FOXP2 and human evolution

From Wikipedia, the free encyclopedia
Jump to: navigation, search
Forkhead box P2
Protein FOXP2 PDB 2a07.png
PDB rendering based on 2a07.
Available structures
PDB Ortholog search: PDBe, RCSB
Symbols FOXP2 ; CAGH44; SPCH1; TNRC10
External IDs OMIM605317 MGI2148705 HomoloGene33482 GeneCards: FOXP2 Gene
RNA expression pattern
PBB GE FOXP2 gnf1h09377 at tn.png
More reference expression data
Species Human Mouse
Entrez 93986 114142
Ensembl ENSG00000128573 ENSMUSG00000029563
UniProt O15409 P58463
RefSeq (mRNA) NM_001172766 NM_053242
RefSeq (protein) NP_001166237 NP_444472
Location (UCSC) Chr 7:
113.73 – 114.33 Mb
Chr 6:
14.9 – 15.44 Mb
PubMed search [1] [2]

The FOXP2 gene is encoded for production of the forkhead box protein P2 which is involved in human speech and language (as well as bird song and mouse vocalization) and may have played an important role in human evolution.

Discovery and significance in speech and language disorders[edit]

The importance of FOXP2 is twofold. First, it is one of the few genes that have been found to be under positive selection and is associated with a human-specific phenotype. Second, it was the first gene to be associated with disorders of speech and language development. These disorders are thought to be highly heritable so the study of members within families was the logical approach.

The KE family is a three generation family in which approximately half of the members have an autosomal dominant disorder that causes severe speech and language impairments.[1] More specifically they have developmental verbal dyspraxia (DVD) which involves impairment in the selection and sequencing of fine, complex orofacial movements necessary for articulation together with wider deficits in several aspects of language (expressive and receptive) and grammar (comprehension and production).[1][2][3] These impairments are not specific as they range across a number of components in speech and language, indicating that the underling genetic basis is probably complex. However, there are many cases of single genetic mutations, e.g. in cystic fibrosis, that lead to a complex phenotype. These types of mutations are easier to trace because of their simple inheritance pattern like that seen in the KE family. Therefore, it is likely that a single gene mutation affects these individuals, which is what was eventually found.

The gene SPCH1 located on a 5.6-cM interval of region 7q31 on chromosome 7 was discovered to correlate with the speech and language disorder described in the KE family.[4] Convergent evidence came from a patient unrelated to the KE family, known as CS, who had a disruptive chromosomal translocation within this gene causing similar speech and language difficulties.[5] This gene was eventually designated as FOXP2, as it was found to show a high level of similarity to the DNA-binding domain of the forkhead/winged-helix (FOX) family of transcription factors, particularly the P-subfamily.[3] The resulting protein of this gene is a transcription factor containing polyglutamine tracts, a zinc finger, a leucine zipper motif, and a forkhead DNA-binding domain.[3][6] The DNA binding region is highly conserved and enables FOX proteins to regulate the expression of target genes, without them FOX cannot work as a transcription factor. A missense mutation causing an arginine-to-histidine substitution (R553H) in this DNA-binding domain is thought to be responsible for the observed deficits in KE.[3][7] Moreover, a heterozygous nonsense mutation, known as the R328X variant, was found to produce a truncated protein that correlated with speech and language difficulties in an individual and two of their close family members.[8] The importance of identifying more mutations in FOXP2 is that they each give invaluable information regarding its function in speech and language. Several other studies have associated FOXP2 to speech and language impairment.[9][10][11] A more recent examination of the R553H and R328X mutations showed that they affected nuclear localization, DNA-binding and the transactivation (increased gene expression) properties of FOXP2.[12][13] Moreover, the R553H mutation causes a reduction in positive charge in the forkhead DNA-binding region which would disrupt DNA binding.[14] Although, DVD associated with FOXP2 disruptions are thought to be rare (~2% by one estimate),[8] a faulty copy of FOXP2 in individuals always causes speech and language problems.

In a related disorder to DVD, known as specific language impairment (SLI), individuals have similar impairments but do not share the core articulation difficulties.[15] Moreover, analysis of the coding-region variants of FOXP2 in families with SLI yielded no evidence to support association between FOXP2 mutations and SLI.[16] this implies that FOXP2 is not associated with any disorder affecting speech and language; rather, it may be specific to DVD even if, as suggested above, it is rare. On the other hand, analysis of FOXP2, using the chromatin immunoprecipitation technique, revealed that it binds onto and directly down-regulates expression of CNTNAP2, a gene found to be associated with nonsense-word repetition, a major marker of SLI.[15] Now that a direct genetic-phenotype link is found with FOXP2 the next important task is to determine the precise mechanism by which mutation of this gene leads to speech and language deficits. This will involve studying, due to FOXP2 role as a transcription factor, its interaction with other genes such as CNTNAP2 (see below for further discussion).

Evolutionary selection[edit]

The FOXP2 gene is highly conserved between humans with no amino-acid polymorphisms. Furthermore, in a comparison between humans, chimpanzees, orangutans, gorilla, rhesus macaque and mice[17][18] all the non-human primates had identical proteins, differing from humans by two amino acid substitutions (T303N, N325S),[7] while mice differed to humans by three substitutions. This is significant because after the split from the chimpanzee-human last common ancestor (CHLCA) at a relatively short period of ~4-8 million years (Myr) two amino acid substitutions became fixed in the human lineage, whereas with a relatively long period of ~130Myr of evolution between this ancestor and mice only one amino acid change has occurred. Furthermore, using the Tajima's D[19] and the Fay and Wu's H[20] tests Enard et al. 2002 found that the FOXP2 gene showed an extreme skew in the frequency spectrum of allelic variants towards rare and high-frequency derived (or non-ancestral) alleles; prominent markers of recent positive selection or a selective sweep.[17] Positive selection in FOXP2 has also been shown by another study.[18] One interpretation of these findings is that these human specific changes were somehow instrumental in the involvement of speech and language development which is why they were under positive selection. Fixation of these substitutions has been estimated to have occurred in the last 200,000 years around the time anatomically modern humans were emerging, further supporting their role in speech and language. However, in contradiction to the more recent estimates it has been discovered that Neanderthals also share the two human evolutionary changes.[21] This suggests that fixation occurred prior to modern humans and common ancestors of humans and Neanderthals, ~300,000-400,000 years ago. This would also suggest that the genetic changes were related to development of more basic rudimentary language skills possessed by Neanderthals. Furthermore, this development may have been an important step that eventually led to more complex language in modern humans. While these results are important, they are speculative as they rely on Deoxyribonucleic acid (DNA) from only two Neanderthal individuals. Furthermore, possible DNA errors due to molecular damage and contamination may have affected the results.[22] Importantly, further study of the Neanderthal genome will provide more accurate information on the timing of genetic changes on the human lineage, regarding the emergence of the human variant of FOXP2.

