Advertisement

FOXP Genes, Neural Development, Speech and Language Disorders

  • Hiroshi Takahashi
  • Kaoru Takahashi
  • Fu-Chin Liu
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 665)

Abstract

Foxp subfamily genes were recently recognized to be members of the Fox gene family. Foxp subfamily members contain a zinc finger domain and a leucine zipper motif in addition to a forkhead domain and their DNA binding capacities and transcriptional activities are regulated by homo- and heterodimerization via a zinc finger and a leucine zipper motif. Three Foxp subfamily members are abundantly expressed in developing brains. The expression patterns of these genes are overlapping, but they are distinctly expressed in some regions. Thus these genes appear to be involved in the development control of the central nervous system. Recently, FOXP2, a member of the Foxp subfamily, was identified as the first gene to be linked to an inherited form oflanguage and speech disorder. The discovery of a mutation in FOXP2 in a family with a speech and language disorder opened a new window to understanding the genetic cascades and neural circuits that underlie speech and language via molecular approaches. The spatiotemporal FOXP2 mRNA expression pattern suggests that the basic neural network that underlies speech and language may include motor-related circuits, including frontostriatal and/or frontocerebellar circuits. This assumption is supported by brain imaging data obtained by using fMRI and PET on the FOXP2-mutated patients and also by analysis of Foxp2 mutant mice.

