FOXP2 as a molecular window into speech and language.

Rare mutations of the FOXP2 transcription factor gene cause a monogenic syndrome characterized by impaired speech development and linguistic deficits. Recent genomic investigations indicate that its downstream neural targets make broader impacts on common language impairments, bridging clinically distinct disorders. Moreover, the striking conservation of both FoxP2 sequence and neural expression in different vertebrates facilitates the use of animal models to study ancestral pathways that have been recruited towards human speech and language. Intriguingly, reduced FoxP2 dosage yields abnormal synaptic plasticity and impaired motor-skill learning in mice, and disrupts vocal learning in songbirds. Converging data indicate that Foxp2 is important for modulating the plasticity of relevant neural circuits. This body of research represents the first functional genetic forays into neural mechanisms contributing to human spoken language.

[1]  G Baird,et al.  FOXP2 is not a major susceptibility gene for autism or specific language impairment. , 2002, American journal of human genetics.

[2]  T. Holy,et al.  Ultrasonic Songs of Male Mice , 2005, PLoS biology.

[3]  Frédéric E. Theunissen,et al.  Auditory processing of vocal sounds in birds , 2006, Current Opinion in Neurobiology.

[4]  J. Buxbaum,et al.  Altered ultrasonic vocalization in mice with a disruption in the Foxp2 gene. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[5]  Tanya M. Teslovich,et al.  A common genetic variant in the neurexin superfamily member CNTNAP2 increases familial risk of autism. , 2008, American journal of human genetics.

[6]  A. Joyner,et al.  The level of sonic hedgehog signaling regulates the complexity of cerebellar foliation , 2006, Development.

[7]  M. Fee,et al.  Singing-related activity of identified HVC neurons in the zebra finch. , 2007, Journal of neurophysiology.

[8]  D. Lovinger,et al.  Postsynaptic endocannabinoid release is critical to long-term depression in the striatum , 2002, Nature Neuroscience.

[9]  D. Paterson,et al.  Novel quantitative phenotypes of exercise training in mouse models. , 2006, American journal of physiology. Regulatory, integrative and comparative physiology.

[10]  Faraneh Vargha-Khadem,et al.  Bilateral brain abnormalities associated with dominantly inherited verbal and orofacial dyspraxia , 2003, Human brain mapping.

[11]  C. Stringer,et al.  Close correspondence between quantitative- and molecular-genetic divergence times for Neandertals and modern humans , 2008, Proceedings of the National Academy of Sciences.

[12]  A. Monaco,et al.  Assessing the impact of FOXP1 mutations on developmental verbal dyspraxia , 2009, European Journal of Human Genetics.

[13]  K. D. Punta,et al.  An ultra-sparse code underlies the generation of neural sequences in a songbird , 2002 .

[14]  Simon E. Fisher,et al.  Localisation of a gene implicated in a severe speech and language disorder , 1997, Nature Genetics.

[15]  C. Chien,et al.  Molecular cloning and developmental expression of foxP2 in zebrafish , 2005, Developmental dynamics : an official publication of the American Association of Anatomists.

[16]  D. Geschwind,et al.  Identification of the transcriptional targets of FOXP2, a gene linked to speech and language, in developing human brain. , 2007, American journal of human genetics.

[17]  V. Vieland,et al.  A major susceptibility locus for specific language impairment is located on 13q21. , 2002, American journal of human genetics.

[18]  D. Geschwind,et al.  Singing Mice, Songbirds, and More: Models for FOXP2 Function and Dysfunction in Human Speech and Language , 2006, The Journal of Neuroscience.

[19]  Shanru Li,et al.  Transcriptional and DNA Binding Activity of the Foxp1/2/4 Family Is Modulated by Heterotypic and Homotypic Protein Interactions , 2004, Molecular and Cellular Biology.

[20]  Simon E. Fisher,et al.  Tangled webs: Tracing the connections between genes and cognition , 2006, Cognition.

[21]  J. Duffy,et al.  Speech, prosody, and voice characteristics of a mother and daughter with a 7;13 translocation affecting FOXP2. , 2006, Journal of speech, language, and hearing research : JSLHR.

[22]  J. F. Prather,et al.  Precise auditory–vocal mirroring in neurons for learned vocal communication , 2008, Nature.

[23]  H. Burbano,et al.  The Derived FOXP2 Variant of Modern Humans Was Shared with Neandertals , 2007, Current Biology.

[24]  Karl J. Friston,et al.  MRI analysis of an inherited speech and language disorder: structural brain abnormalities. , 2002, Brain : a journal of neurology.

[25]  W. Regehr,et al.  Short-term synaptic plasticity. , 2002, Annual review of physiology.

[26]  M. Farries,et al.  Evidence for “direct” and “indirect” pathways through the song system basal ganglia , 2005, The Journal of comparative neurology.

[27]  Sarah E. London,et al.  Parallel FoxP1 and FoxP2 Expression in Songbird and Human Brain Predicts Functional Interaction , 2004, The Journal of Neuroscience.

