Molecular Neurobiology

, Volume 39, Issue 1, pp 10–23 | Cite as

Nuclear Factor One Transcription Factors in CNS Development

  • Sharon Mason
  • Michael Piper
  • Richard M. Gronostajski
  • Linda J. RichardsEmail author


Transcription factors are key regulators of central nervous system (CNS) development and brain function. Research in this area has now uncovered a new key player–the nuclear factor one (NFI) gene family. It has been almost a decade since the phenotype of the null mouse mutant for the nuclear factor one A transcription factor was reported. Nfia null mice display a striking brain phenotype including agenesis of the corpus callosum and malformation of midline glial populations needed to guide axons of the corpus callosum across the midline of the developing brain. Besides NFIA, there are three other NFI family members in vertebrates: NFIB, NFIC, and NFIX. Since generation of the Nfia knockout (KO) mice, KO mice for all other family members have been generated, and defects in one or more organ systems have been identified for all four NFI family members (collectively referred to as NFI here). Like the Nfia KO mice, the Nfib and Nfix KO mice also display a brain phenotype, with the Nfib KO forebrain phenotype being remarkably similar to that of Nfia. Over the past few years, studies have highlighted NFI as a key payer in a variety of CNS processes including axonal outgrowth and guidance and glial and neuronal cell differentiation. Here, we discuss the importance and role of NFI in these processes in the context of several CNS systems including the neocortex, hippocampus, cerebellum, and spinal cord at both cellular and molecular levels.


Pax6 Ngn Emx Cerebellum Spinal cord Cerebral cortex Hippocampus Cellular differentiation 



We thank Dr Guy Barry and Ms Erica Little for comments on the manuscript. This work was funded by a National Health and Medical Research Council (NHMRC) project grant (LJR) and a Clive and Vera Ramaciotti grant (MP). LJR is supported by a NHMRC Senior Research Fellowship, SM is supported by a University of Queensland F.G Meade PhD Scholarship, and MP is supported by a NHMRC Howard Florey Centenary Fellowship.


  1. 1.
    Nagata K, Guggenheimer RA, Enomoto T, Lichy JH, Hurwitz J (1982) Adenovirus DNA replication in vitro: identification of a host factor that stimulates synthesis of the preterminal protein-dCMP complex. Proc Natl Acad Sci U S A 79(21):6438–6442PubMedCrossRefGoogle Scholar
  2. 2.
    Nagata K, Guggenheimer RA, Hurwitz J (1983) Specific binding of a cellular DNA replication protein to the origin of replication of adenovirus DNA. Proc Natl Acad Sci U S A 80(20):6177–6181PubMedCrossRefGoogle Scholar
  3. 3.
    Kruse U, Sippel AE (1994) Transcription factor nuclear factor I proteins form stable homo- and heterodimers. FEBS Lett 348(1):46–50PubMedCrossRefGoogle Scholar
  4. 4.
    Gronostajski RM, Adhya S, Nagata K, Guggenheimer RA, Hurwitz J (1985) Site-specific DNA binding of nuclear factor I: analyses of cellular binding sites. Mol Cell Biol 5(5):964–971PubMedGoogle Scholar
  5. 5.
    Leegwater PA, van Driel W, van der Vliet PC (1985) Recognition site of nuclear factor I, a sequence-specific DNA-binding protein from HeLa cells that stimulates adenovirus DNA replication. Embo J. 4(6):1515–1521PubMedGoogle Scholar
  6. 6.
    Gronostajski RM (1986) Analysis of nuclear factor I binding to DNA using degenerate oligonucleotides. Nucleic Acids Res 14(22):9117–9132PubMedCrossRefGoogle Scholar
  7. 7.
    Gronostajski RM (1987) Site-specific DNA binding of nuclear factor I: effect of the spacer region. Nucleic Acids Res 15(14):5545–5559PubMedCrossRefGoogle Scholar
  8. 8.
    Meisterernst M, Gander I, Rogge L, Winnacker EL (1988) A quantitative analysis of nuclear factor I/DNA interactions. Nucleic Acids Res 16(10):4419–4435PubMedCrossRefGoogle Scholar
  9. 9.
