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FOXP2 As a Molecular Window Into Speech and Language

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FOXP2 As a Molecular Window Into Speech and Language Review FOXP2 as a molecular window into speech and language Simon E. Fisher1 and Constance Scharff2 1 Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, OX3 7BN, UK 2 Department of Animal Behavior, Institute of Biology, Freie Universita¨ t, Berlin, Germany Rare mutations of the FOXP2 transcription factor gene Nevertheless, the gene provides a molecular entry point cause a monogenic syndrome characterized by impaired into neurogenetic mechanisms facilitating human spoken speech development and linguistic deficits. Recent language [8], opening up innovative avenues of investi- genomic investigations indicate that its downstream gation that are already proving fruitful. neural targets make broader impacts on common Two characteristics make FOXP2 especially amenable language impairments, bridging clinically distinct dis- for this purpose. First, the gene encodes a regulatory orders. Moreover, the striking conservation of both protein, belonging to the Forkhead-box group of transcrip- FoxP2 sequence and neural expression in different tion factors [9]; hence, functional genomics can identify vertebrates facilitates the use of animal models to study other elements of the pathways in which it participates, ancestral pathways that have been recruited towards including targets that it regulates. Second, FoxP2 ortho- human speech and language. Intriguingly, reduced logues exist in highly similar forms in many vertebrates, FoxP2 dosage yields abnormal synaptic plasticity and showing comparable neural expression patterns; in impaired motor-skill learning in mice, and disrupts vocal humans, monkeys, mice, rats, birds, crocodiles and zebra- learning in songbirds. Converging data indicate that fish, FoxP2 is consistently expressed in distributed circuits Foxp2 is important for modulating the plasticity of involving (among others) the cortex, basal ganglia (BG), relevant neural circuits. This body of research represents thalamus and cerebellum [10–17]. Such remarkable con- the first functional genetic forays into neural mechan- servation has led some to posit that the link between isms contributing to human spoken language. FOXP2 and language is weak [18]. This claim is based on the misconception that a unique trait requires genes A genetic perspective on speech and language that are exclusive to the species and organs that exhibit it. The anatomical, neural and cognitive bases of speech and By contrast, we argue that because the human faculty for language have been open to investigation for some years. spoken language is built on multiple traits that predate its Only recently have modern genetic tools been brought to emergence, its evolution is unlikely to be explained in bear on this fascinating aspect of being human [1]. A novel terms of a single human-specific or brain-specific molecular molecular perspective is emerging, driven by isolation of agent [1,19]. Here, we update findings [20] regarding genomic variants that are correlated with disturbances in FoxP2 function in a range of species (including human, speech, language and/or reading [2,3]. One finding at the mice and songbirds) and reveal how they help elucidate the heart of this new wave of research was the discovery of contributions of this gene to speech and language. FOXP2 mutations that cause a monogenic speech and language disorder [4,5]. Given adequate environmental Building bridges between distinct language disorders input, children normally acquire highly proficient spoken Although mutations of FOXP2 itself are rare, it is plaus- language without conscious effort or formal tuition [6].By ible that the downstream pathways it regulates could have contrast, individuals carrying heterozygous FOXP2 broader relevance for common language impairments mutations have difficulties mastering complex sequences (Box 2). Recently, Vernes et al. [21] employed unbiased of mouth movements underlying speech (developmental genomic screening to isolate direct neural targets of verbal dyspraxia), and have impaired expressive and FOXP2 that might be implicated in language disorders. receptive language, whereas other aspects of cognition The strategy exploited chromatin-immunoprecipitation and development are relatively spared [7] (Box 1). (ChIP) with FOXP2-recognizing antibodies to purify geno- A role for FOXP2 first became apparent based on inves- mic fragments that the protein binds in native chromatin tigations of a multigenerational pedigree (the KE family) of human neuronal cell models, followed by shotgun- in which all affected members inherited a missense sequencing to establish identity of enriched fragments. mutation (R553H) disturbing the DNA-binding domain This technique uncovered