While there is a lot of evidence for FOXP2’s involvement in speech and language, there are still some caveats. For example, the N325S that was suggested by Enard et al. 2002 to be a potential phosphorylation site has also occurred independently in a number of species in the carnivore lineage.[17][18] It would indicate that N325S was selected for reasons other than for speech and language development, or that it is not a sufficient mechanism that enabled speech and/or language to evolve. The functional significance of the other amino acid change (T303N), which remains at present found only in humans, is still unknown as it lies in an uncharacterized region.[17] Even with these problems the significant evidence of human FOXP2 positive selection and the deficits seen when it is faulty support its, somewhat unknown, involvement in the evolution of human speech and language. FOXP2, despite its important role, is probably part of a network of genes that are important for speech and language development (see below for further discussion). This is due to the fact that individuals with a mutated FOXP2 are not completely incapable of speech and language expression. Furthermore, the complex nature of these processes makes it unlikely that the effects of a singular gene could underlie speech and language capability despite the suggestion made in the first section. Rather, it may facilitate a specific part of neurodevelopment and its early functional loss, i.e. during the development phase, may have severely affected these processes. Importantly, elucidating the aspects of speech and language FOXP2 is involved in should give us a better understanding of the neurodevelopmental biology of these processes.

Transcription factors like FOXP2 interact with regulatory regions of other genes to control their expression levels and therefore influence the levels of downstream proteins inside cells.[23] Furthermore, they regulate expression at different stages of development and/or during certain states in adulthood. As a consequence, they enable control and production of diverse types of cells with various morphologies and functions. One interesting transcription factor is PAX6 dubbed the ‘master control gene’[24] as it can be used to artificially induce eye production in different parts of the Drosophilia body.[25][26] Furthermore, it has been shown to interact, indirectly and directly, with ~2500 genes in the development of the eye. Similarly, FOXP2 may act as a master control triggering a cascade of downstream events, involving a network of genes in the development of neural circuits supporting speech and language. Importantly, knowledge of such genes, e.g. CNTNAP2, and also those that regulate FOXP2, will enable better understanding of FOXP2’s role in speech and language, the genetic makeup of these processes themselves and ultimately why the gene is under such positive selection.

Specific effects in speech and language[edit]

Like FOXP2, FOX proteins, in general, are highly conserved transcription factors that are generally involved in development. Collectively, their functions encompass a wide range of roles in different tissues during embryonic development including cellular differentiation and proliferation, cell cycle regulation, pattern formation, and also have roles in adults, e.g. metabolism.[27] Mutations of many FOX genes either give rise to different developmental disorders affecting many organs or result in death due to improper development.[27][28] like FOXP2 most of the FOX development disorders are inherited in an autosomal dominant fashion due to mutations in the conserved DNA-binding domain.[28] Furthermore, studies suggest that the mutations in one gene copy, e.g. in FOXC1,[29] may cause reduced functional gene dosage during key stages in embryological development that lead to disease. This seems to be the case, as argued by MacDermot et al. 2005, for the KE family and CS who all have one mutated FOXP2 copy.[8] Overall, evidence from other FOX proteins is highly indicative of FOXP2 having multiple roles in embryogenesis in different tissues. This supported by the evidence of high FOXP2 expression in fetal tissues (as well as adult tissues), as well as the complex patterning of expression seen during lung, heart, brain, and gut development.[3][30] FOXP2 role in the brain is interesting, not only because of the speech and language link but also because the brain is the only region that seems to be affected. A likely explanation is that one functional copy of FOXP2 is enough to enable development of all non-neural tissue, while the brain or certain structures/neuron types have some susceptibility towards loss of a copy.[31]

Study of the alternative splicing of the FOXP2 gene is important as the way the proteins are spliced together dramatically affects their function, for example, causing changes in their levels of expression, subcellular localization and/or DNA-binding site recognition/affinity.[32] One alternative isoform of FOXP2 known as FOXP2.10+ has been studied in vitro and evidence suggests that it may play a regulatory role in controlling the quantity of active protein available in the nucleus as well as regulating the activity of other FOXP2 isoforms.[12] Although not fully known, if there is spatiotemporal distinction in the expression of alternative isoforms in the brain then splicing will give FOXP2 more diverse functionalities in neural structures/circuits. It will be important to study the effects of alternative splicing in animal models in order to understand the mechanisms by which the isoforms of FOXP2 exert their role spatiotemporally in the brain during development and in adults.

Further study of the two substitutions suggests that one of them may be of functional consequence. It causes the FOXP2 protein to be a potential target site for phosphorylation by protein kinase C, which could be an important mechanism in transcriptional regulation.[17] Some of the FOX genes, similarly, are phosphorylated by protein kinases, enabling them to change their function from transcriptional repressors (reduces transcription of target gene) to activators (decreases transcription of target gene), and vice versa. For example, LIN-3, a forkhead protein in C. Elegans, regulates vulva development and when phosphorylated acts as a transcriptional activator, promoting cells to adopt a particular cell type.[27] Likewise, although acting as transcriptional repressors, both FOXP2 and FOXP1 are co-expressed differentially in the lungs of mice to spatially restrict epithelial gene expression during lung development.[30] FOXP2’s activity in the brain also seems to indicate that it acts as a transcriptional repressor.[33][34] Functional loss of a gene copy could reduce levels of FOXP2 weakening transcriptional repression of many target genes resulting in imbalances during development.

