Forkhead box protein P2 (FOXP2) is aprotein that, in humans, is encoded by theFOXP2gene. FOXP2 is a member of theforkhead box family oftranscription factors, proteins thatregulate gene expression bybinding to DNA. It is expressed in the brain, heart, lungs and digestive system.[5][6]
FOXP2 is found in manyvertebrates, where it plays an important role in mimicry in birds (such asbirdsong) andecholocation in bats.FOXP2 is also required for the proper development of speech and language in humans.[7] In humans, mutations inFOXP2 cause the severe speech and language disorderdevelopmental verbal dyspraxia.[7][8] Studies of the gene in mice and songbirds indicate that it is necessary for vocal imitation and the related motor learning.[9][10][11] Outside the brain,FOXP2 has also been implicated in development of other tissues such as the lung and digestive system.[12]
Initially identified in 1998 as the genetic cause of aspeech disorder in a British family designated theKE family,FOXP2 was the first gene discovered to be associated with speech and language[13] and was subsequently dubbed "the language gene".[14] However, other genes are necessary for human language development, and a 2018 analysis confirmed that there was no evidence of recent positiveevolutionary selection ofFOXP2 in humans.[15][16]
As aFOX protein, FOXP2 contains a forkhead-box domain. In addition, it contains apolyglutamine tract, azinc finger and aleucine zipper. The protein binds directly to DNA to control expression of other proteins and controls their activity through the forkhead-box domain. Only a few targeted genes have been identified, however researchers believe that there could be up to hundreds of other genes targeted by the FOXP2 gene. The forkhead box P2 protein is active in the brain and other tissues before and after birth, and many studies show that it is paramount for the growth of nerve cells and transmission between them. The FOXP2 gene is also involved in synaptic plasticity, making it imperative for learning and memory.[17]
FOXP2 is required for proper brain and lung development.Knockout mice with only one functional copy of theFOXP2 gene have significantly reduced vocalizations as pups.[18] Knockout mice with no functional copies ofFOXP2 are runted, display abnormalities in brain regions such as thePurkinje layer, and die an average of 21 days after birth from inadequate lung development.[12]
FOXP2 is expressed in many areas of the brain,[19] including thebasal ganglia and inferiorfrontal cortex, where it is essential for brain maturation and speech and language development.[20] In mice, the gene was found to be twice as highly expressed in male pups than female pups, which correlated with an almost double increase in the number of vocalisations the male pups made when separated from mothers. Conversely, in human children aged 4–5, the gene was found to be 30% more expressed in theBroca's areas of female children. The researchers suggested that the gene is more active in "the more communicative sex".[21][22]
The expression ofFOXP2 is subject topost-transcriptional regulation, particularlymicroRNA (miRNA), causing the repression of the FOXP23' untranslated region.[23]
Three amino acid substitutions distinguish the humanFOXP2 protein from that found in mice, while two amino acid substitutions distinguish the humanFOXP2 protein from that found in chimpanzees,[19] but only one of these changes is unique to humans.[12] Evidence from genetically manipulated mice[24] and human neuronal cell models[25] suggests that these changes affect the neural functions ofFOXP2.