    Fletcher CF, Jenkins NA, Copeland NG, Chaudhry AZ, Gronostajski RM (1999) Exon structure of the nuclear factor I DNA-binding domain from C. elegans to mammals. Mamm Genome 10(4):390–396PubMedCrossRefGoogle Scholar
  10. 10.
    Gronostajski RM (2000) Roles of the NFI/CTF gene family in transcription and development. Gene 249(1–2):31–45PubMedCrossRefGoogle Scholar
  11. 11.
    Strausberg RL, Feingold EA, Grouse LH, Derge JG, Klausner RD, Collins FS, Wagner L, Shenmen CM, Schuler GD, Altschul SF, Zeeberg B, Buetow KH, Schaefer CF, Bhat NK, Hopkins RF, Jordan H, Moore T, Max SI, Wang J, Hsieh F, Diatchenko L, Marusina K, Farmer AA, Rubin GM, Hong L, Stapleton M, Soares MB, Bonaldo MF, Casavant TL, Scheetz TE, Brownstein MJ, Usdin TB, Toshiyuki S, Carninci P, Prange C, Raha SS, Loquellano NA, Peters GJ, Abramson RD, Mullahy SJ, Bosak SA, McEwan PJ, McKernan KJ, Malek JA, Gunaratne PH, Richards S, Worley KC, Hale S, Garcia AM, Gay LJ, Hulyk SW, Villalon DK, Muzny DM, Sodergren EJ, Lu X, Gibbs RA, Fahey J, Helton E, Ketteman M, Madan A, Rodrigues S, Sanchez A, Whiting M, Young AC, Shevchenko Y, Bouffard GG, Blakesley RW, Touchman JW, Green ED, Dickson MC, Rodriguez AC, Grimwood J, Schmutz J, Myers RM, Butterfield YS, Krzywinski MI, Skalska U, Smailus DE, Schnerch A, Schein JE, Jones SJ, Marra MA (2002) Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proc Natl Acad Sci U S A 99(26):16899–16903PubMedCrossRefGoogle Scholar
  12. 12.
    Kruse U, Qian F, Sippel AE (1991) Identification of a fourth nuclear factor I gene in chicken by cDNA cloning: NFI-X. Nucleic Acids Res 19(23):6641PubMedCrossRefGoogle Scholar
  13. 13.
    Rupp RA, Kruse U, Multhaup G, Gobel U, Beyreuther K, Sippel AE (1990) Chicken NFI/TGGCA proteins are encoded by at least three independent genes: NFI-A, NFI-B and NFI-C with homologues in mammalian genomes. Nucleic Acids Res 18(9):2607–2616PubMedCrossRefGoogle Scholar
  14. 14.
    Puzianowska-Kuznicka M, Shi YB (1996) Nuclear factor I as a potential regulator during postembryonic organ development. J Biol Chem 271(11):6273–6282PubMedCrossRefGoogle Scholar
  15. 15.
    Roulet E, Armentero MT, Krey G, Corthesy B, Dreyer C, Mermod N, Wahli W (1995) Regulation of the DNA-binding and transcriptional activities of Xenopus laevis NFI-X by a novel C-terminal domain. Mol Cell Biol 15(10):5552–5562PubMedGoogle Scholar
  16. 16.
    Apt D, Liu Y, Bernard HU (1994) Cloning and functional analysis of spliced isoforms of human nuclear factor I-X: interference with transcriptional activation by NFI/CTF in a cell-type specific manner. Nucleic Acids Res. 22(19):3825–3833PubMedCrossRefGoogle Scholar
  17. 17.
    Kulkarni S, Gronostajski RM (1996) Altered expression of the developmentally regulated NFI gene family during phorbol ester-induced differentiation of human leukemic cells. Cell Growth Differ 7(4):501–510PubMedGoogle Scholar
  18. 18.
    Mermod N, O’Neill EA, Kelly TJ, Tjian R (1989) The proline-rich transcriptional activator of CTF/NF-I is distinct from the replication and DNA binding domain. Cell 58(4):741–753PubMedCrossRefGoogle Scholar
  19. 19.