The other transcription factor FOX genes in the P-subfamily, particularly FOXP1 and FOXP4, have been found to influence the transcriptional function of FOXP2.[35] The authors found that FOXP2 and FOXP1 share two separate, distinct and functional transcriptional repression subdomains, while FOXP4 also shares them, abeit only one is functional. Furthermore, these three proteins can undergo homo- and heterodimerization interactions with each other, dependent on a highly conserved leucine zipper domain. Importantly, these dimerizations were found to be essential for their transcriptional activity and DNA binding. Moreover, they could also enable better flexibility or an added level of regulation. More simply, this means that FOXP2 needs to interact and dimerize with either FOXP1 or FOXP4 in order to carry out its function as a transcriptional repressor. Li et al. also found that both FOXP1 and FOXP2 interacted with the corepressor CtBP-1 to synergistically repress transcription. this corepressor is able to recruit many other transcription regulators and can also act as a bridge between them and other proteins. In the same study, the zinc finger domain of FOXP2, although not essential for its function, was found to increase transcription more than threefold. Together, these findings suggest that the dimerization of three P-subfamily proteins along with interactions with other molecules, such as CtBP-1, allow FOXP2 to carry out complex transcriptional regulation in different tissues. This is supported by the suggestion made by the authors that these FOX proteins likely have a region that acts as a complex docking site for other transcription factors. Furthermore, all three proteins have high levels of co-expression in distinct but overlapping regions in the lungs, gut and brain.[30][36][37] In particular, Takahashi et al. described how expression of these proteins changes in the rat forebrain where their differential overlap seen at different developmental stages and in distinct regions is likely intrinsic to how they perform their functions correctly to achieve normal development.[37] In fact, it has been shown using knockout mice that FOXP1 and FOXP2 co-operate with each other when regulating lung and oesophagus development.[38] Surprisingly, deletions in FOXP1, resulting in a faulty copy of the gene, have been found in individuals with speech and language difficulties remarkably similar to those affected with Developmental verbal dyspraxia caused by FOXP2 mutations.[39] This could implicate FOXP1 to be either important role by itself or have a secondary role likely interacting with FOXP2 for speech and language development.

Apart from CtBP-1, protection of telomeres 1 (POT1) is another protein found to be associated with FOXP2.[13] It is part of a complex protecting the enzyme telomerase in human chromosomes from the DNA damage response, as impairment of POT1 results in cell cycle arrest. FOXP2 was found to be involved in the nuclear translocation of this protein and the R553H mutation prevented this.[13] Due to POT1’s important role in preventing cell cycle arrest, its incomplete localization, caused by FOXP2 impairment, could prevent neurons from developing leading to eventual neurodegeneration. As such, neurons expressing high levels of FOXP2, such as the basal ganglia, will be more susceptible to this, especially during periods of development. Tanabe et al. 2011 importantly provides the first line of evidence of a possible mechanism by which FOXP2 mutations could cause Developmental Verbal Dyspraxia in the KE family.[13]

Communication in mice and birds[edit]

FOXP2 has been found to be involved in verbal communication in mice and birds.[40][41][42][43] In a mouse FOXP2 knockout study,[40] loss of both copies of the gene caused severe motor impairment related to cerebellar abnormalities and lack of ultrasonic vocalisations normally elicited when pups are removed from their mothers. These vocalizations have important communicative roles in mother-offspring interactions. Loss of one copy was associated with impairment of ultrasonic vocalisations and a modest developmental delay. Although, vocalisations were affected the apparatus necessary for their production, including the neural control, in the vocal tract, and brainstem, were found to be normal. It is interesting to find cerebellar abnormalities related the purkinje cells in mice as FOXP2 is highly expressed in the cerebellum of both mice, songbirds and humans,[42][44][45] and cerebellar deficits are seen in the KE family.[45][46] The study overall showed that FOXP2 expression is involved in the development of the cerebellum and the production of vocalisations in mice. It also demonstrates rudimentary communicative connections between FOXP2 roles in humans and mice, and provides independent evidence for FOXP2’s role in communication. Further study of FOXP2 in mice will be required to elucidate the role of FOXP2 in human language and speech.

Mice studies[edit]

More recently, two amino acid substitutions, orthologous to the human substitutions, were introduced into the endogenous mouse FOXP2 gene to make it a partly “humanized” version (Foxp2hum), in order to explore human evolution using an animal model.[47] Homozygous mice with this gene were healthy and phenotypic analysis revealed that only the brain was affected, as compared to wild type mice. Effects on the brain included increased exploratory behavior, dopamine levels, striatal gene expression patterns and striatal synaptic plasticity. Conversely, in mice with one non-functional copy (Foxp2wt/ko) the effects on the brain were opposite. A more detailed analysis showed that vocalisations of Foxp2hum mice were specific compared to vocalisations made by Foxp2wt/ko mice in that the structure of the calls changed. This gives support to the hypothesis that the human-specific amino acid substitutions affected speech and/or language, although, the extent mouse vocalization are able to model the evolution of these human processes is still speculative, particularly as it is thought that the voluntary, rather than innate, control of neural circuitry underlying vocalizations was pivotal in the evolution of human speech.[48][49] However, evidence of shared molecular mechanism between human speech and mouse ultrasonic vocalizations has been shown.[50] The authors created mice with the human-specific R553H mutation and that that they exhibited abnormal ultrasonic vocalizations. Essentially, this demonstrated similarities and therefore a shared communicative role between the FOXP2 function in humans and mice.

Despite this, it has been discovered that male mice on encountering female mice produce complex ultrasonic vocalisations that have characteristics of song.[51] It may not be on par with birdsong but as mice are the “gold standard” genetic model organisms this will be an important approach towards better understanding the role of FOXP2. As will be discussed later if these vocalisations are learned as in humans their study, particularly the effect of FOXP2 mutations/knockouts, will be fruitful. Enard et al. 2009 further suggested that cortico-basal ganglia circuits in mice may be able to model some aspects of human speech and language evolution as some studies suggest that these circuits could be important for these processes in humans.[47][52][53] The authors concluded that the human specific changes in FOXP2 led to more efficient fine-tuning of motor control required for articulation involving the coordination of muscles in the lungs, larynx, tongue and lips. Again this is one possibility and their contribution to human capacity is still speculative.