The FOXP2 gene has been implicated in several cognitive functions including; general brain development, language, and synaptic plasticity. The FOXP2 gene region acts as a transcription factor for the forkhead box P2 protein. Transcription factors affect other regions, and the forkhead box P2 protein has been suggested to also act as a transcription factor for hundreds of genes. This prolific involvement opens the possibility that the FOXP2 gene is much more extensive than originally thought.[17] Other targets of transcription have been researched without correlation to FOXP2. Specifically, FOXP2 has been investigated in correlation with autism and dyslexia, however with no mutation was discovered as the cause.[26] One well identified target is language.[27] Although some research disagrees with this correlation,[28] the majority of research shows that a mutated FOXP2 causes the observed production deficiency.[17][27][29][26][30][31]
There is some evidence that the linguistic impairments associated with a mutation of theFOXP2 gene are not simply the result of a fundamental deficit in motor control. Brain imaging of affected individuals indicates functional abnormalities in language-related cortical and basal ganglia regions, demonstrating that the problems extend beyond the motor system.[32]
Mutations in FOXP2 are among several (26 genes plus 2 intergenic) loci which correlate toADHD diagnosis in adults – clinical ADHD is an umbrella label for a heterogeneous group of genetic and neurological phenomena which may result from FOXP2 mutations or other causes.[33]
A 2020genome-wide association study (GWAS) implicatessingle-nucleotide polymorphisms (SNPs) of FOXP2 in susceptibility tocannabis use disorder.[34]
It is theorized that the translocation of the 7q31.2 region of the FOXP2 gene causes a severe language impairment calleddevelopmental verbal dyspraxia (DVD)[27] or childhood apraxia of speech (CAS)[35] So far this type of mutation has only been discovered in three families across the world including the original KE family.[31] A missense mutation causing an arginine-to-histidine substitution (R553H) in the DNA-binding domain is thought to be the abnormality in KE.[36] This would cause a normally basic residue to be fairly acidic and highly reactive at the body's pH. A heterozygous nonsense mutation, R328X variant, produces a truncated protein involved in speech and language difficulties in one KE individual and two of their close family members. R553H and R328X mutations also affected nuclear localization, DNA-binding, and the transactivation (increased gene expression) properties of FOXP2.[8]
These individuals present with deletions, translocations, and missense mutations. When tasked with repetition and verb generation, these individuals with DVD/CAS had decreased activation in the putamen and Broca's area in fMRI studies. These areas are commonly known as areas of language function.[37] This is one of the primary reasons that FOXP2 is known as a language gene. They have delayed onset of speech, difficulty with articulation including slurred speech, stuttering, and poor pronunciation, as well as dyspraxia.[31] It is believed that a major part of this speech deficit comes from an inability to coordinate the movements necessary to produce normal speech including mouth and tongue shaping.[27] Additionally, there are more general impairments with the processing of the grammatical and linguistic aspects of speech.[8] These findings suggest that the effects of FOXP2 are not limited to motor control, as they include comprehension among other cognitive language functions. General mild motor and cognitive deficits are noted across the board.[29] Clinically these patients can also have difficulty coughing, sneezing, or clearing their throats.[27]
While FOXP2 has been proposed to play a critical role in the development of speech and language, this view has been challenged by the fact that the gene is also expressed in other mammals as well as birds and fish that do not speak.[38] It has also been proposed that the FOXP2 transcription-factor is not so much a hypothetical 'language gene' but rather part of a regulatory machinery related to externalization of speech.[39]
TheFOXP2 gene is highly conserved inmammals.[19] The human gene differs from that innon-human primates by the substitution of two amino acids, athreonine toasparagine substitution at position 303 (T303N) and an asparagine toserine substitution at position 325 (N325S).[36] In mice it differs from that of humans by three substitutions, and inzebra finch by seven amino acids.[19][40][41] One of the two amino acid differences between human and chimps also arose independently in carnivores and bats.[12][42] SimilarFOXP2 proteins can be found insongbirds,fish, andreptiles such asalligators.[43][44]
DNA sampling fromHomo neanderthalensis bones indicates that theirFOXP2 gene is a little different though largely similar to those ofHomo sapiens (i.e. humans).[45][46] Previous genetic analysis had suggested that theH. sapiens FOXP2 gene became fixed in the population around 125,000 years ago.[47] Some researchers consider the Neanderthal findings to indicate that the gene instead swept through the population over 260,000 years ago, before our most recent common ancestor with the Neanderthals.[47] Other researchers offer alternative explanations for how theH. sapiens version would have appeared in Neanderthals living 43,000 years ago.[47]
According to a 2002 study, theFOXP2 gene showed indications of recentpositive selection.[19][48] Some researchers have speculated that positive selection is crucial for theevolution of language in humans.[19] Others, however, were unable to find a clear association between species with learned vocalizations and similar mutations inFOXP2.[43][44] A 2018 analysis of a large sample of globally distributed genomes confirmed there was no evidence of positive selection, suggesting that the original signal of positive selection may be driven by sample composition.[15][16] Insertion of both humanmutations into mice, whose version ofFOXP2 otherwise differs from the human andchimpanzee versions in only one additional base pair, causes changes in vocalizations as well as other behavioral changes, such as a reduction in exploratory tendencies, and a decrease in maze learning time. A reduction in dopamine levels and changes in the morphology of certain nerve cells are also observed.[24]
