Dr Simon E Fisher
| Research Area: | Genetics and Genomics |
|---|---|
| Technology Exchange: | Bioinformatics, Cell sorting, Chromosome mapping, ES cell / homologous recombination, Immunohistochemistry, In situ hybridisation, Microscopy (Confocal), Protein interaction, Transcript profiling and Transgenesis |
| Keywords: | speech and language, FOXP2 gene, functional genomics, human evolution, neurons and central nervous system |
| Web Links: | Wellcome Trust website |
A mutation in the DNA-binding domain of FOXP2 impairs speech & language in a multigenerational ...
Human neurons carrying a mutated version of FOXP2
Chromosomal abnormalities in a child with a severe speech disorder
We are pioneering new ways of uncovering brain pathways that are important for speech and language development. Our research strategy is based on the idea that genes implicated in language disorders can provide "molecular windows" into neural mechanisms contributing to human communication. People who carry abnormalities in a gene known as FOXP2 have difficulties with learning and producing the complicated sequences of mouth movements needed for speech, accompanied by impaired language and grammar. The FOXP2 gene encodes a conserved regulatory protein that switches on and off other genes in the developing and mature brain. FOXP2 appears to help regulate a subset of neuronal circuits in a wide range of non-speaking vertebrates, but its role may have been modified during human evolution. The discovery of FOXP2 represented the first time that a gene has been clearly linked to speech and language development.
Taking FOXP2 as a starting point, complementary approaches for uncovering the origins and bases of speech and language pathways are underway. These include identification and study of people who have speech/language deficits as a consequence of FOXP2 mutation, investigations of gene function in neurons grown in the laboratory, and exploration of the ways that this gene impacts on the development of the mammalian central nervous system. State-of-the-art functional genomic techniques (including high-throughput gene expression profiling and chromatin-immunoprecipitation) are used to identify other elements of the pathways that FOXP2 regulates in living cells. Our research also benefits from a strong multidisciplinary remit, integrating data from diverse fields including psychology, neuroscience, genetics, developmental biology and evolutionary anthropology.
There are no collaborations listed for this principal investigator.
2009. A Humanized Version of Foxp2 Affects Cortico-Basal Ganglia Circuits in Mice CELL, 137 (5), pp. 961-971. | Read more
2009. FOXP2 as a molecular window into speech and language. Trends Genet, 25 (4), pp. 166-177. Read abstract | Read more
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. Hide abstract
2008. A functional genetic link between distinct developmental language disorders. N Engl J Med, 359 (22), pp. 2337-2345. Read abstract | Read more
Rare mutations affecting the FOXP2 transcription factor cause a monogenic speech and language disorder. We hypothesized that neural pathways downstream of FOXP2 influence more common phenotypes, such as specific language impairment. Hide abstract
2008. Impaired synaptic plasticity and motor learning in mice with a point mutation implicated in human speech deficits. Curr Biol, 18 (5), pp. 354-362. Read abstract | Read more
The most well-described example of an inherited speech and language disorder is that observed in the multigenerational KE family, caused by a heterozygous missense mutation in the FOXP2 gene. Affected individuals are characterized by deficits in the learning and production of complex orofacial motor sequences underlying fluent speech and display impaired linguistic processing for both spoken and written language. The FOXP2 transcription factor is highly similar in many vertebrate species, with conserved expression in neural circuits related to sensorimotor integration and motor learning. In this study, we generated mice carrying an identical point mutation to that of the KE family, yielding the equivalent arginine-to-histidine substitution in the Foxp2 DNA-binding domain. Homozygous R552H mice show severe reductions in cerebellar growth and postnatal weight gain but are able to produce complex innate ultrasonic vocalizations. Heterozygous R552H mice are overtly normal in brain structure and development. Crucially, although their baseline motor abilities appear to be identical to wild-type littermates, R552H heterozygotes display significant deficits in species-typical motor-skill learning, accompanied by abnormal synaptic plasticity in striatal and cerebellar neural circuits. Hide abstract
2007. High-throughput analysis of promoter occupancy reveals direct neural targets of FOXP2, a gene mutated in speech and language disorders. Am J Hum Genet, 81 (6), pp. 1232-1250. Read abstract | Read more
We previously discovered that mutations of the human FOXP2 gene cause a monogenic communication disorder, primarily characterized by difficulties in learning to make coordinated sequences of articulatory gestures that underlie speech. Affected people have deficits in expressive and receptive linguistic processing and display structural and/or functional abnormalities in cortical and subcortical brain regions. FOXP2 provides a unique window into neural processes involved in speech and language. In particular, its role as a transcription factor gene offers powerful functional genomic routes for dissecting critical neurogenetic mechanisms. Here, we employ chromatin immunoprecipitation coupled with promoter microarrays (ChIP-chip) to successfully identify genomic sites that are directly bound by FOXP2 protein in native chromatin of human neuron-like cells. We focus on a subset of downstream targets identified by this approach, showing that altered FOXP2 levels yield significant changes in expression in our cell-based models and that FOXP2 binds in a specific manner to consensus sites within the relevant promoters. Moreover, we demonstrate significant quantitative differences in target expression in embryonic brains of mutant mice, mediated by specific in vivo Foxp2-chromatin interactions. This work represents the first identification and in vivo verification of neural targets regulated by FOXP2. Our data indicate that FOXP2 has dual functionality, acting to either repress or activate gene expression at occupied promoters. The identified targets suggest roles in modulating synaptic plasticity, neurodevelopment, neurotransmission, and axon guidance and represent novel entry points into in vivo pathways that may be disturbed in speech and language disorders. Hide abstract
