FOXP2
Encyclopedia
Forkhead box protein P2 also known as FOXP2 is a protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...

 that in humans is encoded by the FOXP2 gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...

, located on human chromosome 7 (7q31, at the SPCH1 locus). FOXP2 orthologs  have also been identified in all mammals for which complete genome data are available. The FOXP2 protein contains a forkhead-box DNA-binding domain
DNA-binding domain
A DNA-binding domain is an independently folded protein domain that contains at least one motif that recognizes double- or single-stranded DNA. A DBD can recognize a specific DNA sequence or have a general affinity to DNA...

, making it a member of the FOX
FOX proteins
FOX proteins are a family of transcription factors that play important roles in regulating the expression of genes involved in cell growth, proliferation, differentiation, and longevity...

 group of transcription factors, involved in regulation of gene expression
Regulation of gene expression
Gene modulation redirects here. For information on therapeutic regulation of gene expression, see therapeutic gene modulation.Regulation of gene expression includes the processes that cells and viruses use to regulate the way that the information in genes is turned into gene products...

. In addition to this characteristic forkhead-box domain, the protein contains a polyglutamine tract
Polyglutamine tract
A polyglutamine tract or polyQ tract is a portion of a protein consisting of a sequence of several glutamine units. A tract typically consists of about 10 to a few hundred such units....

, a zinc finger
Zinc finger
Zinc fingers are small protein structural motifs that can coordinate one or more zinc ions to help stabilize their folds. They can be classified into several different structural families and typically function as interaction modules that bind DNA, RNA, proteins, or small molecules...

 and a leucine zipper
Leucine zipper
A leucine zipper, aka leucine scissors, is a common three-dimensional structural motif in proteins. These motifs are usually found as part of a DNA-binding domain in various transcription factors, and are therefore involved in regulating gene expression...

.

In humans, mutations of FOXP2 cause a severe speech and language disorder. Versions of FOXP2 exist in similar forms in distantly related vertebrates; functional studies of the gene in mice and in songbirds indicate that it is important for modulating plasticity of neural circuits. Outside the brain FOXP2 has also been implicated in development of other tissues such as the lung and gut. FOXP2 directly regulates a large number of downstream target genes.

One particular target that is directly downregulated by FOXP2 in human neurons is the CNTNAP2
CNTNAP2
Contactin-associated protein-like 2 is a protein that in humans is encoded by the CNTNAP2 gene.This gene encodes a member of the neurexin family which functions in the vertebrate nervous system as cell adhesion molecules and receptors. This protein, like other neurexin proteins, contains epidermal...

 gene, a member of the neurexin
Neurexin
A neurexin is a presynaptic protein that helps to glue together neurons at the synapse. Neurexins are type I membrane proteins that can be classified into two types, α-NRXNs and β-NRXNs. The α-NRXNs are larger and have different amino-terminal extracellular sequences...

 family; variants in this target gene have been associated with common forms of language impairment. Two amino-acid substitutions distinguish the human FOXP2 protein from that found in chimpanzees, but only one of these two 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.

Function

FOXP2 is required for proper brain and lung development. Knockout mice
Knockout mouse
A knockout mouse is a genetically engineered mouse in which researchers have inactivated, or "knocked out," an existing gene by replacing it or disrupting it with an artificial piece of DNA...

 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.

Different studies of FOXP2 in songbirds suggest that FOXP2 may regulate genes involved in neuroplasticity
Neuroplasticity
Neuroplasticity is a non-specific neuroscience term referring to the ability of the brain and nervous system in all species to change structurally and functionally as a result of input from the environment. Plasticity occurs on a variety of levels, ranging from cellular changes involved in...

:
During song learning FOXP2 is upregulated
Downregulation and upregulation
Downregulation is the process by which a cell decreases the quantity of a cellular component, such as RNA or protein, in response to an external variable...

 in brain regions critical for song learning in young zebra finch
Zebra Finch
The Zebra Finch, Taeniopygia guttata, is the most common and familiar estrildid finch of Central Australia and ranges over most of the continent, avoiding only the cool moist south and the tropical far north. It also can be found natively in Indonesia and East Timor...

es.
Knockdown
Gene knockdown
Gene knockdown refers to techniques by which the expression of one or more of an organism's genes is reduced, either through genetic modification or by treatment with a reagent such as a short DNA or RNA oligonucleotide with a sequence complementary to either an mRNA transcript or a gene...

 of FOXP2 in Area X of the basal ganglia
Basal ganglia
The basal ganglia are a group of nuclei of varied origin in the brains of vertebrates that act as a cohesive functional unit. They are situated at the base of the forebrain and are strongly connected with the cerebral cortex, thalamus and other brain areas...

 of these birds results in incomplete and inaccurate song imitation.
Similarly, in adult canaries higher FOXP2 levels also correlate with song changes.
In addition, 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. Differences between song-learning and non-song-learning birds have been shown to be caused by differences in FOXP2 gene expression
Gene expression
Gene expression is the process by which information from a gene is used in the synthesis of a functional gene product. These products are often proteins, but in non-protein coding genes such as ribosomal RNA , transfer RNA or small nuclear RNA genes, the product is a functional RNA...