FOXP2 is known to regulateCNTNAP2,CTBP1,[49]SRPX2 andSCN3A.[50][20][51]
FOXP2 downregulatesCNTNAP2, a member of theneurexin family found in neurons.CNTNAP2 is associated with common forms of language impairment.[52]
FOXP2 also downregulatesSRPX2, the 'Sushi Repeat-containing Protein X-linked 2'.[53][54] It directly reduces its expression, by binding to its gene'spromoter. SRPX2 is involved inglutamatergicsynapse formation in thecerebral cortex and is more highly expressed in childhood. SRPX2 appears to specifically increase the number of glutamatergic synapses in the brain, while leaving inhibitoryGABAergic synapses unchanged and not affectingdendritic spine length or shape. On the other hand, FOXP2's activity does reduce dendritic spine length and shape, in addition to number, indicating it has other regulatory roles in dendritic morphology.[53]
In chimpanzees, FOXP2 differs from the human version by two amino acids.[55] A study in Germany sequenced FOXP2's complementary DNA in chimps and other species to compare it with human complementary DNA in order to find the specific changes in the sequence.[19] FOXP2 was found to be functionally different in humans compared to chimps. Since FOXP2 was also found to have an effect on other genes, its effects on other genes is also being studied.[56] Researchers deduced that there could also be further clinical applications in the direction of these studies in regards to illnesses that show effects on human language ability.[25]
In a mouseFOXP2gene knockouts, loss of both copies of the gene causes severe motor impairment related to cerebellar abnormalities and lack ofultrasonicvocalisations normally elicited when pups are removed from their mothers.[18] 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. Male mice on encountering female mice produce complex ultrasonic vocalisations that have characteristics of song.[57] Mice that have the R552H point mutation carried by the KE family show cerebellar reduction and abnormalsynaptic plasticity in striatal andcerebellar circuits.[9]
Humanized FOXP2 mice display alteredcortico-basal ganglia circuits. The human allele of the FOXP2 gene was transferred into the mouse embryos throughhomologous recombination to create humanized FOXP2 mice. The human variant of FOXP2 also had an effect on the exploratory behavior of the mice. In comparison to knockout mice with one non-functional copy ofFOXP2, the humanized mouse model showed opposite effects when testing its effect on the levels of dopamine, plasticity of synapses, patterns of expression in the striatum and behavior that was exploratory in nature.[24]
When FOXP2 expression was altered in mice, it affected many different processes including the learning motor skills and the plasticity of synapses. Additionally, FOXP2 is found more in thesixth layer of the cortex than in thefifth, and this is consistent with it having greater roles in sensory integration. FOXP2 was also found in themedial geniculate nucleus of the mouse brain, which is the processing area that auditory inputs must go through in the thalamus. It was found that its mutations play a role in delaying the development of language learning. It was also found to be highly expressed in the Purkinje cells and cerebellar nuclei of the cortico-cerebellar circuits. High FOXP2 expression has also been shown in the spiny neurons that expresstype 1 dopamine receptors in the striatum,substantia nigra,subthalamic nucleus andventral tegmental area. The negative effects of the mutations of FOXP2 in these brain regions on motor abilities were shown in mice through tasks in lab studies. When analyzing the brain circuitry in these cases, scientists found greater levels of dopamine and decreased lengths of dendrites, which caused defects inlong-term depression, which is implicated in motor function learning and maintenance. ThroughEEG studies, it was also found that these mice had increased levels of activity in their striatum, which contributed to these results. There is further evidence for mutations of targets of the FOXP2 gene shown to have roles inschizophrenia,epilepsy,autism,bipolar disorder and intellectual disabilities.[58]
FOXP2 has implications in the development ofbatecholocation.[36][42][59] Contrary to apes and mice,FOXP2 is extremely diverse inecholocating bats.[42] Twenty-two sequences of non-bateutherian mammals revealed a total number of 20 nonsynonymous mutations in contrast to half that number of bat sequences, which showed 44 nonsynonymous mutations.[42] Allcetaceans share three amino acid substitutions, but no differences were found between echolocatingtoothed whales and non-echolocatingbaleen cetaceans.[42] Within bats, however, amino acid variation correlated with different echolocating types.[42] There is also evidence of ongoing intraspecific selection in at least one species of bat, in response to environmental changes.[60]
Insongbirds,FOXP2 most likely regulates genes involved inneuroplasticity.[10][61]Gene knockdown ofFOXP2 in area X of thebasal ganglia in songbirds results in incomplete and inaccurate song imitation.[10] Overexpression ofFOXP2 was accomplished through injection ofadeno-associated virus serotype 1 (AAV1) into area X of the brain. This overexpression produced similar effects to that of knockdown; juvenile zebra finch birds were unable to accurately imitate their tutors.[62] Similarly, in adult canaries, higherFOXP2 levels also correlate with song changes.[41]
Levels ofFOXP2 in adult zebra finches are significantly higher when males direct their song to females than when they sing song in other contexts.[61] "Directed" singing refers to when a male is singing to a female usually for a courtship display. "Undirected" singing occurs when for example, a male sings when other males are present or is alone.[63] Studies have found that FoxP2 levels vary depending on the social context. When the birds were singing undirected song, there was a decrease of FoxP2 expression in Area X. This downregulation was not observed and FoxP2 levels remained stable in birds singing directed song.[61]
Differences between song-learning and non-song-learning birds have been shown to be caused by differences inFOXP2gene expression, rather than differences in the amino acid sequence of theFOXP2 protein.