Structural and functional neural abnormalities in the basal ganglia, a region implicated in a number of speech and language disorders, or more specifically the striatum (reduced grey matter in caudate) are seen in affected individuals with FOXP2 mutations.[45][46][54] The striatum is a region that has high FOXP2 expression in developing and adult human and mice brains.[44][45] FOXP2 expression is found to be restricted in a number of interconnected brain regions in humans, which are also found to be impaired in the KE family, including those involved in motor-related functions such as basal ganglia, various thalamic nuclei, inferior olives and the purkinje cells of the cerebellum.[7][44] The authors suggested that the orofacial difficulties seen in individuals the FOXP2 mutation can be explained by loss of these corticostriatal and olivocerebellar circuits, while other problems may be due to either impairment of secondary functions processed by these regions or an essential component of certain functions that rely on these regions are unable to work properly. For example, reasons for impairment of grammar and linguistics may be due to deficits in motor planning and sequencing.

Bird studies[edit]

Human speech is very dynamic and unique. Our brains are able to, through the fine control of many muscles, recombine a finite set of basic sounds to generate infinite meaning, i.e. language. Speech in humans is a complex form of vocal learning, while bird species are capable of song are the closest to it involving the experience-based modification of innate vocalisations to produce a large number of sounds beyond their genetic repertoire.[32] These bird species include oscine songbirds, parrots and hummingbirds, other species capable of song are whales, dolphins and speculatively in bats.[7][55] Human speech and birdsong requires elaborate neural control and fine co-ordination of vocal apparatus. Studying vocal learning birds may help to determine their independent evolution of vocal learning is similar to humans. Vocal learning involves the interaction of auditory and motor regions for acquisition and production along with specialized forebrain structures (see figure 4).[56] Importantly, young birds must first learn from listening to the sounds made by adults of their own species in order to develop normal vocalisations, involving both innate and experience-based mechanisms. If not, i.e. in isolation, vocalisations will become abnormal once they reach adulthood. Conversely, in non-vocal learners, e.g. chickens, doves or non-human primates (there is speculation that there may be a degree of learning in non-human primates), vocalisations are innate and do not require learning from adults of their species.

Evidence suggest that human speech and birdsong share a number of behavioural and neural similarities.[55] For example, biases occur in human babies with prolonged exposure to their first language due to alteration of their phonetic perception.[57] Similarly, songbird brains become specialised to process conspecific sounds while filtering out sounds from other species. Essentially, humans and songbirds, due to their specialized neural systems, have innate predispositions for vocal sounds generated from their own species. Other behavioural similarities include importance of hearing self vocalisations, auditory sensitive periods for learning and plasticity after this period.[55][56] Neurally, there are a number of anatomical and functional similarities between avian and human organization of neural pathways for vocal production and processing.[56] For example, the lobus paraolfactorius (LPO) and the paleostriatum augmentatum (PA) in the avian brain are considered to be equivalent to the mammalian striatum. Other neural similarities include left side lateralization in some, but not all, songbird species, hierarchical neural pathways, neural constraints, predispositions that bias the organism for assistance in vocal learning, neurogenesis in brain regions related to song during neurodevelopment and neurogenesis to maintain long-term plasticity for new experiences in adult brains.[55][56]

Zebra finches[edit]

FOXP2 expression seems to be highly similar in mice, songbird and humans, during development and in adults, suggestive of FOXP2 having an evolutionary role in motor control and sensory-motor integration.[42][45][58] Teramitsu et al. found that there are several regions important for vocal learning and production where FOXP1 and FOXP2 expression were higher than surrounding regions and also overlapped in zebra finches. FOXP2 expression was not found to be sexually dimorphic (i.e. not higher in singing males than non-singing females), while FOXP1 expression was.[58] They suggested that in overlapping regions FOXP1 through interactions with FOXP2, as discussed previously, may confer some song function in males. Otherwise, they thought that similarity between FOXP2 expression in females and males implies that FOXP2 is not special for vocal learning. However, studies on the dorsal striatal vocal nucleus, also known as Area X (or equivalent regions), a region of high FOXP2 expression, suggests otherwise.[41][42][43] This is a specialised region in the anterior forebrain pathway (AFP) important for song learning and monitoring adult song in avian vocal-learners located within the avian equivalent of the mammalian cortico-basal-ganglia loop. Haeslar et al. 2004 found that male zebra finches expressed FOXP2 in their development phase when they are trying to imitate song and not before and after this period.[42][59] This was also seen in male adult canaries during the period where they remodel their song. Collectively, FOXP2 expression seems to be important for learning during development and post-learning in adults, i.e. vocal plasticity. it is the regulation of FOXP2 itself that seems be important for this vocal plasticity. In the adults of six other songbirds studied FOXP2 expression in Area X were consistent with either seasonal/breeding periods where expression is higher than surrounding striatum or at periods where singing is not required where expression is lower. Despite not having an Area X (or equivalent region) adult non-vocal learners had FOXP2 expression distributed similarly to adult vocal-learners where highest expression was in the striatal and subtelencephalonic regions, including striatum, dorsal thalamus, midbrain nuclei, inferior olive and cerebellum (Purkinje cells). These results are consistent with another bird related study[58] and studies of mice and humans.[42][45] The FOXP2 expressing spiny neurons in Area X of zebra finches are found to be increasingly recruited for behavioural plasticity in response to song relevant stimuli.[60] This neurogenesis occurred the most during the late sensory-motor phase of vocal learning compared to early vocalisation stage and the stage after the song becomes crystallised. expression of FOXP2 expression in Area X is found to occur prior to neurogenesis of spiny neurons suggesting that FOXP2 may have some function in facilitating sensory-motor learning at the time new neurons are recruited. This study highlights the importance of using animal models for studying FOXP2’s role in humans. However, as it was found that FOXP2 is not expressed in regions of the mouse brain where neurogenesis occurs suggestive of specific roles of this gene in songbirds during neurogenesis or it could be a lineage marker for spiny neurons.