, rather than differences in the amino acid sequence of the FOXP2 protein.

FOXP2 also has possible implications in the development of bat
Bat
Bats are mammals of the order Chiroptera "hand" and pteron "wing") whose forelimbs form webbed wings, making them the only mammals naturally capable of true and sustained flight. By contrast, other mammals said to fly, such as flying squirrels, gliding possums, and colugos, glide rather than fly,...

 echolocation
Animal echolocation
Echolocation, also called biosonar, is the biological sonar used by several kinds of animals.Echolocating animals emit calls out to the environment and listen to the echoes of those calls that return from various objects near them. They use these echoes to locate and identify the objects...

.

Clinical significance

Several cases of developmental verbal dyspraxia in humans have been linked to mutations in the FOXP2 gene. Such individuals have little or no cognitive handicaps but are unable to correctly perform the coordinated movements required for speech. fMRI
Functional magnetic resonance imaging
Functional magnetic resonance imaging or functional MRI is a type of specialized MRI scan used to measure the hemodynamic response related to neural activity in the brain or spinal cord of humans or other animals. It is one of the most recently developed forms of neuroimaging...

 analysis of these individuals performing silent verb
Verb
A verb, from the Latin verbum meaning word, is a word that in syntax conveys an action , or a state of being . In the usual description of English, the basic form, with or without the particle to, is the infinitive...

 generation and spoken word repetition tasks showed underactivation of Broca's area
Broca's area
Broca's area is a region of the hominid brain with functions linked to speech production.The production of language has been linked to the Broca’s area since Pierre Paul Broca reported impairments in two patients. They had lost the ability to speak after injury to the posterior inferior frontal...

 and the putamen
Putamen
The putamen is a round structure located at the base of the forebrain . The putamen and caudate nucleus together form the dorsal striatum. It is also one of the structures that comprises the basal ganglia. Through various pathways, the putamen is connected to the substantia nigra and globus pallidus...

, brain centers thought to be involved in language tasks. Because of this, FOXP2 has been dubbed the "language gene." People with this mutation also experience symptoms not related to language (not surprisingly, as FOXP2 is known to affect development in other parts of the body as well). Scientists have also looked for associations between FOXP2 and autism
Autism
Autism is a disorder of neural development characterized by impaired social interaction and communication, and by restricted and repetitive behavior. These signs all begin before a child is three years old. Autism affects information processing in the brain by altering how nerve cells and their...

 and both positive and negative findings have been reported.

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. For example:
  • the impairments include difficulties in comprehension;
  • 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.

Evolution

The FOXP2 protein sequence is generally thought to be highly conserved. Similar FOXP2 proteins can be found in songbirds, fish, and reptiles such as alligators. However, recent studies in bats (chiroptera) has prompted some researchers to conclude that FoxP2 is not well conserved in non-human mammals and write: "We found that contrary to previous reports, FoxP2 is not highly conserved across all nonhuman mammals but is extremely diverse in echolocating bats." Aside from a polyglutamine tract
Polyglutamine tract
A polyglutamine tract or polyQ tract is a portion of a protein consisting of a sequence of several glutamine units. A tract typically consists of about 10 to a few hundred such units....

, human FOXP2 differs from chimp FOXP2 by only two amino acids, mouse FOXP2 by only 3 amino acids, and zebra finch FOXP2 by only 7 amino acids. One of the two amino acid difference between human and chimps also arose independently in carnivores and bats. A recent extraction of DNA from Neanderthal
Neanderthal
The Neanderthal is an extinct member of the Homo genus known from Pleistocene specimens found in Europe and parts of western and central Asia...

 bones indicates that Neanderthals had the same version (allele) of the FOXP2 gene as modern humans. Evidence that the two amino acid substitutions existed so far back in evolutionary history is corroborated by a more recent extraction of DNA from the remains of a related, previously unknown hominid in Denisova Cave. in that, according to University of Wisconsin Professor John Hawk’s website (http://johnhawks.net/weblog/reviews/denisova/foxp2-denisova-humanlike-2011.html), this hominid also shares the two substitutions.
Some researchers have speculated that the two amino acid differences between chimps and humans led to the evolution of language in humans. Others, however, have been unable to find a clear association between species with learned vocalizations and similar mutations in FOXP2. Insertion of both human mutation
Mutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...

