Hostname: page-component-586b7cd67f-2plfb Total loading time: 0 Render date: 2024-11-25T04:25:15.388Z Has data issue: false hasContentIssue false

Dissection of molecular mechanisms underlying speech and language disorders

Published online by Cambridge University Press:  01 January 2005

SIMON E. FISHER
Affiliation:
Wellcome Trust Centre for Human Genetics

Abstract

Developmental disorders affecting speech and language are highly heritable, but very little is currently understood about the neuromolecular mechanisms that underlie these traits. Integration of data from diverse research areas, including linguistics, neuropsychology, neuroimaging, genetics, molecular neuroscience, developmental biology, and evolutionary anthropology, is becoming essential for unraveling the relevant pathways. Recent studies of the FOXP2 gene provide a case in point. Mutation of FOXP2 causes a rare form of speech and language disorder, and the gene appears to be a crucial regulator of embryonic development for several tissues. Molecular investigations of the central nervous system indicate that the gene may be involved in establishing and maintaining connectivity of corticostriatal and olivocerebellar circuits in mammals. Notably, it has been shown that FOXP2 was subject to positive selection in recent human evolution. Consideration of findings from multiple levels of analysis demonstrates that FOXP2 cannot be characterized as “the gene for speech,” but rather as one critical piece of a complex puzzle. This story gives a flavor of what is to come in this field and indicates that anyone expecting simple explanations of etiology or evolution should be prepared for some intriguing surprises.