    Bandyopadhyay S, Gronostajski RM (1994) Identification of a conserved oxidation-sensitive cysteine residue in the NFI family of DNA-binding proteins. J Biol Chem 269(47):29949–29955PubMedGoogle Scholar
  20. 20.
    Bandyopadhyay S, Starke DW, Mieyal JJ, Gronostajski RM (1998) Thioltransferase (glutaredoxin) reactivates the DNA-binding activity of oxidation-inactivated nuclear factor I. J Biol Chem 273(1):392–397PubMedCrossRefGoogle Scholar
  21. 21.
    Chaudhry AZ, Lyons GE, Gronostajski RM (1997) Expression patterns of the four nuclear factor I genes during mouse embryogenesis indicate a potential role in development. Dev Dyn 208(3):313–325PubMedCrossRefGoogle Scholar
  22. 22.
    Chaudhry AZ, Vitullo AD, Gronostajski RM (1999) Nuclear factor I-mediated repression of the mouse mammary tumor virus promoter is abrogated by the coactivators p300/CBP and SRC-1. J Biol Chem 274(11):7072–7081PubMedCrossRefGoogle Scholar
  23. 23.
    Santoro C, Mermod N, Andrews PC, Tjian R (1988) A family of human CCAAT-box-binding proteins active in transcription and DNA replication: cloning and expression of multiple cDNAs. Nature. 334(6179):218–224PubMedCrossRefGoogle Scholar
  24. 24.
    Grunder A, Qian F, Ebel TT, Mincheva A, Lichter P, Kruse U, Sippel AE (2003) Genomic organization, splice products and mouse chromosomal localization of genes for transcription factor Nuclear Factor One. Gene 304:171–181PubMedCrossRefGoogle Scholar
  25. 25.
    Kruse U, Sippel AE (1994) The genes for transcription factor nuclear factor I give rise to corresponding splice variants between vertebrate species. J Mol Biol 238(5):860–865PubMedCrossRefGoogle Scholar
  26. 26.
    Wang W, Stock RE, Gronostajski RM, Wong YW, Schachner M, Kilpatrick DL (2004) A role for nuclear factor I in the intrinsic control of cerebellar granule neuron gene expression. J Biol Chem 279(51):53491–53497PubMedCrossRefGoogle Scholar
  27. 27.
    Meisterernst M, Rogge L, Foeckler R, Karaghiosoff M, Winnacker EL (1989) Structural and functional organization of a porcine gene coding for nuclear factor I. Biochemistry 28(20):8191–8200PubMedCrossRefGoogle Scholar
  28. 28.
    Kane R, Murtagh J, Finlay D, Marti A, Jaggi R, Blatchford D, Wilde C, Martin F (2002) Transcription factor NFIC undergoes N-glycosylation during early mammary gland involution. J Biol Chem 277(29):25893–25903PubMedCrossRefGoogle Scholar
  29. 29.
    Mukhopadhyay SS, Rosen JM (2007) The C-terminal domain of the nuclear factor I-B2 isoform is glycosylated and transactivates the WAP gene in the JEG-3 cells. Biochem Biophys Res Commun 358(3):770–776PubMedCrossRefGoogle Scholar
  30. 30.
    Kawamura H, Nagata K, Masamune Y, Nakanishi Y (1993) Phosphorylation of NF-I in vitro by cdc2 kinase. Biochem Biophys Res Commun 192(3):1424–1431PubMedCrossRefGoogle Scholar
  31. 31.
    Bisgrove DA, Monckton EA, Packer M, Godbout R (2000) Regulation of brain fatty acid-binding protein expression by differential phosphorylation of nuclear factor I in malignant glioma cell lines. J Biol Chem 275(39):30668–30676PubMedCrossRefGoogle Scholar
  32. 32.
    Nilsson J, Bjursell G, Kannius-Janson M (2006) Nuclear Jak2 and transcription factor NF1-C2: a novel mechanism of prolactin signaling in mammary epithelial cells. Mol Cell Biol 26(15):5663–5674PubMedCrossRefGoogle Scholar
  33. 33.
