic R, Mo Z, Rasband MN, Zecevic N, Antic SD. Electrical Excitability of Early Neurons in the Human Cerebral Cortex during the Second Trimester of Gestation. Cerebral Cortex. 2009;19(8):1795–805. doi: 10.1093/cercor/bhn206 19015375

73. Selemon LD, Zecevic N. Schizophrenia: a tale of two critical periods for prefrontal cortical development. Transl Psychiatry. 2015;5:e623. doi: 10.1038/tp.2015.115 26285133.

74. Cech Thomas R, Steitz Joan A. The Noncoding RNA Revolution—Trashing Old Rules to Forge New Ones. Cell. 2014;157(1):77–94. doi: 10.1016/j.cell.2014.03.008 24679528

75. Faghihi MA, Modarresi F, Khalil AM, Wood DE, Sahagan BG, Morgan TE, et al. Expression of a noncoding RNA is elevated in Alzheimer’s disease and drives rapid feed-forward regulation of b-secretase. Nat Med. 2008;14(7):723–30. doi: 10.1038/nm1784 18587408

76. Barry G, Briggs JA, Vanichkina DP, Poth EM, Beveridge NJ, Ratnu VS, et al. The long non-coding RNA Gomafu is acutely regulated in response to neuronal activation and involved in schizophrenia-associated alternative splicing. Mol Psychiatry. 2014;19(4):486–94. Epub 2013/05/01. doi: 10.1038/mp.2013.45 23628989.

77. Moore DL, Blackmore MG, Hu Y, Kaestner KH, Bixby JL, Lemmon VP, et al. KLF family members regulate intrinsic axon regeneration ability. Science. 2009;326(5950):298–301. Epub 2009/10/10. doi: 10.1126/science.1175737 19815778.

78. Caiazzoa M, Colucci-D’Amato L, Esposito MT, Parisi S, Stifani S, Ramirez F, et al. Transcription factor KLF7 regulates differentiation of neuroectodermal and mesodermal cell lineages. Exp Cell Res. 2010;316. doi: 10.1016/j.yexcr.2010.05.021 20580711

79. Jang DH, Chae H, Kim M. Autistic and Rett-like features associated with 2q33.3-q34 interstitial deletion. Am J Med Genet. 2015;167A(9):2213–8. Epub 2015/04/23. doi: 10.1002/ajmg.a.37119 25899208.

80. Harms FL, Girisha KM, Hardigan AA, Kortum F, Shukla A, Alawi M, et al. Mutations in EBF3 Disturb Transcriptional Profiles and Cause Intellectual Disability, Ataxia, and Facial Dysmorphism. Am J Hum Genet. 2017;100(1):117–27. Epub 2016/12/27. doi: 10.1016/j.ajhg.2016.11.012 28017373.

81. Lee JE, Hollenberg SM, Snider L, Turner DL, Lipnick N, Weintraub H. Conversion of Xenopus Ectoderm into Neurons by NeuroD, a Basic Helix-Loop-Helix Protein. Science. 1995;268:836–44. doi: 10.1126/science.7754368 7754368

82. Pastrana E, Cheng LC, Doetsch F. Simultaneous prospective purification of adult subventricular zone neural stem cells and their progeny. PNAS. 2009;106:6387–92. doi: 10.1073/pnas.0810407106 19332781

83. Kim D, Pertea G, Trapnell C, Pimentel H, Kelley R, Salzberg SL. TopHat2: accurate alignment of transcriptomes in the presence of insertions, deletions and gene fusions. Genome Biology. 2013;14(4). doi: 10.1186/gb-2013-14-4-r36 23618408

84. Trapnell C, Williams BA, Pertea G, Mortazavi A, Kwan G, van Baren MJ, et al. Transcript assembly and quantification by RNA-Seq reveals unannotated transcripts and isoform switching during cell differentiation. Nat Biotechnol. 2010;28(5):511–5. doi: 10.1038/nbt.1621 20436464.

85. Mudge JM, Harrow J. Creating reference gene annotation for the mouse C57BL6/J genome assembly. Mamm Genome. 2015;26(9–10):366–78. Epub 2015/07/19. doi: 10.1007/s00335-015-9583-x 26187010.

86. Trapnell C, Hendrickson DG, Sauvageau M, Goff L, Rinn JL, Pachter L. Differential analysis of gene regulation at transcript resolution with RNA-seq. Nat Biotechnol. 2013;31(1):46–53. Epub 2012/12/12. doi: 10.1038/nbt.2450 23222703.

87. Hu XL, Chen G, Zhang S, Zheng J, Wu J, Bai QR, et al. Persistent Expression of VCAM1 in Radial Glial Cells Is Required for the Embryonic Origin of Postnatal Neural Stem Cells. Neuron. 2017;95(2):309–25 e1-e6. Epub 2017/07/21. doi: 10.1016/j.neuron.2017.06.047 28728023.

88. Qian X, Shen Q, Goderie SK, He W, Capela A, Davis AA, et al. Timing of CNS Cell Generation: A Programmed Sequence of Neuron and Glial Cell Production from Isolated Murine Cortical Stem Cells. Neuron. 2000;28:69–80. doi: 10.1016/s0896-6273(00)00086-6 11086984

89. Shen Q, Goderie SK, Jin L, Karanth N, Sun Y, Abramova N, et al. Endothelial cells stimulate self-renewal and expand neurogenesis of neural stem cells. Science. 2004;304(5675):1338–40. Epub 2004/04/03. doi: 10.1126/science.1095505 15060285.

90. Kloosterman WP, Wienholds E, de Bruijn E, Kauppinen S, Plasterk RH. In situ detection of miRNAs in animal embryos using LNA-modified oligonucleotide probes. Nat Methods. 2006;3(1):27–9. Epub 2005/12/22. doi: 10.1038/nmeth843 16369549.

91. Obernosterer G, Martinez J, Alenius M. Locked nucleic acid-based in situ detection of microRNAs in mouse tissue sections. Nat Protoc. 2007;2(6):1508–14. Epub 2007/06/16. doi: 10.1038/nprot.2007.153 17571058.

92. Shen X, Kim W, Fujiwara Y, Simon MD, Liu Y, Mysliwiec MR, et al. Jumonji modulates polycomb activity and self-renewal versus differentiation of stem cells. Cell. 2009;139(7):1303–14. doi: 10.1016/j.cell.2009.12.003 20064376.

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