Keywords

Caudate Nucleus Specific Language Impairment FOXP2 Expression Forkhead Transcription Factor Language Disorder 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Kaufmann E, Knochel W. Five years on the wings of fork head. Mech Dev 1996; 57:3–20.Google Scholar
  2. 2.
    Carlsson P, Mahlapuu M. Forkhead transcription factors: key players in development and metabolism. Dev Biol 2002; 250:1–23.CrossRefPubMedGoogle Scholar
  3. 3.
    Shu W, Yang H, Zhang L et al. Characterization of a new subfamily of winged-helix/forkhead (Fox) genes that are expressed in the lung and act as transcriptional repressors. J Biol Chem 2001; 276:27488–27497.CrossRefPubMedGoogle Scholar
  4. 4.
    Lai CSL, Fisher SE, Hurst JA et al. A forkhead-domain gene is mutated in a severe speech and language disorder. Nature 2001; 413:519–523.CrossRefPubMedGoogle Scholar
  5. 5.
    Lu MM, Li S, Yang H et al. Foxp4: a novel member of Foxp subfamily of winged-helix genes co-expressed with Foxpl and Foxp2 in pulmonary and gut tissues. Mech Dev 2002; 119S:S197–S202.CrossRefGoogle Scholar
  6. 6.
    Teufel A, Wong EA, Mukhopadhyay N et al. FoxP4, novel forkhead transcriptional factor. Biochim Biophys Acta 2003; 1627:147–152.PubMedGoogle Scholar
  7. 7.
    Li S, Weidenfeld J, Morrisey EE. Transcriptional and DNA binding activity of the Foxpl/2/4 family is modulated by heterotypic and homotypic protein interactions. Mol Cell Biol 2004; 24:809–822CrossRefPubMedGoogle Scholar
  8. 8.
    Enard W, Przeworski M, Fisher SE et al. Molecular evolution of FOXP2, a gene involved in speech and language. Nature 2002; 418:869–872.CrossRefPubMedGoogle Scholar
  9. 9.
    Krause J, Lalueza-Fox C, Orlando L et al. The derived FOXP2 variant of modern humans was shared with Neandertals. Curr Biol 2007; 17:1908–1912.CrossRefPubMedGoogle Scholar
  10. 10.
    Hurst J, Baraitser M, Auger E et al. An extended family with a dominantly inherited speech disorder. Dev Med Child Neuro 1990; 32:347–355.Google Scholar
  11. 11.
    Fisher SE, Vargha-Khadem F, Watkins KE et al. Localisation of a gene implicated in a severe speech and language disorder. Nature Genet 1998; 18:168–170.CrossRefPubMedGoogle Scholar
  12. 12.
    MacDermot KD, Bonora E, Sykes N et al. Identification of FOXP2 truncation as a novel cause of developmental speech and language deficits. Am J Hum Genet 2005; 76:1074–1080.CrossRefPubMedGoogle Scholar
  13. 13.
    Clifton-Bligh RJ, Wentworth JM, Heinz P et al. Mutation of the gene encoding human TTF-2 associated with thyroid agenesis, cleft palate and choanal atresia. Nat Genet 1998; 19:399–401.CrossRefPubMedGoogle Scholar
  14. 14.
    Crisponi L, Deiana M, Loi A et al. The putative forkhead transcription factor FOXL2 is mutated in blepharophimosis/ptosis/epicanthus inversus syndrome. Nat Genet 2001; 27:159–166.CrossRefPubMedGoogle Scholar
  15. 15.
    Fang J, Dagenais SL, Erickson RP et al. Mutations in FOXC2(MFH-l), a forkhead family transcription factor, are responsible for the hereditary lymphederna-distichiasis syndrome. Am J Hum Genet 2000; 67:1382–1388.CrossRefPubMedGoogle Scholar
  16. 16.
    Nishimura DY, Swiderski RE, Alward WL et al. The forkhead transcription factor gene FKHL7 is responsible for glaucoma phenotypes which map to 6p25. Nat Genet 1998; 19(2):140–147.CrossRefPubMedGoogle Scholar
  17. 17.
    Kaminen N, Hannula-Jouppi K, Kestilä M et al. A genome scan for developmental dyslexia confirms linkage to chromosome 2pll and suggests a new locus on 7q32. J Med Genet 2003; 40:340–345.CrossRefPubMedGoogle Scholar
  18. 18.
    O’Brien EK, Zhang X, Nishimura C et al. Association of specific language impairment (SLI) to the region of 7q31. Am J Hum Genet 2003; 72:1536–1543.CrossRefPubMedGoogle Scholar