s 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; a reduction in dopamine levels and changes in the morphology of certain nerve cells are also observed. It may also be, based on general observations of development
Evolutionary developmental biology
Evolutionary developmental biology is a field of biology that compares the developmental processes of different organisms to determine the ancestral relationship between them, and to discover how developmental processes evolved...

 and songbird results, that any difference between humans and non-humans would be due to regulatory sequence
Regulatory sequence
A regulatory sequence is a segment of DNA where regulatory proteins such as transcription factors bind preferentially. These regulatory proteins bind to short stretches of DNA called regulatory regions, which are appropriately positioned in the genome, usually a short distance 'upstream' of the...

 divergence (affecting where and when FOXP2 is expressed) rather than the two amino acid differences mentioned above. However the mutation rate of FOXP2 is slower in the human lineage than in the lineage before the human-chimpanzee split, and proposed that purifying selection would not have relaxed due to negative deleterious effects. Thus, it was most likely positive selection that drove the two amino acid differences to fixation in humans, suggesting that differences between humans and non-humans are a result of the two amino acid changes.

Li et al. (2007) found that exons 7 and 17 of FoxP2 in bats are highly variable and not as conserved as in other vertebrates. 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. Interestingly, all cetaceans share three amino acid substitutions, but there are not differences between echolocating and non-echolocating baleen cetaceans. Within bats, however, amino acid variation correlated with different echolocating types. Accelerated evolution in bats is likely due to positive selection on echolocation. Given this hypothesis that a novel FOXP2 sequence can aid echolocation, echolocating and non echolocating cetaceans might be predicted to display differences in their FOXP2 sequences. However, they produce the necessary sounds for echolocation with a complex called a melon (located on the forehead) rather than with the orofacial muscles. Li et al speculate that because FOXP2 has been tied to orofiacial muscle control in humans its role in bat echolocation may be to increase coordination in these muscles, and that therefore echolocating and non-echolocating cetaceans would not necessarily be expected to show a diverse FOXP2 genotype.

Discovery

The human gene was identified through molecular investigations of an unusual family known as the KE family
KE family
The KE family is an extended family, about half of whom exhibit severe forms of specific language impairment . The genetic trace across many individuals spanning three generations of the family has been the subject of intense worldwide research since at least 1990, concerning the genetic origin of...

. Researchers in London discovered that around half of the family members - fifteen individuals across three generations - suffered from severe speech and language deficits. Remarkably, the transmission 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
Autosome
An autosome is a chromosome that is not a sex chromosome, or allosome; that is to say, there is an equal number of copies of the chromosome in males and females. For example, in humans, there are 22 pairs of autosomes. In addition to autosomes, there are sex chromosomes, to be specific: X and Y...

 (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 risk factors.

In the mid-1990s Oxford scientists began to search for the damaged gene in the KE family, performing a genome-wide scan of DNA samples taken from the affected and unaffected members. This scan confirmed autosomal dominant monogenic inheritance and localized the gene responsible to a small section of chromosome 7. 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
Bacterial artificial chromosome
A bacterial artificial chromosome is a DNA construct, based on a functional fertility plasmid , used for transforming and cloning in bacteria, usually E. coli. F-plasmids play a crucial role because they contain partition genes that promote the even distribution of plasmids after bacterial cell...

 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
Translocation
Translocation may refer to:* Chromosomal translocation, in genetics* Translocation in plants, transport of food or pesticides through phloem or xylem* Protein translocation or protein targeting, a process in protein biosynthesis...

) 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.

The team went on to pinpoint the precise position of the chromosome-7 breakage in case CS, and found that it lay directly in the middle of a protein-coding gene. Using a combination of bioinformatics
Bioinformatics
Bioinformatics is the application of computer science and information technology to the field of biology and medicine. Bioinformatics deals with algorithms, databases and information systems, web technologies, artificial intelligence and soft computing, information and computation theory, software...

 and RNA
RNA
Ribonucleic acid , or RNA, is one of the three major macromolecules that are essential for all known forms of life....

 analyses they deciphered the full coding region of the gene, discovering that it encoded a novel member of 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 uncovered a heterozygous point mutation
Point mutation
A point mutation, or single base substitution, is a type of mutation that causes the replacement of a single base nucleotide with another nucleotide of the genetic material, DNA or RNA. Often the term point mutation also includes insertions or deletions of a single base pair...

 that was shared by all the affected individuals, but absent from unaffected members and a large panel of controls from the general population. This mutation yields an amino-acid substitution at a crucial point of the DNA-binding domain of the FOXP2 protein, disrupting its function. Further screening of the gene has since identified multiple additional cases of FOXP2 disruption, including different point mutations and chromosomal rearrangements, providing further evidence that damage to one copy of this gene is sufficient to derail speech and language development.

