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|Home / College Guide / FOXP2
| Posted on Sunday, February 11 @ 00:00:05 PST
Forkhead box protein P2 (FOXP2) is a
protein that, in humans, is encoded by the FOXP2 gene. FOXP2 is a member of the forkhead box family of transcription factors, proteins that regulate gene expression by binding to DNA. It is expressed in the brain, heart, lungs and digestive system.
FOXP2 is found in many
vertebrates, where it plays an important role in mimicry in birds (such as birdsong) and echolocation in bats. FOXP2 is also required for the proper development of speech and language in humans. In humans, mutations in FOXP2 cause the severe speech and language disorder developmental verbal dyspraxia. Studies of the gene in mice and songbirds indicate that it is necessary for vocal imitation and the related motor learning. Outside the brain, FOXP2 has also been implicated in development of other tissues such as the lung and digestive system.
Initially identified in 1998 as the genetic cause of a
speech disorder in a British family designated the KE family, FOXP2 was the first gene discovered to be associated with speech and language and was subsequently dubbed the language gene.
However, other genes are necessary for human language development, and a
2018 analysis confirmed that there was no evidence of recent positive evolutionary selection of FOXP2 in humans.
Structure and function
FOX protein, FOXP2 contains a forkhead-box domain. In addition, it contains a polyglutamine tract, a zinc finger and a leucine zipper.
The protein attaches to the DNA 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,
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.
FOXP2 is required for proper brain and lung development.
Knockout mice with only one functional copy of the FOXP2 gene have significantly reduced vocalizations as pups. Knockout mice with no functional copies of FOXP2 are runted, display abnormalities in brain regions such as the Purkinje layer, and die an average of 21 days after birth from inadequate lung development.
FOXP2 is expressed in many areas of the brain, including the
basal ganglia and inferior frontal cortex, where it is essential for brain maturation and speech and language development.
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 the Brocas areas of female children. The researchers suggested that the gene is more active in the more communicative sex.
The expression of FOXP2 is subject to
post-transcriptional regulation, particularly microRNA (miRNA), causing the repression of the FOXP2 3 untranslated region.
Three amino acid substitutions distinguish the human FOXP2 protein from that found in mice, while two amino acid substitutions distinguish the human FOXP2 protein from that found in chimpanzees, but only one of these changes is unique to humans. Evidence from genetically manipulated mice and human neuronal cell models suggests that these changes affect the neural functions of FOXP2.
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. 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. One well identified target is language. Although some research disagrees with this correlation, the majority of research shows that a mutated FOXP2 causes the observed production deficiency.
There is some evidence that the linguistic impairments associated with a mutation of the FOXP2 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.
Mutations in FOXP2 are among several (26 genes plus 2 intergenic) loci which correlate to
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.
genome-wide association study (GWAS) implicates single-nucleotide polymorphisms (SNPs) of FOXP2 in susceptibility to cannabis use disorder.
It is theorized that the translocation of the 7q31.2 region of the FOXP2 gene causes a severe language impairment called
developmental verbal dyspraxia (DVD) or childhood apraxia of speech (CAS) So far this type of mutation has only been discovered in three families across the world including the original KE family.
A missense mutation causing an arginine-to-histidine substitution
(R553H) in the DNA-binding domain is thought to be the abnormality in
This would cause a normally basic residue to be fairly acidic and
highly reactive at the bodys 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.
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 Brocas area in fMRI studies.
These areas are commonly known as areas of language function. 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. 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. Additionally, there are more general impairments with the processing of the grammatical and linguistic aspects of speech. 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. Clinically these patients can also have difficulty coughing, sneezing, or clearing their throats.
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. 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.
The FOXP2 gene is highly conserved in
mammals. The human gene differs from that in non-human primates by the substitution of two amino acids, a threonine to asparagine substitution at position 303 (T303N) and an asparagine to serine substitution at position 325 (N325S). In mice it differs from that of humans by three substitutions, and in zebra finch by seven amino acids. One of the two amino acid differences between human and chimps also arose independently in carnivores and bats. Similar FOXP2 proteins can be found in songbirds, fish, and reptiles such as alligators.
DNA sampling from
Homo neanderthalensis bones indicates that their FOXP2 gene is a little different though largely similar to those of Homo sapiens (i.e. humans). Previous genetic analysis had suggested that the H. sapiens FOXP2 gene became fixed in the population around 125,000 years ago.
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. Other researchers offer alternative explanations for how the H. sapiens version would have appeared in Neanderthals living 43,000 years ago.
According to a 2002 study, the FOXP2 gene showed indications of recent
positive selection. Some researchers have speculated that positive selection is crucial for the evolution of language in humans. Others, however, were unable to find a clear association between species with learned vocalizations and similar mutations in FOXP2.
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. Insertion of both human mutations into mice, whose version of FOXP2 otherwise differs from the human and chimpanzee
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.
FOXP2 is known to regulate
CNTNAP2, CTBP1, SRPX2 and SCN3A.
FOXP2 downregulates CNTNAP2, a member of the
neurexin family found in neurons. CNTNAP2 is associated with common forms of language impairment.
FOXP2 also downregulates SRPX2, the Sushi Repeat-containing Protein X-linked 2.
It directly reduces its expression, by binding to its genes
promoter). SRPX2 is involved in glutamatergic synapse formation in the cerebral cortex
and is more highly expressed in childhood. SRPX2 appears to
specifically increase the number of glutamatergic synapses in the brain,
while leaving inhibitory GABAergic synapses unchanged and not affecting dendritic spine
length or shape. On the other hand, FOXP2s activity does reduce
dendritic spine length and shape, in addition to number, indicating it
has other regulatory roles in dendritic morphology.