FOXP2 mRNA expression levels in Area X of male zebra finches have been found to vary in a socially dependant way, where expression decreased when males sung alone (undirected) and increased when they sung to females (directed).[41] This suggests that FOXP2 function in adult zebra finches isn’t purely involved in song learning/development or the act of singing itself but also involved in the real-time behavioural regulation of vocal-learning for song consolidation. As such this supports the idea that FOXP2 is involved in communication, conclusively in humans and song birds. It further suggests that FOXP2 not merely acts to function in development and in motor-related functions but also in certain social contexts such as in birdsong and speech. It is important to note that while zebra finches only sing one song they, like speech in humans, require maintenance to ensure quality in adulthood. Converse to FOXP2 mRNA, protein levels are downregulated in Area X in adult songbirds during both directed and undirected singing, compared to nonsinging birds.[61] This somewhat contradictory finding is not erroneous; rather, it demonstrates that mRNA levels are not parallel with protein levels and cannot wholly be used to describe the functionality of FOXP2. The authors hypothesised that socially-dependent decrease in protein levels may be critical for circuit modification and vocal variability for song maintenance. As FOXP2 acts as a transcriptional repressor its downregulation may enable this maintenance. The work by Miller et al. and Teramitsu and White suggest that FOXP2 has important regulatory functions of behaviour in adults.[41][61] However, the significance of the contradiction is still unclear and again conclusions are still speculative. A further example of socially-dependent regulation of FOXP2 comes from a study where the FOXP2 mRNA levels and protein levels in Area X (spiny neurons) were experimentally reduced, using lentivirus-mediated ribonucleic acid interference (RNAi).[43] This impaired the ability of zebra finches to completely and accurately imitate the song of an adult male tutor leading to a more variable performance. The authors concluded that due to the deficits seen with FOXP2, it seems to be important for auditory-guided vocal motor learning. The results are consistence with song variability hypothesis argued by Miller et al. where reduced FOXP2 protein levels allow for circuit modification underlying song.[62] Juveniles also seem to downregulate their FOXP2 levels in Area X when singing.[63] Together, evidence suggests FOXP2 is related to song modification rather than just song stability as downregulation occurs more frequently in juveniles, especially during the sensorimotor phase, where they have very variable songs compared to adults who generally have more stable songs. This study also showed that contradictory to the suggestive role of FOXP2 in development deafening juveniles did not affect FOXP2 basal levels before or during the critical sensorimotor phase, and downregulation also occurred in deafened juveniles during singing. However, the level of downregulation in hearing juveniles negatively correlated on the amount of time the birds spent singing. The authors suggest that the regulation of FOXP2 levels is likely to have differential effects on the brain. High levels are involved with structural development and song stability while low levels allow vocal variability for vocal fine-tuning. Downregulation is acute especially in adults which follow a rise in protein levels for neural growth to consolidate neural pathways. This is possibly the reason why mRNA levels are high in directed singing as fast replenishment will enable rapid learning in the social context.

Evolutionary differences[edit]

More recently, it was found that knockout of FOXP2 reduced dendritic spines of spiny neurons in Area X which was even more pronounced when knockout occurred before they differentiated into spiny neurons.[64] This seems to be in line with the results of Haesler et al. 2007 as reduction in dendritic spines may underlie the abnormal song produced in knockout songbirds. Furthermore, the results are suggestive of FOXP2 acting at the synaptic/cellular level either in spine formation or maintenance of spiny neurons to regulate functions related to song.[43] Mice that have the R552H point mutation carried by the KE family show cerebellar reduction and interestingly show abnormal synaptic plasticity in striatal and cerebellar circuits.[65] Similarly, the mice with one functional copy of the partly “humanized” version of FOXP2 (Foxp2wt/ko) had decreased both dendrite lengths and synaptic plasticity in medium spiny neurons whereas mice with both functional copies have the opposite characteristics.[47] Together, evidence implies the possibility of FOXP2 role in synaptic plasticity and cellular biology in cortico-basal ganglia circuits.

Similarity of the human and songbird FOXP2 genes would suggest that changes (i.e. the two human-specific substitutions) were important for the independent evolution of song-learning/human speech mechanisms. However, there is no evidence to suggest positive selection on this gene in vocal-learning of non-humans as vocal-learning birds, whales, bats and dolphins all have FOXP2 that are all identical to the mouse.[42][66] Haesler et al. did find that zebra finches had a FOXP2 RNA transcript that is similar in size to the one found in humans suggestive, although still hypothetical, selection in this species acted on regulatory mechanisms.[42] Furthermore, Teramitsu et al. 2004 found that there were five amino acid differences in birds; four situated outside the protein domain and one in the zinc domain.[58] If these changes affected FOXP2 secondary structure or gene expression then it could be possible that they evolutionarily contributed to vocal-learning in birds. At the moment, it seems that evidence suggests that human-specific substitutions cannot be corroborated in other species capable of vocal-learning, as such FOXP2 sequence changes cannot account for vocal-learning. However, it does not mean that these changes weren’t pivotal given the complexity of human speech and language, the evidence of strong pressure for FOXP2 selection, the relatively unknown regulatory roles of FOXP2 and the mechanism involved in regulation of FOXP2 itself.

The compilation of evidence provided here overall gives a complex picture of FOXP2 in the expression/activity of its alternative isoforms, its function as a transcription factor and possible role as a master control gene in the brain.

See also[edit]