  19. 19.
    Meaburn E, Dale PS, Craig IW et al. Language-impaired children: no sign of the FOXP2 mutation. NeuroReport 2002; 13:1075–1077.CrossRefPubMedGoogle Scholar
  20. 20.
    Newbury DF, Bonora E, Lamb JA et al. FOXP2 is not a major susceptibility gene for autism or specific language impairment. Am J Genet 2002; 70:1318–1327.CrossRefGoogle Scholar
  21. 21.
    Gong X, Jia M, Ruan Y et al. Association between the FOXP2 gene and autistic disorder in Chinese population. Am J Med Genet B Neuropsychiatr Genet 2004; 127B:113–116.CrossRefPubMedGoogle Scholar
  22. 22.
    Li H, Yamagata T, Mori M et al. Absence of causative mutations and presence of autism-related allele in FOXP2 in Japanese autistic patients. Brain Dev 2005; 27:207–210.CrossRefPubMedGoogle Scholar
  23. 23.
    Gauthier J, Joober R, Mottron L er al. Mutation screening of FOXP2 in individuals diagnosed with autistic disorder. Am J Med Genet A 2003; Apr 15; 118A:172–175.CrossRefPubMedGoogle Scholar
  24. 24.
    Marui T, Koishi S, Funatogawa I et al. No association of FOXP2 and PTPRZI on 7q31 with autism from the Japanese population. Neuroscience Res 2005; 53:91–94.CrossRefGoogle Scholar
  25. 25.
    Wassink TH, Piven J, Vieland VJ et al. Evaluation of FOXP2 as an autism susceptibility gene. Am J Med Genet 2002; 114:566–569.CrossRefPubMedGoogle Scholar
  26. 26.
    Bruce HA, Margolis RL. FOXP2: novel exons, splice variants and CAG repeat length stability. Hum Genet 2002; 111:136–144.CrossRefPubMedGoogle Scholar
  27. 27.
    Brunkow ME, Jeffery EW, Hjerrild KA et al. Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse. Nat Genet 2001; 27:68–73.CrossRefPubMedGoogle Scholar
  28. 28.
    Wang B, Weidenfeld J, Lu MM et al. Foxp1 regulates cardiac outflow tract, endocardial cushion morphogenesis and myocyte proliferation and maturation. Development 2004; 131:4477–4487.CrossRefPubMedGoogle Scholar
  29. 29.
    Dasen JS, De Camilli A, Wang B et al. Hox repertoires for motor neuron diversity and connectivity gated by a single accessory factor, FoxPl. Cell 2008; 134:304–316.CrossRefPubMedGoogle Scholar
  30. 30.
    Rousso DL, Gaber ZB, Wellik D et al. Coordinated actions of the forkhead protein Foxpl and Hox proteins in the columnar organization of spinal motor neurons. Neuron 2008; 59:226–240.CrossRefPubMedGoogle Scholar
  31. 31.
    Banham AH, Beasley N, Campo E et al. The FOXPI winged helix transcription factor is a novel candidate tumor suppressor gene on chromosome 3p. Cancer Res 2001; 61:8820–8829.PubMedGoogle Scholar
  32. 32.
    Li S, Zhou D, Lu MM et al. Advanced cardiac morphogenesis does not require heart tube fusion. Science 2004; 305: 1619–1622.CrossRefPubMedGoogle Scholar
  33. 33.
    Ferland RJ, Cherry TJ, Preware PO et al. Characterization of Foxp2 and Foxpl mRNA and protein in the developing and mature brain. J Comp Neuro1 2003; 460:266–279.CrossRefGoogle Scholar
  34. 34.
    Lai CS, Gerrelli D, Monaco AP et al. FOXP2 expression during brain development coincides with adult sites of pathology in a severe speech and language disorder. Brain 2003; 126:2455–2462.CrossRefPubMedGoogle Scholar
  35. 35.
    Takahashi K, Liu F-C, Hirokawa K et al. Expression of Foxp2, a gene involved in speech and language, in the developing and adult striatum. J Neurosci Res 2003; 73:61–72.CrossRefPubMedGoogle Scholar
  36. 36.
    Takahashi K, Liu FC, Hirokawa K et al. Expression of Foxp4 in the developing and adult rat forebrain. J Neurosci Res 2008; 86:3106–3116.CrossRefPubMedGoogle Scholar
  37. 37.
    Takahashi K, Liu FC, Oishi T et al. Expression of FOXP2 in the developing monkey forebrain: comparison with the expression of the genes FOXP1, PBX3 and MEIS2. J Comp Neuro1 2008; 509:180–189.CrossRefGoogle Scholar
  38. 38.