[28]  A. Monaco,et al.  The SPCH1 region on human 7q31: genomic characterization of the critical interval and localization of translocations associated with speech and language disorder. , 2000, American journal of human genetics.

[29]  D. Geschwind,et al.  Birdsong decreases protein levels of FoxP2, a molecule required for human speech. , 2008, Journal of neurophysiology.

[30]  G. Coop,et al.  The Timing of Selection at the Human FOXP2 Gene , 2008, Molecular biology and evolution.

[31]  M. Stumpf Neuroscience of birdsong , 2009, Human Genomics.

[32]  Jessica Brian,et al.  Speech and language impairment and oromotor dyspraxia due to deletion of 7q31 that involves FOXP2 , 2006, American journal of medical genetics. Part A.

[33]  Christopher A Walsh,et al.  Characterization of Foxp2 and Foxp1 mRNA and protein in the developing and mature brain , 2003, The Journal of comparative neurology.

[34]  Steve D. M. Brown,et al.  Impaired Synaptic Plasticity and Motor Learning in Mice with a Point Mutation Implicated in Human Speech Deficits , 2008, Current Biology.

[35]  M. Hauser,et al.  A Biolinguistic Agenda , 2008, Science.

[36]  Fu-Chin Liu,et al.  Expression of FOXP2 in the developing monkey forebrain: Comparison with the expression of the genes FOXP1, PBX3, and MEIS2 , 2008, The Journal of comparative neurology.

[37]  M. Barton,et al.  Many forkheads in the road to regulation , 2008, EMBO reports.

[38]  Katarzyna Chawarska,et al.  Molecular cytogenetic analysis and resequencing of contactin associated protein-like 2 in autism spectrum disorders. , 2008, American journal of human genetics.

[39]  C. Scharff,et al.  An evolutionary perspective on FoxP2: strictly for the birds? , 2005, Current Opinion in Neurobiology.

[40]  S. White,et al.  FoxP2 Regulation during Undirected Singing in Adult Songbirds , 2006, The Journal of Neuroscience.

[41]  C. Chien,et al.  Domain-specific regulation of foxP2 CNS expression by lef1 , 2008, BMC Developmental Biology.

[42]  J. DeFelipe,et al.  Voltage-gated ion channels in the axon initial segment of human cortical pyramidal cells and their relationship with chandelier cells. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[43]  C. Scharff,et al.  FoxP2 Expression in Avian Vocal Learners and Non-Learners , 2004, The Journal of Neuroscience.

[44]  P. Strick,et al.  Basal ganglia and cerebellar loops: motor and cognitive circuits , 2000, Brain Research Reviews.

[45]  D. Geschwind,et al.  A functional genetic link between distinct developmental language disorders. , 2008, The New England journal of medicine.

[46]  F. Nottebohm,et al.  Expression profiling of intermingled long-range projection neurons harvested by laser capture microdissection , 2006, Journal of Neuroscience Methods.

[47]  Jianzhi Zhang,et al.  Accelerated protein evolution and origins of human-specific features: Foxp2 as an example. , 2002, Genetics.

[48]  A. Monaco,et al.  FOXP2 expression during brain development coincides with adult sites of pathology in a severe speech and language disorder. , 2003, Brain : a journal of neurology.

[49]  Highly Significant Linkage to the SLI 1 Locus in an Expanded Sample of Individuals Affected by Specific Language Impairment The SLI Consortium ( SLIC ) , 2004 .

[50]  F. Nottebohm,et al.  For Whom The Bird Sings Context-Dependent Gene Expression , 1998, Neuron.

[51]  A. Monaco,et al.  Deciphering the genetic basis of speech and language disorders. , 2003, Annual review of neuroscience.

[52]  W. Schultz Behavioral dopamine signals , 2007, Trends in Neurosciences.

[53]  Enrico Alleva,et al.  Ultrasonic vocalisation emitted by infant rodents: a tool for assessment of neurobehavioural development , 2001, Behavioural Brain Research.

[54]  D. Bishop,et al.  Genetic and environmental risks for specific language impairment in children. , 2001, Philosophical transactions of the Royal Society of London. Series B, Biological sciences.

[55]  Henry H Yin,et al.  The Role of Protein Synthesis in Striatal Long-Term Depression , 2006, The Journal of Neuroscience.

[56]  K. Davies,et al.  Functional genetic analysis of mutations implicated in a human speech and language disorder. , 2006, Human molecular genetics.

[57]  F. Nottebohm,et al.  A comparative study of the behavioral deficits following lesions of various parts of the zebra finch song system: implications for vocal learning , 1991, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[58]  Mariko Y Momoi,et al.  Ultrasonic vocalization impairment of Foxp2 (R552H) knockin mice related to speech-language disorder and abnormality of Purkinje cells , 2008, Proceedings of the National Academy of Sciences.