2006. Functional genetic analysis of mutations implicated in a human speech and language disorder. Hum Mol Genet, 15 (21), pp. 3154-3167. Read abstract | Read more
Mutations in the FOXP2 gene cause a severe communication disorder involving speech deficits (developmental verbal dyspraxia), accompanied by wide-ranging impairments in expressive and receptive language. The protein encoded by FOXP2 belongs to a divergent subgroup of forkhead-box transcription factors, with a distinctive DNA-binding domain and motifs that mediate hetero- and homodimerization. Here we report the first direct functional genetic investigation of missense and nonsense mutations in FOXP2 using human cell-lines, including a well-established neuronal model system. We focused on three unusual FOXP2 coding variants, uniquely identified in cases of verbal dyspraxia, assessing expression, subcellular localization, DNA-binding and transactivation properties. Analysis of the R553H forkhead-box substitution, found in all affected members of a large three-generation family, indicated that it severely affects FOXP2 function, chiefly by disrupting nuclear localization and DNA-binding properties. The R328X truncation mutation, segregating with speech/language disorder in a second family, yields an unstable, predominantly cytoplasmic product that lacks transactivation capacity. A third coding variant (Q17L) observed in a single affected child did not have any detectable functional effect in the present study. In addition, we used the same systems to explore the properties of different isoforms of FOXP2, resulting from alternative splicing in human brain. Notably, one such isoform, FOXP2.10+, contains dimerization domains, but no DNA-binding domain, and displayed increased cytoplasmic localization, coupled with aggresome formation. We hypothesize that expression of alternative isoforms of FOXP2 may provide mechanisms for post-translational regulation of transcription factor function. Hide abstract
2006. The eloquent ape: genes, brains and the evolution of language. Nat Rev Genet, 7 (1), pp. 9-20. Read abstract | Read more
The human capacity to acquire complex language seems to be without parallel in the natural world. The origins of this remarkable trait have long resisted adequate explanation, but advances in fields that range from molecular genetics to cognitive neuroscience offer new promise. Here we synthesize recent developments in linguistics, psychology and neuroimaging with progress in comparative genomics, gene-expression profiling and studies of developmental disorders. We argue that language should be viewed not as a wholesale innovation, but as a complex reconfiguration of ancestral systems that have been adapted in evolutionarily novel ways. Hide abstract
2005. Identification of FOXP2 truncation as a novel cause of developmental speech and language deficits. Am J Hum Genet, 76 (6), pp. 1074-1080. Read abstract | Read more
FOXP2, the first gene to have been implicated in a developmental communication disorder, offers a unique entry point into neuromolecular mechanisms influencing human speech and language acquisition. In multiple members of the well-studied KE family, a heterozygous missense mutation in FOXP2 causes problems in sequencing muscle movements required for articulating speech (developmental verbal dyspraxia), accompanied by wider deficits in linguistic and grammatical processing. Chromosomal rearrangements involving this locus have also been identified. Analyses of FOXP2 coding sequence in typical forms of specific language impairment (SLI), autism, and dyslexia have not uncovered any etiological variants. However, no previous study has performed mutation screening of children with a primary diagnosis of verbal dyspraxia, the most overt feature of the disorder in affected members of the KE family. Here, we report investigations of the entire coding region of FOXP2, including alternatively spliced exons, in 49 probands affected with verbal dyspraxia. We detected variants that alter FOXP2 protein sequence in three probands. One such variant is a heterozygous nonsense mutation that yields a dramatically truncated protein product and cosegregates with speech and language difficulties in the proband, his affected sibling, and their mother. Our discovery of the first nonsense mutation in FOXP2 now opens the door for detailed investigations of neurodevelopment in people carrying different etiological variants of the gene. This endeavor will be crucial for gaining insight into the role of FOXP2 in human cognition. Hide abstract
2002. Molecular evolution of FOXP2, a gene involved in speech and language NATURE, 418 (6900), pp. 869-872. | Read more
2001. A forkhead-domain gene is mutated in a severe speech and language disorder. Nature, 413 (6855), pp. 519-523. Read abstract | Read more
Individuals affected with developmental disorders of speech and language have substantial difficulty acquiring expressive and/or receptive language in the absence of any profound sensory or neurological impairment and despite adequate intelligence and opportunity. Although studies of twins consistently indicate that a significant genetic component is involved, most families segregating speech and language deficits show complex patterns of inheritance, and a gene that predisposes individuals to such disorders has not been identified. We have studied a unique three-generation pedigree, KE, in which a severe speech and language disorder is transmitted as an autosomal-dominant monogenic trait. Our previous work mapped the locus responsible, SPCH1, to a 5.6-cM interval of region 7q31 on chromosome 7 (ref. 5). We also identified an unrelated individual, CS, in whom speech and language impairment is associated with a chromosomal translocation involving the SPCH1 interval. Here we show that the gene FOXP2, which encodes a putative transcription factor containing a polyglutamine tract and a forkhead DNA-binding domain, is directly disrupted by the translocation breakpoint in CS. In addition, we identify a point mutation in affected members of the KE family that alters an invariant amino-acid residue in the forkhead domain. Our findings suggest that FOXP2 is involved in the developmental process that culminates in speech and language. Hide abstract