    Teramitsu I, Kudo LC, London SE et al. ParallelFoxP1 and FoxP2 expression in songbird and human brain predicts functional interaction. J Neurosci 2004; 24:3152–3163.CrossRefPubMedGoogle Scholar
  39. 39.
    Tamura S, Morikawa Y, Iwanishi H et al. Expression pattern of the winged-helix/forkhead transcription factor Foxp1 in the developing central nervous system. Gene Expression Patterns 2003; 3:193–197.CrossRefPubMedGoogle Scholar
  40. 40.
    Tamura S, Morikawa Y, Iwanishi H et al. Foxp1 gene expression in projection neurons of the mouse striatum. Neuroscience 2004; 124:261–267.CrossRefPubMedGoogle Scholar
  41. 41.
    Campbell K. Dorsal-ventral patterning in the mammalian telencephalon. Curr Opin Neurobiol 2003; 13:50–56.CrossRefPubMedGoogle Scholar
  42. 42.
    Graybiel AM. Neurotransmitters and neuromodulators in the basal ganglia. Trends In Neuroscience 1990; 15:244–254.CrossRefGoogle Scholar
  43. 43.
    Graybiel AM, Penney JB. Chemical architecture of the basalganglia.In: Bloom FE, Bjorklund A, Hokfelt T: eds. Handbook of Chemical Neuroanatomy. The Primate Nervous System. Part III. Amsterdam: Elsevier Science, 1999; 15:227–284.CrossRefGoogle Scholar
  44. 44.
    Gerfen CR, Wilson CJ. The basal ganglia. In: Swanson LW, Björklund A, Hokfelt T, eds. Handbook of Chemical Neuroanatomy. Integrated Systems of the CNS. Part III. Amsterdam: Elsevier Science, 1996; 12:371–468.Google Scholar
  45. 45.
    Belton E, Salmond CH, Watkins KE et al. Bilateral brain abnormalities associated with dominantly inherited verbal and orofacial dyspraxia. Hum Brain Mapp 2003; 18:194–200.CrossRefPubMedGoogle Scholar
  46. 46.
    Watkins KE, Vargha-Khadem F, Ashburner J et al. MRI analysis of an inherited speech and language disorder: structural brain abnormalities. Brain 2002; 125:465–478.CrossRefPubMedGoogle Scholar
  47. 47.
    Liégeois F, Baldeweg T, Connelly A et al. Language fMRI abnormalities associated with FOXP2 gene mutation. Nat Neurosci 2003; 6:1230–1237.CrossRefPubMedGoogle Scholar
  48. 48.
    Vargha-Khadem F, Watkins KE, Price CJ et al. Neural basis of an inherited speech and language disorder. Proc Natl Acad Sci USA 1998; 95:12695–12700.CrossRefPubMedGoogle Scholar
  49. 49.
    Graybiel AM, Ragsdale Jr CWo Histochemically distinct compartments in the striatum of human, monkey and cat demonstrated by acetylthiocholinesterase staining. Proc Natl Acad Sci USA 1978; 75:5723–5726.CrossRefPubMedGoogle Scholar
  50. 50.
    Canales JJ, Graybiel AM. A measure of striatal function predicts motor stereotypy. Nat Neurosci 2000; 3:377–383.CrossRefPubMedGoogle Scholar
  51. 51.
    Cenci MA, Tranberg A, Andersson M et al. Changes in the regional and compartmental distribution of FosB-and JunB-like immunoreactivity induced in the dopamine-denervated rat striatum by acute or chronic L-dopa treatment. Neuroscience 1999; 94:515–527.CrossRefPubMedGoogle Scholar
  52. 52.
    Saka E, Elibol B, Erdem S et al. Compartmental changes in expressionofc-Fos and FosBproteins in intact and dopamine-depleted striatum after chronic apomorphine treatment. Brain Res 1999; 825:104–114.CrossRefPubMedGoogle Scholar
  53. 53.
    Crinion J, Turner R, Grogan A et al. Language control in the bilingual brain. Science 2006; 312:1537–1540.CrossRefPubMedGoogle Scholar
  54. 54.
    Ullman MT, Corkin S, Coppola M et al. A neural dissociation within language: evidence that the mental dictionary is part of declarative memory and that grammatical rules are processed by the procedural system. J Cogn Neurosci 1997; 9:266–276.CrossRefGoogle Scholar
  55. 55.
    Ullman MT. A neurocognitive perspective on language: the declarative/procedural model. Nature Rev Neurosci 2001; 2:717–726.CrossRefGoogle Scholar
  56. 56.