Inzebrafish, FOXP2 is expressed in the ventral anddorsal thalamus,telencephalon,diencephalon where it likely plays a role in nervous system development. The zebrafish FOXP2 gene has an 85% similarity to the human FOX2P ortholog.[64]
FOXP2 and its gene were discovered as a result of investigations on an English family known as theKE family, half of whom (15 individuals across three generations) had a speech and language disorder calleddevelopmental verbal dyspraxia. Their case was studied at theInstitute of Child Health of University College London.[65] In 1990,Myrna Gopnik, Professor of Linguistics atMcGill University, reported that the disorder-affected KE family had severe speech impediment with incomprehensible talk, largely characterized by grammatical deficits.[66] She hypothesized that the basis was not of learning or cognitive disability, but due to genetic factors affecting mainly grammatical ability.[67] (Her hypothesis led to a popularised existence of "grammar gene" and a controversial notion of grammar-specific disorder.[68][69]) In 1995, theUniversity of Oxford and the Institute of Child Health researchers found that the disorder was purely genetic.[70] Remarkably, the inheritance of the disorder from one generation to the next was consistent withautosomal dominant inheritance, i.e., mutation of only a single gene on anautosome (non-sex chromosome) acting in a dominant fashion. This is one of the few known examples ofMendelian (monogenic) inheritance for a disorder affecting speech and language skills, which typically have a complex basis involving multiple genetic risk factors.[71]
In 1998, Oxford University geneticistsSimon Fisher,Anthony Monaco, Cecilia S. L. Lai, Jane A. Hurst, andFaraneh Vargha-Khadem identified an autosomal dominant monogenic inheritance that is localized on a small region ofchromosome 7 from DNA samples taken from the affected and unaffected members.[5] The chromosomal region (locus) contained 70 genes.[72] The locus was given the official name "SPCH1" (for speech-and-language-disorder-1) by the Human Genome Nomenclature committee. Mapping and sequencing of the chromosomal region was performed with the aid ofbacterial artificial chromosome clones.[6] Around this time, the researchers identified an individual who was unrelated to the KE family but had a similar type of speech and language disorder. In this case, the child, known as CS, carried a chromosomal rearrangement (atranslocation) in which part of chromosome 7 had become exchanged with part of chromosome 5. The site of breakage of chromosome 7 was located within the SPCH1 region.[6]
In 2001, the team identified in CS that the mutation is in the middle of a protein-coding gene.[7] Using a combination ofbioinformatics andRNA analyses, they discovered that the gene codes for a novel protein belonging to theforkhead-box (FOX) group oftranscription factors. As such, it was assigned with the official name of FOXP2. When the researchers sequenced theFOXP2 gene in the KE family, they found aheterozygouspoint mutation shared by all the affected individuals, but not in unaffected members of the family and other people.[7] This mutation is due to an amino-acid substitution that inhibits the DNA-binding domain of theFOXP2 protein.[73] Further screening of the gene identified multiple additional cases ofFOXP2 disruption, including different point mutations[8] and chromosomal rearrangements,[74] providing evidence that damage to one copy of this gene is sufficient to derail speech and language development.
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