    Campbell CE, Piper M, Plachez C, Yeh YT, Baizer JS, Osinski JM, Litwack ED, Richards LJ, Gronostajski RM (2008) The transcription factor Nfix is essential for normal brain development. BMC Dev Biol 8:52PubMedCrossRefGoogle Scholar
  34. 34.
    das Neves L, Duchala CS, Tolentino-Silva F, Haxhiu MA, Colmenares C, Macklin WB, Campbell CE, Butz KG, Gronostajski RM (1999) Disruption of the murine nuclear factor I-A gene (Nfia) results in perinatal lethality, hydrocephalus, and agenesis of the corpus callosum. Proc Natl Acad Sci U S A 96(21):11946–11951PubMedCrossRefGoogle Scholar
  35. 35.
    Driller K, Pagenstecher A, Uhl M, Omran H, Berlis A, Grunder A, Sippel AE (2007) Nuclear factor I X deficiency causes brain malformation and severe skeletal defects. Mol Cell Biol 27(10):3855–3867PubMedCrossRefGoogle Scholar
  36. 36.
    Shu T, Butz KG, Plachez C, Gronostajski RM, Richards LJ (2003) Abnormal development of forebrain midline glia and commissural projections in Nfia knock-out mice. J Neurosci 23(1):203–212PubMedGoogle Scholar
  37. 37.
    Steele-Perkins G, Plachez C, Butz KG, Yang G, Bachurski CJ, Kinsman SL, Litwack ED, Richards LJ, Gronostajski RM (2005) The transcription factor gene Nfib is essential for both lung maturation and brain development. Mol Cell Biol 25(2):685–698PubMedCrossRefGoogle Scholar
  38. 38.
    Lu W, Quintero-Rivera F, Fan Y, Alkuraya FS, Donovan DJ, Xi Q, Turbe-Doan A, Li QG, Campbell CG, Shanske AL, Sherr EH, Ahmad A, Peters R, Rilliet B, Parvex P, Bassuk AG, Harris DJ, Ferguson H, Kelly C, Walsh CA, Gronostajski RM, Devriendt K, Higgins A, Ligon AH, Quade BJ, Morton CC, Gusella JF, Maas RL (2007) NFIA haploinsufficiency is associated with a CNS malformation syndrome and urinary tract defects. PLoS Genet 3(5):e80PubMedCrossRefGoogle Scholar
  39. 39.
    Steele-Perkins G, Butz KG, Lyons GE, Zeichner-David M, Kim HJ, Cho MI, Gronostajski RM (2003) Essential role for NFI-C/CTF transcription-replication factor in tooth root development. Mol Cell Biol 23(3):1075–1084PubMedCrossRefGoogle Scholar
  40. 40.
    Park JC, Herr Y, Kim HJ, Gronostajski RM, Cho MI (2007) Nfic gene disruption inhibits differentiation of odontoblasts responsible for root formation and results in formation of short and abnormal roots in mice. J Periodontol 78(9):1795–1802PubMedCrossRefGoogle Scholar
  41. 41.
    Plachez C, Lindwall C, Sunn N, Piper M, Moldrich RX, Campbell CE, Osinski JM, Gronostajski R, Richards LJ (2008) Nuclear factor I gene expression in the developing forebrain. J Comp Neurol 508(3):385–401PubMedCrossRefGoogle Scholar
  42. 42.
    Wang W, Mullikin-Kilpatrick D, Crandall JE, Gronostajski RM, Litwack ED, Kilpatrick DL (2007) Nuclear factor I coordinates multiple phases of cerebellar granule cell development via regulation of cell adhesion molecules. J Neurosci 27(23):6115–61127PubMedCrossRefGoogle Scholar
  43. 43.
    Shu T, Richards LJ (2001) Cortical axon guidance by the glial wedge during the development of the corpus callosum. J Neurosci 21(8):2749–2758PubMedGoogle Scholar
  44. 44.
    Shu T, Li Y, Keller A, Richards LJ (2003) The glial sling is a migratory population of developing neurons. Development 130(13):2929–2937PubMedCrossRefGoogle Scholar
  45. 45.