FoxP2 in songbirds

In zebra finch, FoxP2 mRNA expression is observed in structures analogous to FoxP2 rich structures in the human brain including the basal ganglia
Basal ganglia
The basal ganglia are a group of nuclei of varied origin in the brains of vertebrates that act as a cohesive functional unit. They are situated at the base of the forebrain and are strongly connected with the cerebral cortex, thalamus and other brain areas...

, cortex
Cerebral cortex
The cerebral cortex is a sheet of neural tissue that is outermost to the cerebrum of the mammalian brain. It plays a key role in memory, attention, perceptual awareness, thought, language, and consciousness. It is constituted of up to six horizontal layers, each of which has a different...

 (referred to as pallium
Pallium (neuroanatomy)
In a neuroanatomy context, the word pallium refers to the layers of gray and white matter that cover the upper surface of the telencephalon in vertebrates. The non-pallial part of the telencephalon builds the subpallium. In basal vertebrates the pallium is a relatively simple three-layered...

 in birds) and the cerebellum
Cerebellum
The cerebellum is a region of the brain that plays an important role in motor control. It may also be involved in some cognitive functions such as attention and language, and in regulating fear and pleasure responses, but its movement-related functions are the most solidly established...

. Notably, FoxP2 is expressed in the song control nucleus Area X, which is a basal ganglia-like nucleus dedicated to singing behaviors. In zebra finch, FoxP2 mRNA shows a developmental increased during sensorimotor learning without any change in other FoxP2 enriched structures. Reinforcing the idea that this increase is tied to sensorimotor learning (as opposed to age per se), the canary
Domestic Canary
The Domestic Canary, often simply known as the canary, is a domesticated form of the wild Canary, a small songbird in the finch family originating from the Macaronesian Islands ....

- which relearns song every year- shows a similar increase in FoxP2 during late summer and early-fall, a time period which corresponds to their yearly sensorimotor learning. Interestingly, blocking this upregulation using lentiviral mediated knockdown in zebra finches impairs song learning and increases variability upon maturation.

See also

  • FOX proteins
    FOX proteins
    FOX proteins are a family of transcription factors that play important roles in regulating the expression of genes involved in cell growth, proliferation, differentiation, and longevity...

  • FOXP1
    FOXP1
    FOXP1 is a gene that is necessary for the proper development of the brain and lung in mammals. It is a member of the large FOX family of transcription factors....

  • dyspraxia
    Dyspraxia
    Developmental dyspraxia is a motor learning difficulty that can affect planning of movements and co-ordination as a result of brain messages not being accurately transmitted to the body...

  • Broca's area
    Broca's area
    Broca's area is a region of the hominid brain with functions linked to speech production.The production of language has been linked to the Broca’s area since Pierre Paul Broca reported impairments in two patients. They had lost the ability to speak after injury to the posterior inferior frontal...

  • Evolution of Homo sapiens
  • Human evolutionary genetics
    Human evolutionary genetics
    Human evolutionary genetics studies how one human genome differs from the other, the evolutionary past that gave rise to it, and its current effects. Differences between genomes have anthropological, medical and forensic implications and applications...

  • Human Genome Project
    Human Genome Project
    The Human Genome Project is an international scientific research project with a primary goal of determining the sequence of chemical base pairs which make up DNA, and of identifying and mapping the approximately 20,000–25,000 genes of the human genome from both a physical and functional...

  • Chimpanzee genome project
    Chimpanzee genome project
    The Chimpanzee Genome Project is an effort to determine the DNA sequence of the Chimpanzee genome. It is expected that by comparing the genomes of humans and other apes, it will be possible to better understand what makes humans distinct from other species....

  • Origin of language
    Origin of language
    The origin of language is the emergence of language in the human species. This is a highly controversial topic. Empirical evidence is so limited that many regard it as unsuitable for serious scholars. In 1866, the Linguistic Society of Paris went so far as to ban debates on the subject...

  • Vocal learning
    Vocal learning
    Vocal learning is the ability of animals to modify vocal signals in form as a result of experience with those of other individuals. This can lead to signals that are either similar or dissimilar to the model...


External links

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