  1. ^ a b Vargha-Khadem F, Watkins K, Alcock K, Fletcher P, Passingham R (January 1995). "Praxic and nonverbal cognitive deficits in a large family with a genetically transmitted speech and language disorder". Proc. Natl. Acad. Sci. U.S.A. 92 (3): 930–3. doi:10.1073/pnas.92.3.930. PMC 42734. PMID 7846081. 
  2. ^ Vargha-Khadem F, Watkins KE, Price CJ, et al. (October 1998). "Neural basis of an inherited speech and language disorder". Proc. Natl. Acad. Sci. U.S.A. 95 (21): 12695–700. doi:10.1073/pnas.95.21.12695. PMC 22893. PMID 9770548. 
  3. ^ a b c d e Lai, Cecilia S. L.; Fisher, Simon E.; Hurst, Jane A.; Vargha-Khadem, Faraneh; Monaco, Anthony P. (2001). "A forkhead-domain gene is mutated in a severe speech and language disorder". Nature 413 (6855): 519–523. doi:10.1038/35097076. PMID 11586359. 
  4. ^ Fisher SE, Vargha-Khadem F, Watkins KE, Monaco AP, Pembrey ME (February 1998). "Localisation of a gene implicated in a severe speech and language disorder". Nat. Genet. 18 (2): 168–70. doi:10.1038/ng0298-168. PMID 9462748. 
  5. ^ Lai CS, Fisher SE, Hurst JA, et al. (August 2000). "The SPCH1 region on human 7q31: genomic characterization of the critical interval and localization of translocations associated with speech and language disorder". Am. J. Hum. Genet. 67 (2): 357–68. doi:10.1086/303011. PMC 1287211. PMID 10880297. 
  6. ^ Wang B, Lin D, Li C, Tucker P (July 2003). "Multiple domains define the expression and regulatory properties of Foxp1 forkhead transcriptional repressors". J. Biol. Chem. 278 (27): 24259–68. doi:10.1074/jbc.M207174200. PMID 12692134. 
  7. ^ a b c d Preuss, TM. (Jun 2012). "Human brain evolution: from gene discovery to phenotype discovery.". Proc Natl Acad Sci U S A. 109 Suppl 1: 10709–16. doi:10.1073/pnas.1201894109. PMC 3386880. PMID 22723367. 
  8. ^ a b c MacDermot KD, Bonora E, Sykes N, et al. (June 2005). "Identification of FOXP2 truncation as a novel cause of developmental speech and language deficits". Am. J. Hum. Genet. 76 (6): 1074–80. doi:10.1086/430841. PMC 1196445. PMID 15877281. 
  9. ^ Feuk L, Kalervo A, Lipsanen-Nyman M, et al. (November 2006). "Absence of a paternally inherited FOXP2 gene in developmental verbal dyspraxia". Am. J. Hum. Genet. 79 (5): 965–72. doi:10.1086/508902. PMC 1698557. PMID 17033973. 
  10. ^ Shriberg LD, Ballard KJ, Tomblin JB, Duffy JR, Odell KH, Williams CA (June 2006). "Speech, prosody, and voice characteristics of a mother and daughter with a 7;13 translocation affecting FOXP2". J. Speech Lang. Hear. Res. 49 (3): 500–25. doi:10.1044/1092-4388(2006/038). PMID 16787893. 
  11. ^ Zeesman S, Nowaczyk MJ, Teshima I, et al. (March 2006). "Speech and language impairment and oromotor dyspraxia due to deletion of 7q31 that involves FOXP2". Am. J. Med. Genet. A 140 (5): 509–14. doi:10.1002/ajmg.a.31110. PMID 16470794. 
  12. ^ a b Vernes SC, Nicod J, Elahi FM, et al. (November 2006). "Functional genetic analysis of mutations implicated in a human speech and language disorder". Hum. Mol. Genet. 15 (21): 3154–67. doi:10.1093/hmg/ddl392. PMID 16984964. 
  13. ^ a b c d Tanabe Y, Fujita E, Momoi T (July 2011). "FOXP2 promotes the nuclear translocation of POT1, but FOXP2(R553H), mutation related to speech-language disorder, partially prevents it". Biochem. Biophys. Res. Commun. 410 (3): 593–6. doi:10.1016/j.bbrc.2011.06.032. PMID 21684252. 
  14. ^ Banerjee-Basu, Sharmila; Baxevanis, Andreas D. (2004). "Structural analysis of disease-causing mutations in the P-subfamily of forkhead transcription factors". Proteins: Structure, Function, and Bioinformatics 54 (4): 639–647. doi:10.1002/prot.10621. PMID 14997560. 
  15. ^ a b Vernes SC, Newbury DF, Abrahams BS, et al. (November 2008). "A functional genetic link between distinct developmental language disorders". N. Engl. J. Med. 359 (22): 2337–45. doi:10.1056/NEJMoa0802828. PMC 2756409. PMID 18987363. 
  16. ^ Newbury DF, Bonora E, Lamb JA, et al. (May 2002). "FOXP2 is not a major susceptibility gene for autism or specific language impairment". Am. J. Hum. Genet. 70 (5): 1318–27. doi:10.1086/339931. PMC 447606. PMID 11894222. 
  17. ^ a b c d e Enard W, Przeworski M, Fisher SE, et al. (August 2002). "Molecular evolution of FOXP2, a gene involved in speech and language". Nature 418 (6900): 869–72. doi:10.1038/nature01025. PMID 12192408. 
  18. ^ a b c Zhang J, Webb DM, Podlaha O (December 2002). "Accelerated protein evolution and origins of human-specific features: Foxp2 as an example". Genetics 162 (4): 1825–35. PMC 1462353. PMID 12524352. 
  19. ^ Tajima F (November 1989). "Statistical method for testing the neutral mutation hypothesis by DNA polymorphism". Genetics 123 (3): 585–95. PMC 1203831. PMID 2513255. 
  20. ^ Fay, JC.; Wu, CI. (Jul 2000). "Hitchhiking under positive Darwinian selection.". Genetics 155 (3): 1405–13. PMC 1461156. PMID 10880498. 
  21. ^ Krause, Johannes; Lalueza-Fox, Carles; Orlando, Ludovic; Enard, Wolfgang; Green, Richard E.; Burbano, Hernán A.; Hublin, Jean-Jacques; et, al. (2007). "The Derived FOXP2 Variant of Modern Humans Was Shared with Neandertals". Current Biology 17 (21): 1908–1912. doi:10.1016/j.cub.2007.10.008. PMID 17949978. 