    Damasio AR, Damasio H. Brain and language. Sci Am 1992; 267:88–95.CrossRefPubMedGoogle Scholar
  57. 57.
    Ackermann H. Cerebellar contributions to speech production and speech perception: psycholinguistic and neurobiological perspectives. Trends Neurosci 2008; 31:265–272.CrossRefPubMedGoogle Scholar
  58. 58.
    Vargha-Khadem F, Gadian DG, Copp A et al. FOXP2 and the neuroanatomy of speech and language. Nat Rev Neurosci 2005; 6:131–138.CrossRefPubMedGoogle Scholar
  59. 59.
    Fujita E, Tanabe Y, Shiota A et al. Ultrasonic vocalization impairment of Foxp2 (R552H) knockin mice related to speech-language disorder and abnormality of Purkinje cells. Proc Nat! Acad Sci USA 2008; 105:3117–3122.CrossRefPubMedGoogle Scholar
  60. 60.
    Groszer M, Keays DA, Deacon RM et al. Impaired synaptic plasticity and motor learning in mice with a point mutation implicated in human speech deficits. Curr BioI 2008; 18:354–362.CrossRefGoogle Scholar
  61. 61.
    Shu W Cho JY Jiang Y et al. Altered ultrasonic vocalization in mice with a disruption in the Foxp2 gene. Proc Nat! Acad Sci USA 2005; 102:9643–9648.CrossRefPubMedGoogle Scholar
  62. 62.
    Vernes SC, Nicod J, Elahi FM et al. Functional genetic analysis of mutations implicated in a human speech and language disorder. Hum Mol Genet 2006; 15:3154–3167.CrossRefPubMedGoogle Scholar
  63. 63.
    Mizutani A, Matsuzaki A, Momoi MY et al. Intracellular distribution of a speech/language disorder associated FOXP2 mutant. Biochem Biophys Res Commun 2007; 353:869–874.CrossRefPubMedGoogle Scholar
  64. 64.
    Wang B, Lin D, Li C et al. Multiple domains define the expression and regulatory properties of Foxp1 forkhead transcriptional repressors. J BioI Chern 2003; 278:24259–24268.Google Scholar
  65. 65.
    Spiteri E, Konopka G, Coppola G et al. Identification of the transcriptional targets of FOXP2, a gene linked to speech and language, in developing human brain. Am J Hum Genet 2007; 81:1144–1157.CrossRefPubMedGoogle Scholar
  66. 66.
    Vernes SC, Spiteri E, Nicod J et al. High-throughput analysis of promoter occupancy reveals direct neural targets of FOXP2, a gene mutated in speech and language disorders. Am J Hum Genet 2007; 81:1232–1250.CrossRefPubMedGoogle Scholar
  67. 67.
    Takahashi H, Liu F-C. Genetic patterning of the mammalian telencephalon by morphogenetic molecules and transcription factors. Birth Defects Res C Embryo Today 2006; 78:256–266.CrossRefPubMedGoogle Scholar
  68. 68.
    Burglin TR. Analysis of TALE superclasshomeobox genes (MEIS, PBC, KNOX, Iroquois, TGIF) reveals a novel domain conserved between plants and animals. Nucleic Acids Res 1997; 25:4173–4180.CrossRefPubMedGoogle Scholar
  69. 69.
    Berkes CA, Bergstrom DA, Penn BH et al 2004. Pbx marks genes for activation by MyoD indicating a role for a homeodomain protein in establishing myogenic potential. Mol Cell 2004; 14:465–477.CrossRefPubMedGoogle Scholar
  70. 70.
    Mann RS, Affolter M. Hox proteins meet more partners. Curr Opin Genet Dev 1998; 8:423–429.CrossRefPubMedGoogle Scholar
  71. 71.
    Bonkowsky JL, Wang X, Fujimoto E et al. Domain-specific regulation of foxP2 CNS expression by lefl. BMC Dev Bioi 2008; 8:103.CrossRefGoogle Scholar

Copyright information

© Landes Bioscience and Springer+Business Media 2009

Authors and Affiliations

  • Hiroshi Takahashi
    • 1
  • Kaoru Takahashi
    • 1
    • 3
  • Fu-Chin Liu
    • 2
  1. 1.Developmental Neurobiology GroupMitsubishi Kagaku Institute of Life SciencesTokyoJapan
  2. 2.Institute of NeuroscienceNational Yang-Ming UniversityTaipeiTaiwan Republic of China
  3. 3.Alzheimer’s Disease Research Group, Mitsubishi Kagaku Institute of Life SciencesTokyo Medical and Dental UniversityTokyoJapan

Personalised recommendations