Type
Articles
Copyright
© 2005 Cambridge University Press

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Alcock K. J., Passingham R. E., Watkins K. E., & Vargha–Khadem F. 2000. Oral dyspraxia in inherited speech and language impairment and acquired dysphasia. Brain and Language, 75, 1733.Google Scholar
Belton E., Salmond C. H., Watkins K. E., Vargha–Khadem F., & Gadian D. G. 2003. Bilateral brain abnormalities associated with dominantly inherited verbal and orofacial dyspraxia. Human Brain Mapping, 18, 194200.Google Scholar
Bishop D. V. M. 2001. Genetic and environmental risks for specific language impairment in children. Philosophical Transactions of the Royal Society of London B Biological Sciences, 356, 369380.Google Scholar
Botstein D., & Risch N. 2003. Discovering genotypes underlying human phenotypes: Past successes for mendelian disease, future approaches for complex disease. Nature Genetics, 33 (Suppl.), 228237.Google Scholar
Boyd R., & Silk J. B. 2000 How humans evolved. New York: W. W. Norton.
Carlsson P., & Mahlapuu M. 2002. Forkhead transcription factors: Key players in development and metabolism. Developmental Biology, 250, 123.Google Scholar
Clark A. G., Glanowski S., Nielsen R., Thomas P. D., Kejariwal A., Todd M. A., Tanenbaum D. M., Civello D., Lu F., Murphy B., Ferriera S., Wang G., Zheng X., White T. J., Sninsky J. J., Adams M. D., & Cargill M. 2003. Inferring nonneutral evolution from human–chimp–mouse orthologous gene trios. Science, 302, 19601963.Google Scholar
DiMaio S., Grizenko N., & Joober R. 2003. Dopamine genes and attention-deficit hyperactivity disorder: A review. Journal of Psychiatry and Neuroscience, 28, 2738.Google Scholar
Enard W., Przeworski M., Fisher S. E., Lai C. S. L., Wiebe V., Kitano T., Monaco A. P., & Pääbo S. 2002. Molecular evolution of FOXP2, a gene involved in speech and language. Nature, 418, 869872.Google Scholar
Ferland R. J., Cherry T. J., Preware P. O., Morrisey E. E., & Walsh C. A. 2003. Characterization of Foxp2 and Foxp1 mRNA and protein in the developing and mature brain. Journal of Comparative Neurology, 460, 266279.Google Scholar
Fisher S. E. (in press). Tangled webs: Tracing the connections between genes and cognition. Cognition.
Fisher S. E., & DeFries J. C. 2002. Developmental dyslexia: Genetic dissection of a complex cognitive trait. Nature Reviews Neuroscience, 3, 767780.Google Scholar
Fisher S. E., Lai C. S. L., & Monaco A. P. 2003. Deciphering the genetic basis of speech and language disorders. Annual Review of Neuroscience, 26, 5780.Google Scholar
Fisher S. E., Vargha–Khadem F., Watkins K. E., Monaco A. P., & Pembrey M. E. 1998. Localisation of a gene implicated in a severe speech and language disorder. Nature Genetics, 18, 168170.Google Scholar
Folstein S. E., & Rosen–Sheidley B. 2001. Genetics of autism: Complex aetiology for a heterogeneous disorder. Nature Reviews Genetics, 2, 943955.Google Scholar
Gauthier J., Joober R., Mottron L., Laurent S., Fuchs M., De Kimpe V., & Rouleau G. A. 2003. Mutation screening of FOXP2 in individuals diagnosed with autistic disorder. American Journal of Medical Genetics, 118A, 172175.Google Scholar
Gopnik M., & Crago M. B. 1991. Familial aggregation of a developmental language disorder. Cognition, 39, 150.Google Scholar
Hauser M. D., Chomsky N., & Fitch W. T. 2002. The faculty of language: What is it, who has it, and how did it evolve? Science, 298, 15691579.Google Scholar
Hevner R. F., Shi L., Justice N., Hsueh Y., Sheng M., Smiga S., Bulfone A., Goffinet A. M., Campagnoni A. T., & Rubenstein J. L. 2001. Tbr1 regulates differentiation of the preplate and layer 6. Neuron, 29, 353366.Google Scholar
Hurst J. A., Baraitser M., Auger E., Graham F., & Norell S. 1990. An extended family with a dominantly inherited speech disorder. Developmental Medicine and Child Neurology, 32, 347355.Google Scholar
Jain M., Armstrong R. J., Barker R. A., & Rosser A. E. 2001. Cellular and molecular aspects of striatal development. Brain Research Bulletin, 55, 533540.Google Scholar
Kaestner K. H., Knöchel W., & Martinez D. E. 2000. Unified nomenclature for the winged helix/forkhead transcription factors. Genes and Development, 14, 142146.Google Scholar
Kaminen N., Hannula–Jouppi K., Kestila M., Lahermo P., Muller K., Kaaranen M., Myllyluoma B., Voutilainen A., Lyytinen H., Nopola–Hemmi J., & Kere J. 2003. A genome scan for developmental dyslexia confirms linkage to chromosome 2p11 and suggests a new locus on 7q32. Journal of Medical Genetics, 40, 340345.Google Scholar
Kume T., Deng K. Y., Winfrey V., Gould D. B., Walter M. A., & Hogan B. L. 1998. The forkhead/winged helix gene Mf1 is disrupted in the pleiotropic mouse mutation congenital hydrocephalus. Cell, 93, 985996.Google Scholar
Lai C. S. L., Fisher S. E., Hurst J. A., Levy E. R., Hodgson S., Fox M., Jeremiah S., Povey S., Jamison D. C., Green E. D., Vargha–Khadem F., & Monaco A.P. 2000. The SPCH1 region on human 7q31: Genomic characterization of the critical interval and localization of translocations associated with speech and language disorder. American Journal of Human Genetics, 67, 357368.Google Scholar
Lai C. S. L., Fisher S. E., Hurst J. A., Vargha–Khadem F., & Monaco A. P. 2001. A novel forkhead-domain gene is mutated in a severe speech and language disorder. Nature, 413, 519523.Google Scholar
Lai C. S. L., Gerrelli D., Monaco A. P., Fisher S. E., & Copp A. J. 2003. FOXP2 expression during brain development coincides with adult sites of pathology in a severe speech and language disorder. Brain, 126, 24552462.Google Scholar
Lander E. S., & Schork N. J. 1994. Genetic dissection of complex traits. Science, 265, 20372048.Google Scholar