  22. ^ Pääbo S, Poinar H, Serre D, et al. (2004). "Genetic analyses from ancient DNA". Annu. Rev. Genet. 38: 645–79. doi:10.1146/annurev.genet.37.110801.143214. PMID 15568989. 
  23. ^ Marcus GF, Fisher SE (June 2003). "FOXP2 in focus: what can genes tell us about speech and language?". Trends Cogn. Sci. (Regul. Ed.) 7 (6): 257–262. doi:10.1016/S1364-6613(03)00104-9. PMID 12804692. 
  24. ^ Matsumoto Y, Osumi N (April 2008). "Role of Pax6 in the developing central nervous system". Brain Nerve (in Japanese) 60 (4): 365–74. PMID 18421978. 
  25. ^ Halder, G.; Callaerts, P.; Gehring, WJ. (Mar 1995). "Induction of ectopic eyes by targeted expression of the eyeless gene in Drosophila.". Science 267 (5205): 1788–92. doi:10.1126/science.7892602. PMID 7892602. 
  26. ^ Wawersik S, Maas RL (April 2000). "Vertebrate eye development as modeled in Drosophila". Hum. Mol. Genet. 9 (6): 917–25. doi:10.1093/hmg/9.6.917. PMID 10767315. 
  27. ^ a b c Carlsson, P.; Mahlapuu, M. (Oct 2002). "Forkhead transcription factors: key players in development and metabolism.". Dev Biol 250 (1): 1–23. doi:10.1006/dbio.2002.0780. PMID 12297093. 
  28. ^ a b Lehmann OJ, Sowden JC, Carlsson P, Jordan T, Bhattacharya SS (June 2003). "Fox's in development and disease". Trends Genet. 19 (6): 339–44. doi:10.1016/S0168-9525(03)00111-2. PMID 12801727. 
  29. ^ Nishimura DY, Searby CC, Alward WL, et al. (February 2001). "A spectrum of FOXC1 mutations suggests gene dosage as a mechanism for developmental defects of the anterior chamber of the eye". Am. J. Hum. Genet. 68 (2): 364–72. doi:10.1086/318183. PMC 1235270. PMID 11170889. 
  30. ^ a b c Shu W, Yang H, Zhang L, Lu MM, Morrisey EE (July 2001). "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. 276 (29): 27488–97. doi:10.1074/jbc.M100636200. PMID 11358962. 
  31. ^ Fisher SE, Lai CS, Monaco AP (2003). "Deciphering the genetic basis of speech and language disorders". Annu. Rev. Neurosci. 26: 57–80. doi:10.1146/annurev.neuro.26.041002.131144. PMID 12524432. 
  32. ^ a b White SA, Fisher SE, Geschwind DH, Scharff C, Holy TE (October 2006). "Singing mice, songbirds, and more: models for FOXP2 function and dysfunction in human speech and language". J. Neurosci. 26 (41): 10376–9. doi:10.1523/JNEUROSCI.3379-06.2006. PMC 2683917. PMID 17035521. 
  33. ^ Spiteri E, Konopka G, Coppola G, et al. (December 2007). "Identification of the transcriptional targets of FOXP2, a gene linked to speech and language, in developing human brain". Am. J. Hum. Genet. 81 (6): 1144–57. doi:10.1086/522237. PMC 2276350. PMID 17999357. 
  34. ^ Vernes SC, Spiteri E, Nicod J, et al. (December 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): 1232–50. doi:10.1086/522238. PMC 2276341. PMID 17999362. 
  35. ^ Li S, Weidenfeld J, Morrisey EE (January 2004). "Transcriptional and DNA binding activity of the Foxp1/2/4 family is modulated by heterotypic and homotypic protein interactions". Mol. Cell. Biol. 24 (2): 809–22. doi:10.1128/MCB.24.2.809-822.2004. PMC 343786. PMID 14701752. 
  36. ^ Lu MM, Li S, Yang H, Morrisey EE (December 2002). "Foxp4: a novel member of the Foxp subfamily of winged-helix genes co-expressed with Foxp1 and Foxp2 in pulmonary and gut tissues". Gene Expr. Patterns 2 (3-4): 223–8. doi:10.1016/S1567-133X(02)00058-3. PMID 12617805. 
  37. ^ a b Takahashi K, Liu FC, Hirokawa K, Takahashi H (November 2008). "Expression of Foxp4 in the developing and adult rat forebrain". J. Neurosci. Res. 86 (14): 3106–16. doi:10.1002/jnr.21770. PMID 18561326. 
  38. ^ Shu W, Lu MM, Zhang Y, Tucker PW, Zhou D, Morrisey EE (May 2007). "Foxp2 and Foxp1 cooperatively regulate lung and esophagus development". Development 134 (10): 1991–2000. doi:10.1242/dev.02846. PMID 17428829. 
  39. ^ Horn D, Kapeller J, Rivera-Brugués N, et al. (November 2010). "Identification of FOXP1 deletions in three unrelated patients with mental retardation and significant speech and language deficits". Hum. Mutat. 31 (11): E1851–60. doi:10.1002/humu.21362. PMC 3049153. PMID 20848658. 
  40. ^ a b Shu W, Cho JY, Jiang Y, et al. (July 2005). "Altered ultrasonic vocalization in mice with a disruption in the Foxp2 gene". Proc. Natl. Acad. Sci. U.S.A. 102 (27): 9643–8. doi:10.1073/pnas.0503739102. PMC 1160518. PMID 15983371. 
  41. ^ a b c d Teramitsu I, White SA (July 2006). "FoxP2 regulation during undirected singing in adult songbirds". J. Neurosci. 26 (28): 7390–4. doi:10.1523/JNEUROSCI.1662-06.2006. PMC 2683919. PMID 16837586. 
  42. ^ a b c d e f g h Haesler S, Wada K, Nshdejan A, et al. (March 2004). "FoxP2 expression in avian vocal learners and non-learners". J. Neurosci. 24 (13): 3164–75. doi:10.1523/JNEUROSCI.4369-03.2004. PMID 15056696. 
  43. ^ a b c d Haesler S, Rochefort C, Georgi B, Licznerski P, Osten P, Scharff C (December 2007). "Incomplete and inaccurate vocal imitation after knockdown of FoxP2 in songbird basal ganglia nucleus Area X". PLoS Biol. 5 (12): e321. doi:10.1371/journal.pbio.0050321. PMC 2100148. PMID 18052609. 