[59]  M. Mishkin,et al.  Language fMRI abnormalities associated with FOXP2 gene mutation , 2003, Nature Neuroscience.

[60]  B. Frenkel,et al.  Foxp2 inhibits Nkx2.1-mediated transcription of SP-C via interactions with the Nkx2.1 homeodomain. , 2008, American journal of respiratory cell and molecular biology.

[61]  J. Sebat,et al.  Linkage, association, and gene-expression analyses identify CNTNAP2 as an autism-susceptibility gene. , 2008, American journal of human genetics.

[62]  D. Geschwind,et al.  Genome-wide analyses of human perisylvian cerebral cortical patterning , 2007, Proceedings of the National Academy of Sciences.

[63]  Gang Li,et al.  Accelerated FoxP2 Evolution in Echolocating Bats , 2007, PloS one.

[64]  Dorothy V. M. Bishop,et al.  Genetic influences on language impairment and phonological short-term memory , 2005, Trends in Cognitive Sciences.

[65]  K. Gunderson,et al.  Deletion of 7q31.1 supports involvement of FOXP2 in language impairment: Clinical report and review , 2007, American journal of medical genetics. Part A.

[66]  N. Sykes,et al.  Identification of FOXP2 truncation as a novel cause of developmental speech and language deficits. , 2005, American journal of human genetics.

[67]  S. Fisher,et al.  Molecular windows into speech and language disorders , 2006, International Journal of Developmental Neuroscience.

[68]  A. Monaco,et al.  Molecular evolution of FOXP2, a gene involved in speech and language , 2002, Nature.

[69]  D. M. Webb,et al.  FoxP2 in song-learning birds and vocal-learning mammals. , 2005, The Journal of heredity.

[70]  C. A. French,et al.  Generation of mice with a conditional Foxp2 null allele , 2007, Genesis.

[71]  D. Stephan,et al.  Recessive symptomatic focal epilepsy and mutant contactin-associated protein-like 2. , 2006, The New England journal of medicine.

[72]  A. Monaco,et al.  A forkhead-domain gene is mutated in a severe speech and language disorder , 2001, Nature.

[73]  R. Myers,et al.  Multiple transcription start sites for FOXP2 with varying cellular specificities. , 2008, Gene.

[74]  Wendy Roberts,et al.  Absence of a paternally inherited FOXP2 gene in developmental verbal dyspraxia. , 2006, American journal of human genetics.

[75]  C. Francks,et al.  Genes, cognition and dyslexia: learning to read the genome , 2006, Trends in Cognitive Sciences.

[76]  D. Geschwind,et al.  High-throughput analysis of promoter occupancy reveals direct neural targets of FOXP2, a gene mutated in speech and language disorders. , 2007, American journal of human genetics.

[77]  G. Marcus,et al.  The eloquent ape: genes, brains and the evolution of language , 2006, Nature Reviews Genetics.

[78]  Johannes Schwarz,et al.  A Humanized Version of Foxp2 Affects Cortico-Basal Ganglia Circuits in Mice , 2009, Cell.

[79]  Karl J. Friston,et al.  Neural basis of an inherited speech and language disorder. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[80]  M. Lu,et al.  Foxp2 and Foxp1 cooperatively regulate lung and esophagus development , 2007, Development.

[81]  C Donlan,et al.  GENETIC BASIS OF SPECIFIC LANGUAGE IMPAIRMENT: EVIDENCE FROM A TWIN STUDY , 1995, Developmental medicine and child neurology.

[82]  P. Lieberman On the nature and evolution of the neural bases of human language. , 2002, American journal of physical anthropology.

[83]  J. Tomblin,et al.  Prevalence of specific language impairment in kindergarten children. , 1997, Journal of speech, language, and hearing research : JSLHR.

[84]  Li-Fang Chu,et al.  Expression of FoxP2 during zebrafish development and in the adult brain. , 2006, The International journal of developmental biology.

[85]  F. Vargha-Khadem,et al.  Behavioural analysis of an inherited speech and language disorder: comparison with acquired aphasia. , 2002, Brain : a journal of neurology.

[86]  H. Williams,et al.  Auditory responses in avian vocal motor neurons: a motor theory for song perception in birds. , 1985, Science.

[87]  R. Reep,et al.  Conservation and diversity of Foxp2 expression in muroid rodents: Functional implications , 2009, The Journal of comparative neurology.

[88]  G. Ehret Infant Rodent Ultrasounds – A Gate to the Understanding of Sound Communication , 2005, Behavior genetics.

[89]  G. Baird,et al.  A genomewide scan identifies two novel loci involved in specific language impairment. , 2002, American journal of human genetics.

[90]  David J. Paterson,et al.  Novel quantitative phenotypes of exercise training in mouse models. , 2006 .

[91]  C. Scharff,et al.  Incomplete and Inaccurate Vocal Imitation after Knockdown of FoxP2 in Songbird Basal Ganglia Nucleus Area X , 2007, PLoS biology.