    Silver J, Lorenz SE, Wahlsten D, Coughlin J (1982) Axonal guidance during development of the great cerebral commissures: descriptive and experimental studies, in vivo, on the role of preformed glial pathways. J Comp Neurol 210(1):10–29PubMedCrossRefGoogle Scholar
  46. 46.
    Barry G, Piper M, Lindwall C, Moldrich RX, Mason S, Little E, Sarkar A, Tole S, Gronostajski R, Richards LJ (2008) Specific glial populations regulate hippocampal morphogenesis. J Neuroosci 28(47):12328–12340Google Scholar
  47. 47.
    Rickmann M, Amaral DG, Cowan WM (1987) Organization of radial glial cells during the development of the rat dentate gyrus. J Comp Neurol 264(4):449–479PubMedCrossRefGoogle Scholar
  48. 48.
    Sievers J, Hartmann D, Pehlemann FW, Berry M (1992) Development of astroglial cells in the proliferative matrices, the granule cell layer, and the hippocampal fissure of the hamster dentate gyrus. J Comp Neurol 320(1):1–32PubMedCrossRefGoogle Scholar
  49. 49.
    Deneen B, Ho R, Lukaszewicz A, Hochstim CJ, Gronostajski RM, Anderson DJ (2006) The transcription factor NFIA controls the onset of gliogenesis in the developing spinal cord. Neuron 52(6):953–968PubMedCrossRefGoogle Scholar
  50. 50.
    Holm PC, Mader MT, Haubst N, Wizenmann A, Sigvardsson M, Gotz M (2007) Loss- and gain-of-function analyses reveal targets of Pax6 in the developing mouse telencephalon. Mol Cell Neurosci 34(1):99–119PubMedCrossRefGoogle Scholar
  51. 51.
    Gotz M, Stoykova A, Gruss P (1998) Pax6 controls radial glia differentiation in the cerebral cortex. Neuron 21(5):1031–1044PubMedCrossRefGoogle Scholar
  52. 52.
    Gangemi RM, Daga A, Muzio L, Marubbi D, Cocozza S, Perera M, Verardo S, Bordo D, Griffero F, Capra MC, Mallamaci A, Corte G (2006) Effects of Emx2 inactivation on the gene expression profile of neural precursors. Eur J Neurosci 23(2):325–334PubMedCrossRefGoogle Scholar
  53. 53.
    Heins N, Cremisi F, Malatesta P, Gangemi RM, Corte G, Price J, Goudreau G, Gruss P, Gotz M (2001) Emx2 promotes symmetric cell divisions and a multipotential fate in precursors from the cerebral cortex. Mol Cell Neurosci 18(5):485–502PubMedCrossRefGoogle Scholar
  54. 54.
    Pellegrini M, Mansouri A, Simeone A, Boncinelli E, Gruss P (1996) Dentate gyrus formation requires Emx2. Development 122(12):3893–3898PubMedGoogle Scholar
  55. 55.
    Mattar P, Britz O, Johannes C, Nieto M, Ma L, Rebeyka A, Klenin N, Polleux F, Guillemot F, Schuurmans C (2004) A screen for downstream effectors of Neurogenin2 in the embryonic neocortex. Dev Biol 273(2):373–389PubMedCrossRefGoogle Scholar
  56. 56.
    Schuurmans C, Armant O, Nieto M, Stenman JM, Britz O, Klenin N, Brown C, Langevin LM, Seibt J, Tang H, Cunningham JM, Dyck R, Walsh C, Campbell K, Polleux F, Guillemot F (2004) Sequential phases of cortical specification involve Neurogenin-dependent and -independent pathways. Embo J 23(14):2892–2902PubMedCrossRefGoogle Scholar
  57. 57.
    Wong YW, Schulze C, Streichert T, Gronostajski RM, Schachner M, Tilling T (2007) Gene expression analysis of nuclear factor I-A deficient mice indicates delayed brain maturation. Genome Biol. 8(5):R72PubMedCrossRefGoogle Scholar
  58. 58.
    Elder GA, Liang Z, Snyder SE, Lazzarini RA (1992) Multiple nuclear factors interact with the promoter of the human neurofilament M gene. Brain Res Mol Brain Res 15(1–2):99–107PubMedCrossRefGoogle Scholar
  59. 59.