  44. ^ a b c Ferland RJ, Cherry TJ, Preware PO, Morrisey EE, Walsh CA (May 2003). "Characterization of Foxp2 and Foxp1 mRNA and protein in the developing and mature brain". J. Comp. Neurol. 460 (2): 266–79. doi:10.1002/cne.10654. PMID 12687690. 
  45. ^ a b c d e f Lai CS, Gerrelli D, Monaco AP, Fisher SE, Copp AJ (November 2003). "FOXP2 expression during brain development coincides with adult sites of pathology in a severe speech and language disorder". Brain 126 (Pt 11): 2455–62. doi:10.1093/brain/awg247. PMID 12876151. 
  46. ^ a b Belton E, Salmond CH, Watkins KE, Vargha-Khadem F, Gadian DG (March 2003). "Bilateral brain abnormalities associated with dominantly inherited verbal and orofacial dyspraxia". Hum Brain Mapp 18 (3): 194–200. doi:10.1002/hbm.10093. PMID 12599277. 
  47. ^ a b c Enard W, Gehre S, Hammerschmidt K, et al. (May 2009). "A humanized version of Foxp2 affects cortico-basal ganglia circuits in mice". Cell 137 (5): 961–71. doi:10.1016/j.cell.2009.03.041. PMID 19490899. 
  48. ^ Jürgens U (March 2002). "Neural pathways underlying vocal control". Neurosci Biobehav Rev 26 (2): 235–58. doi:10.1016/S0149-7634(01)00068-9. PMID 11856561. 
  49. ^ Krubitzer L (October 2007). "The magnificent compromise: cortical field evolution in mammals". Neuron 56 (2): 201–8. doi:10.1016/j.neuron.2007.10.002. PMID 17964240. 
  50. ^ Fujita E, Tanabe Y, Shiota A, et al. (February 2008). "Ultrasonic vocalization impairment of Foxp2 (R552H) knockin mice related to speech-language disorder and abnormality of Purkinje cells". Proc. Natl. Acad. Sci. U.S.A. 105 (8): 3117–22. doi:10.1073/pnas.0712298105. PMC 2268594. PMID 18287060. 
  51. ^ Holy TE, Guo Z (December 2005). "Ultrasonic songs of male mice". PLoS Biol. 3 (12): e386. doi:10.1371/journal.pbio.0030386. PMC 1275525. PMID 16248680. 
  52. ^ Ullman MT (January 2001). "The declarative/procedural model of lexicon and grammar". J Psycholinguist Res 30 (1): 37–69. doi:10.1023/A:1005204207369. PMID 11291183. 
  53. ^ Lieberman P (2002). "On the nature and evolution of the neural bases of human language". Am. J. Phys. Anthropol. Suppl 35: 36–62. PMID 12653308. 
  54. ^ Watkins KE, Gadian DG, Vargha-Khadem F (November 1999). "Functional and structural brain abnormalities associated with a genetic disorder of speech and language". Am. J. Hum. Genet. 65 (5): 1215–21. doi:10.1086/302631. PMC 1288272. PMID 10521285. 
  55. ^ a b c d Wilbrecht L, Nottebohm F (2003). "Vocal learning in birds and humans". Ment Retard Dev Disabil Res Rev 9 (3): 135–48. doi:10.1002/mrdd.10073. PMID 12953292. 
  56. ^ a b c d Doupe AJ, Kuhl PK (1999). "Birdsong and human speech: common themes and mechanisms". Annu. Rev. Neurosci. 22: 567–631. doi:10.1146/annurev.neuro.22.1.567. PMID 10202549. 
  57. ^ Kuhl PK, Williams KA, Lacerda F, Stevens KN, Lindblom B (January 1992). "Linguistic experience alters phonetic perception in infants by 6 months of age". Science 255 (5044): 606–8. doi:10.1126/science.1736364. PMID 1736364. 
  58. ^ a b c d Teramitsu I, Kudo LC, London SE, Geschwind DH, White SA (March 2004). "Parallel FoxP1 and FoxP2 expression in songbird and human brain predicts functional interaction". J. Neurosci. 24 (13): 3152–63. doi:10.1523/JNEUROSCI.5589-03.2004. PMID 15056695. 
  59. ^ Thompson, CK.; Schwabe, F.; Schoof, A.; Mendoza, E.; Gampe, J.; Rochefort, C.; Scharff, C. (2013). "Young and intense: FoxP2 immunoreactivity in Area X varies with age, song stereotypy, and singing in male zebra finches.". Front Neural Circuits 7: 24. doi:10.3389/fncir.2013.00024. PMID 23450800. 
  60. ^ Rochefort C, He X, Scotto-Lomassese S, Scharff C (May 2007). "Recruitment of FoxP2-expressing neurons to area X varies during song development". Dev Neurobiol 67 (6): 809–17. doi:10.1002/dneu.20393. PMID 17443826. 
  61. ^ a b Miller JE, Spiteri E, Condro MC, Dosumu-Johnson RT, Geschwind DH, White SA (October 2008). "Birdsong decreases protein levels of FoxP2, a molecule required for human speech". J. Neurophysiol. 100 (4): 2015–25. doi:10.1152/jn.90415.2008. PMC 2576221. PMID 18701760. 
  62. ^ Miller, JE.; Hilliard, AT.; White, SA. (2010). "Song practice promotes acute vocal variability at a key stage of sensorimotor learning.". PLoS ONE 5 (1): e8592. doi:10.1371/journal.pone.0008592. PMID 20066039. 
  63. ^ Teramitsu I, Poopatanapong A, Torrisi S, White SA (2010). "Striatal FoxP2 is actively regulated during songbird sensorimotor learning". PLoS ONE 5 (1): e8548. doi:10.1371/journal.pone.0008548. PMC 2796720. PMID 20062527. 
  64. ^ Schulz SB, Haesler S, Scharff C, Rochefort C (October 2010). "Knockdown of FoxP2 alters spine density in Area X of the zebra finch". Genes Brain Behav. 9 (7): 732–40. doi:10.1111/j.1601-183X.2010.00607.x. PMID 20528955. 
  65. ^ Groszer M, Keays DA, Deacon RM, et al. (March 2008). "Impaired synaptic plasticity and motor learning in mice with a point mutation implicated in human speech deficits". Curr. Biol. 18 (5): 354–62. doi:10.1016/j.cub.2008.01.060. PMC 2917768. PMID 18328704. 
  66. ^ Webb DM, Zhang J (2005). "FoxP2 in song-learning birds and vocal-learning mammals". J. Hered. 96 (3): 212–6. doi:10.1093/jhered/esi025. PMID 15618302. 

External links[edit]