Lehmann O. J., Sowden J. C., Carlsson P., Jordan T., & Bhattacharya S. S. 2003. Fox's in development and disease. Trends in Genetics, 19, 339344.Google Scholar
Liegeois F., Baldeweg T., Connelly A., Gadian D. G., Mishkin M., & Vargha–Khadem F. 2003. Language fMRI abnormalities associated with FOXP2 gene mutation. Nature Neuroscience, 6, 12301237.Google Scholar
Liegeois F. J., Lai C. S. L., Baldeweg T., Fisher S. E., Monaco A. P., Connelly A., & Vargha–Khadem F. 2001. Behavioural and neuroimaging correlates of a chromosome 7q31 deletion containing the SPCH1 gene. Society of Neuroscience Abstracts, 27, Program No. 529.17.Google Scholar
Marcus G. F., & Fisher S. E. 2003. FOXP2 in focus: What can genes tell us about speech and language? Trends in Cognitive Sciences, 7, 257262.Google Scholar
Meaburn E., Dale P. S., Craig I. W., & Plomin R. 2002. Language-impaired children: No sign of the FOXP2 mutation. Neuroreport, 13, 10751077.Google Scholar
Middleton F. A., & Strick P. L. 2000. Basal ganglia and cerebellar loops: Motor and cognitive circuits. Brain Research Reviews, 31, 236250.Google Scholar
Newbury D. F., Bonora E., Lamb J. A., Fisher S. E., Lai C. S. L., Baird G., Jannoun L., Slonims V., Stott C. M., Merricks M. J., Bolton P. F., Bailey A., Monaco A. P., & The International Molecular Genetic Study of Autism Consortium. 2002. FOXP2 is not a major susceptibility gene for autism or specific language impairment (SLI). American Journal of Human Genetics, 70, 13181327.Google Scholar
O'Brien E. K., Zhang X., Nishimura C., Tomblin J. B., & Murray J. C. 2003. Association of specific language impairment (SLI) to the region of 7q31. American Journal of Human Genetics, 72, 15361543.Google Scholar
Pääbo S. 2003. The mosaic that is our genome. Nature, 421, 409412.Google Scholar
Pinker S. 1994. The language instinct. London: Allen Lane.
Rutter M., & Mawhood L. 1991. The long-term psychosocial sequelae of specific developmental disorders of speech and language. In M. Rutter & P. Casaer (Eds.), Biological risk factors for psychosocial disorders (pp. 233259). Cambridge: Cambridge University Press.
Saleem R. A., Banerjee–Basu S., Berry F. B., Baxevanis A. D., & Walter M. A. 2003. Structural and functional analyses of disease-causing missense mutations in the forkhead domain of FOXC1. Human Molecular Genetics, 12, 29933005.Google Scholar
Shu W., Yang H., Zhang L., Lu M. M., & Morrisey E. E. 2001. Characterization of a new subfamily of winged-helix/forkhead (Fox) genes that are expressed in the lung and act as transcriptional repressors. Journal of Biological Chemistry, 276, 2748827497.Google Scholar
Smith R. S., Zabaleta A., Kume T., Savinova O. V., Kidson S. H., Martin J. E., Nishimura D. Y., Alward W. L., Hogan B. L., & John S. W. 2000. Haploinsufficiency of the transcription factors FOXC1 and FOXC2 results in aberrant ocular development. Human Molecular Genetics, 9, 10211032.Google Scholar
Takahashi K., Liu F. C., Hirokawa K., & Takahashi H. 2003. Expression of Foxp2, a gene involved in speech and language, in the developing and adult striatum. Journal of Neuroscience Research, 73, 6172.Google Scholar
Tallal P., Townsend J., Curtiss S., & Wulfeck B. 1991. Phenotypic profiles of language-impaired children based on genetic/family history. Brain and Language, 41, 8195.Google Scholar
Ullman M. T., & Gopnik M. 1999. Inflectional morphology in a family with inherited specific language impairment. Applied Psycholinguistics, 20, 51117.Google Scholar
Vargha–Khadem F., Watkins K., Alcock K., Fletcher P., & Passingham R. 1995. Praxic and nonverbal cognitive deficits in a large family with a genetically transmitted speech and language disorder. Proceedings of the National Academy of Sciences USA, 92, 930933.Google Scholar
Vargha–Khadem F., Watkins K. E., Price C. J., Ashburner J., Alcock K. J., Connelly A., Frackowiak R. S., Friston K. J., Pembrey M. E., Mishkin M., Gadian D. G., & Passingham R. E. 1998. Neural basis of an inherited speech and language disorder. Proceedings of the National Academy of Sciences USA, 95, 1269512700.Google Scholar
Wang B., Lin D., Li C., & Tucker P. 2003. Multiple domains define the expression and regulatory properties of Foxp1 forkhead transcriptional repressors. Journal of Biological Chemistry, 278, 2425924268.Google Scholar
Wang V. Y., & Zoghbi H. Y. 2001. Genetic regulation of cerebellar development. Nature Reviews Neuroscience, 2, 484491.Google Scholar
Wassink T. H., Piven J., Vieland V. J., Pietila J., Goedken R. J., Folstein S. E., & Sheffield V. C. 2002. Evaluation of FOXP2 as an autism susceptibility gene. American Journal of Medical Genetics, 114, 566569.Google Scholar
Watkins K. E., Dronkers N. F., & Vargha–Khadem F. 2002. Behavioural analysis of an inherited speech and language disorder: Comparison with acquired aphasia. Brain, 125, 452464.Google Scholar
Weimann J. M., Zhang Y. A., Levin M. E., Devine W. P., Brulet P., & McConnell S. K. 1999. Cortical neurons require Otx1 for the refinement of exuberant axonal projections to subcortical targets. Neuron, 24, 819831.Google Scholar
Welsh J. P., Lang E. J., Suglhara I., & Llinas R. 1995. Dynamic organization of motor control within the olivocerebellar system. Nature, 374, 453457.Google Scholar
Wolfsberg T. G., McEntyre J., & Schuler G. D. 2001. Guide to the draft human genome. Nature, 409, 824826.Google Scholar
Zaki P. A., Quinn J. C., & Price D. J. 2003. Mouse models of telencephalic development. Current Opinion in Genetics and Development, 13, 423437.Google Scholar
Zhang J., Webb D. M., & Podlaha O. 2002. Accelerated protein evolution and origins of human-specific features: Foxp2 as an example. Genetics, 162, 18251835.Google Scholar