FOXP2 - WikiHQ

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. 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

thumbnail|left|upright=.85|FOXP2 is expressed in the developing cerebellum and the hindbrain of the embryonic day-13.5 mouse. [[Allen Brain Atlases.]]

As a FOX protein, FOXP2 contains a forkhead-box domain. In addition, it contains a polyglutamine tract, a zinc finger and a leucine 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.

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 Broca's 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, and human neuronal cell models suggests that these changes affect the neural functions of FOXP2.

Clinical significance

FOXP2 is a transcription factor with multiple functions among which is that it plays a role in the development of neural circuits that are involved in speech and language. It functions by regulating the genes that influence factors such as differentiation of neurons, communication between neurons, and synaptic plasticity. Additionally, FOXP2 helps coordinate the complex movements required for speech; consequently, it is highly expressed in brain regions associated with motor control and language processing, including the basal ganglia and cerebral cortex. Mutations in FOXP2 have been linked to a rare genetic speech and language disorder known as childhood apraxia of speech, which is recognized to cause impaired articulation and difficulty with grammar and comprehension. In mouse models, mutations in FOXP2 have led to deficits in motor learning and impaired synaptic plasticity, highlighting its importance in neural function. Furthermore, mice expressing a "humanized" version of the gene show significant alterations in cortico-basal ganglia circuitry. Additionally, in songbird models, knockdown of FOXP2 disrupts vocal learning, resulting in incomplete and inaccurate song imitation. These findings collectively illustrate that FOXP2 is essential for the development of the neural mechanisms underlying complex vocal communication.

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. 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 ADHD 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.

A 2020 genome-wide association study (GWAS) implicates single-nucleotide polymorphisms (SNPs) of FOXP2 in susceptibility to cannabis use disorder.

Language 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) So far this type of mutation has only been discovered in three families across the world including the original KE family. 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 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. Other researchers have argued that understanding of FOXP2 and its influence upon language disorders should be considered in the context of its interaction with other co-active genes in the human genome.

Evolution

Human FOXP2 gene and evolutionary conservation is shown in a multiple alignment (at bottom of figure) in this image from the [[UCSC Genome Browser. Note that conservation tends to cluster around coding regions (exons).|thumb|right|upright=1.25]]

The FOXP2 gene is highly conserved in mammals. 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.

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. Some researchers have speculated that positive selection is crucial for the evolution of language in humans. 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 gene's 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, FOXP2's activity does reduce dendritic spine length and shape, in addition to number, indicating it has other regulatory roles in dendritic morphology.

In other animals

<span id="Chimpanzees compared with humans"></span>Chimpanzees

In chimpanzees, FOXP2 differs from the human version by two amino acids. 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. 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. Mice that have the R552H point mutation carried by the KE family show cerebellar reduction and abnormal synaptic plasticity in striatal and cerebellar circuits.

Bats

FOXP2 has implications in the development of bat echolocation. Contrary to apes and mice, FOXP2 is extremely diverse in echolocating bats.

Birds

In songbirds, 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. Similarly, in adult canaries, higher FOXP2 levels also correlate with song changes. 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.

History

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. 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 grammatical deficits. 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 risk factors.

thumb|left|The FOXP2 gene is located on the long (q) arm of [[Chromosome 7 (human)|chromosome 7, at position 31.]]

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 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. Further screening of the gene identified multiple additional cases of FOXP2 disruption, including different point mutations providing evidence that damage to one copy of this gene is sufficient to derail speech and language development.

References

External links

Gene information at NCBI
Gene information at Genetic Home Reference
Language and Genetics Research at the Max Planck Institute for Psycholinguistics
The FOXP2 story
Revisiting FOXP2 and the origins of language
FOXP2 and the Evolution of Language