    Tamura T, Miura M, Ikenaka K, Mikoshiba K (1988) Analysis of transcription control elements of the mouse myelin basic protein gene in HeLa cell extracts: demonstration of a strong NFI-binding motif in the upstream region. Nucleic Acids Res 16(24):11441–11459PubMedCrossRefGoogle Scholar
  60. 60.
    Miura M, Tamura T, Mikoshiba K (1990) Cell-specific expression of the mouse glial fibrillary acidic protein gene: identification of the cis- and trans-acting promoter elements for astrocyte-specific expression. J Neurochem. 55(4):1180–1188PubMedCrossRefGoogle Scholar
  61. 61.
    Cebolla B, Vallejo M (2006) Nuclear factor-I regulates glial fibrillary acidic protein gene expression in astrocytes differentiated from cortical precursor cells. J Neurochem 97(4):1057–1070PubMedCrossRefGoogle Scholar
  62. 62.
    Ren T, Anderson A, Shen WB, Huang H, Plachez C, Zhang J, Mori S, Kinsman SL, Richards LJ (2006) Imaging, anatomical, and molecular analysis of callosal formation in the developing human fetal brain. Anat Rec A Discov Mol Cell Evol Biol 288(2):191–204PubMedGoogle Scholar
  63. 63.
    Kralovics R, Guan Y, Prchal JT (2002) Acquired uniparental disomy of chromosome 9p is a frequent stem cell defect in polycythemia vera. Exp Hematol 30(3):229–236PubMedCrossRefGoogle Scholar
  64. 64.
    Italiano A, Ebran N, Attias R, Chevallier A, Monticelli I, Mainguene C, Benchimol D, Pedeutour F (2008) NFIB rearrangement in superficial, retroperitoneal, and colonic lipomas with aberrations involving chromosome band 9p22. Genes Chromosomes Cancer 47(11):971–977PubMedCrossRefGoogle Scholar
  65. 65.
    Yang ZQ, Imoto I, Pimkhaokham A, Shimada Y, Sasaki K, Oka M, Inazawa J (2001) A novel amplicon at 9p23–24 in squamous cell carcinoma of the esophagus that lies proximal to GASC1 and harbors NFIB. Jpn J Cancer Res 92(4):423–428PubMedGoogle Scholar
  66. 66.
    Han W, Jung EM, Cho J, Lee JW, Hwang KT, Yang SJ, Kang JJ, Bae JY, Jeon YK, Park IA, Nicolau M, Jeffrey SS, Noh DY (2008) DNA copy number alterations and expression of relevant genes in triple-negative breast cancer. Genes Chromosomes Cancer 47(6):490–499PubMedCrossRefGoogle Scholar
  67. 67.
    Geurts JM, Schoenmakers EF, Roijer E, Astrom AK, Stenman G, van de Ven WJ (1998) Identification of NFIB as recurrent translocation partner gene of HMGIC in pleomorphic adenomas. Oncogene 16(7):865–872PubMedCrossRefGoogle Scholar
  68. 68.
    Scrideli CA, Carlotti CG Jr, Okamoto OK, Andrade VS, Cortez MA, Motta FJ, Lucio-Eterovic AK, Neder L, Rosemberg S, Oba-Shinjo SM, Marie SK, Tone LG (2008) Gene expression profile analysis of primary glioblastomas and non-neoplastic brain tissue: identification of potential target genes by oligonucleotide microarray and real-time quantitative PCR. J Neurooncol 88(3):281–291PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press Inc. 2008

Authors and Affiliations

  • Sharon Mason
    • 1
  • Michael Piper
    • 1
  • Richard M. Gronostajski
    • 3
  • Linda J. Richards
    • 1
    • 2
    Email author
  1. 1.Queensland Brain InstituteThe University of QueenslandSt LuciaAustralia
  2. 2.School of Biomedical SciencesThe University of QueenslandBrisbaneAustralia
  3. 3.Dept. of Biochemistry, Program in Neurosciences, Developmental Genomics Group, Center of Excellence in Bioinformatics and Life SciencesState University of New York at BuffaloBuffaloUSA

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