a FOXP2-bound fragment in the of the encoded protein [4]. Subsequent studies identified first intron of CNTNAP2, thegeneencoding‘contactin- additional cases of FOXP2 disruption (Box 1), but indicated associated protein-like 2’, a member of the neurexin super- that these are rare. For example, it has been estimated family (Figure 1). Neurexins are neuronal transmem- that only 1 in 50 people diagnosed with developmental brane proteins involved in cell adhesion; classical verbal dyspraxia carry aetiological point mutations [5]. neurexins function primarily as polymorphic synaptic Corresponding author: Fisher, S.E. ([email protected]). receptors, whereas contactin-associated proteins have 166 0168-9525/$ – see front matter ß 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.tig.2009.03.002 Available online 21 March 2009 Review Trends in Genetics Vol.25 No.4 Box 1. FOXP2 mutations in humans Box 2. Defining language disorders The discovery of human FOXP2 and its potential role in speech and The process of speech and language acquisition is extraordinarily language resulted from positional cloning studies of a large complex, yet we often take it for granted. With adequate multigenerational pedigree (the KE family) [4]. Approximately half opportunity, the overwhelming majority of children develop adept (15 people) of the family members had difficulties in sequencing spoken language skills rapidly during the first few years of life. mouth movements, impairing speech (developmental verbal dys- Sometimes when a child fails to acquire normal language this praxia), along with wide-ranging oral and written language deficits, occurs as a secondary consequence of a physical or neurological affecting both expressive and receptive skills [7]. Effects on non- problem such as mental retardation, deafness or cleft-lip or cleft- verbal cognition were less severe and unlikely to be central [7]. After palate. However, significant speech and/or language difficulties in mapping the locus responsible to chromosome 7q31 [74], it was a subset of children remain unexplained [6]. Robust diagnosis of found that all affected individuals carried a heterozygous point this type of developmental disorder can be challenging, being mutation in FOXP2, yielding an arginine-to-histidine substitution at partly based on exclusionary criteria (i.e. absence of particular a crucial residue (R553H) in the DNA-binding domain of the encoded symptoms) [76]. protein [4]. An unrelated child with similar deficits had a de novo Some forms of speech and language disorder, such as the one balanced translocation [75] directly disrupting the FOXP2 locus [4]. caused by mutation of FOXP2, involve problems with controlling Subsequently, mutation screening in a panel of 49 probands with a fine co-ordinated movement sequences of the mouth, tongue, lips diagnosis of developmental verbal dyspraxia identified a novel and soft palate, yielding a diagnosis of development verbal aetiological point mutation [5]. In this case, the change was a dyspraxia (also referred to as childhood apraxia of speech). heterozygous nonsense mutation (R328X) predicted to severely However, it is more common to find children with language truncate the FOXP2 protein. Although there was no specific require- impairments that occur in absence of these kinds of overt ment for familial clustering when selecting the panel for this study, articulation problems. the proband in question had an affected sister and mother, both of Many such children are given a diagnosis of SLI, typically defined whom also carried the R328X mutation [5]. Several heterozygous or as a significant discrepancy between their verbal and non-verbal hemizygous chromosomal rearrangements involving FOXP2 have abilities, assessed by standardized batteries of tests. An epidemio- since been reported, including translocations and deletions [43–46]. logical study of preschool children (aged 5 6 years) in the US has People who have Silver-Russell syndrome associated with maternal – estimated a prevalence of up to 7% [77]. In practice, a diagnosis of uniparental disomy of chromosome 7 sometimes show speech SLI encompasses a large degree of heterogeneity; there can be difficulties, which might correlate with reduced FOXP2 expression considerable variation in profile (i.e. which aspects of language are [43]. One study proposed that the gene is maternally imprinted, impaired) and severity of deficits observed among different affected primarily based on absence of a paternal copy in people with verbal people, or even in the same individual at different ages [3]. SLI can dyspraxia [43]. However, this hypothesis is inconsistent with be divided into categories such as phonological disorder, expressive independent observations of maternally inherited mutations, dele- disorder and mixed (expressive and receptive)
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