In other animals
In chimpanzees, FOXP2 differs from the human version by two amino acids. A study in Germany sequenced FOXP2s complementary DNA in chimps and other species to compare it with human complementary DNA in order to find the specific changes in the sequence. 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. 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.
In a mouse FOXP2
gene knockouts, loss of both copies of the gene causes 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.
Male mice on encountering female mice produce complex ultrasonic
vocalisations that have characteristics of song. Mice that have the R552H point mutation carried by the KE family show cerebellar reduction and abnormal synaptic plasticity in striatal and cerebellar circuits.
Humanized FOXP2 mice display altered
cortico-basal ganglia circuits. The human allele of the FOXP2 gene was transferred into the mouse embryos through homologous 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 of FOXP2, 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.
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 the
sixth layer of the cortex than in the fifth, and this is consistent with it having greater roles in sensory integration. FOXP2 was also found in the medial 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 express type 1 dopamine receptors in the striatum, substantia nigra, subthalamic nucleus and ventral 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 in long-term depression, which is implicated in motor function learning and maintenance.
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 in schizophrenia, epilepsy, autism, bipolar disorder and intellectual disabilities.
FOXP2 has implications in the development of
bat echolocation. Contrary to apes and mice, FOXP2 is extremely diverse in echolocating bats. Twenty-two sequences of non-bat eutherian
mammals revealed a total number of 20 nonsynonymous mutations in
contrast to half that number of bat sequences, which showed 44
nonsynonymous mutations. All cetaceans share three amino acid substitutions, but no differences were found between echolocating toothed whales and non-echolocating baleen cetaceans. Within bats, however, amino acid variation correlated with different echolocating types.
https://en.wikipedia.org/wiki/Songbird, FOXP2 most likely regulates genes involved in neuroplasticity. Gene knockdown of FOXP2 in area X of the basal ganglia in songbirds results in incomplete and inaccurate song imitation. []https://en.wikipedia.org/wiki/FOXP2#cite_note-Haesler_2007-8 Overexpression of FOXP2 was accomplished through injection of adeno-associated virus
serotype 1 (AAV1) into area X of the brain.
produced similar effects to that of knockdown; juvenile zebra finch
birds were unable to accurately imitate their tutors. Similarly, in adult canaries, higher FOXP2 levels also correlate with song changes.
Levels of FOXP2 in adult zebra finches are significantly higher when males direct their song to females than when they sing song in other contexts. 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. 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.
Differences between song-learning and non-song-learning birds have been shown to be caused by differences in FOXP2
gene expression, rather than differences in the amino acid sequence of the FOXP2 protein.
zebrafish, FOXP2 is expressed in the ventral and dorsal thalamus, telencephalon, diencephalon
where it likely plays a role in nervous system development.
zebrafish FOXP2 gene has an 85% similarity to the human FOX2P ortholog.
FOXP2 and its gene were discovered as a result of investigations on an English family known as the
KE family, half of whom (15 individuals across three generations) had a speech and language disorder called developmental verbal dyspraxia. Their case was studied at the Institute of Child Health of University College London. []https://en.wikipedia.org/wiki/FOXP2#cite_note-Hurst_1990-62 In 1990, Myrna Gopnik, Professor of Linguistics at McGill University,
reported that the disorder-affected KE family had severe speech
impediment with incomprehensible talk, largely characterized by
She hypothesized that the basis was not of learning or cognitive
disability, but due to genetic factors affecting mainly grammatical
ability. (Her hypothesis led to a popularised existence of grammar gene and a controversial notion of grammar-specific disorder.) In 1995, the University of Oxford and the Institute of Child Health researchers found that the disorder was purely genetic. Remarkably, the inheritance of the disorder from one generation to the next was consistent with autosomal dominant inheritance, i.
e., mutation of only a single gene on an autosome (non- sex chromosome) acting in a dominant fashion. This is one of the few known examples of Mendelian
(monogenic) inheritance for a disorder affecting speech and language
skills, which typically have a complex basis involving multiple genetic
In 1998, Oxford University geneticists
Simon Fisher, Anthony Monaco, Cecilia S. L. Lai, Jane A. Hurst, and Faraneh Vargha-Khadem identified an autosomal dominant monogenic inheritance that is localized on a small region of chromosome 7 from DNA samples taken from the affected and unaffected members. The chromosomal region (locus) contained 70 genes.
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 of bacterial artificial chromosome clones.
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 (a translocation)
in which part of chromosome 7 had become exchanged with part of
The site of breakage of chromosome 7 was located within
the SPCH1 region.
In 2001, the team identified in CS that the mutation is in the middle of a protein-coding gene. Using a combination of
bioinformatics and RNA analyses, they discovered that the gene codes for a novel protein belonging to the forkhead-box (FOX) group of transcription factors. As such, it was assigned with the official name of FOXP2. When the researchers sequenced the FOXP2 gene in the KE family, they found a heterozygous point mutation shared by all the affected individuals, but not in unaffected members of the family and other people. This mutation is due to an amino-acid substitution that inhibits the DNA-binding domain of the FOXP2 protein. Further screening of the gene identified multiple additional cases of FOXP2 disruption, including different point mutations and chromosomal rearrangements, providing evidence that damage to one copy of this gene is sufficient to derail speech and language development.