FOXP2

edit
Forkhead box P2

PDB rendering based on 2a07.
Identifiers
Symbols FOXP2; CAGH44; DKFZp686H1726; SPCH1; TNRC10
External IDs OMIM: 605317 MGI: 2148705 HomoloGene: 33482 GeneCards: FOXP2 Gene
RNA expression pattern
PBB GE FOXP2 gnf1h09377 at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 93986 114142
Ensembl ENSG00000128573 ENSMUSG00000029563
UniProt O15409 Q8BQ27
RefSeq (mRNA) NM_014491 NM_053242
RefSeq (protein) NP_055306 NP_444472
Location (UCSC) Chr 7:
113.84 - 114.12 Mb		 Chr 6:
15.14 - 15.39 Mb
PubMed search [1] [2]

Forkhead box protein P2 also known as FOXP2 is a protein that in humans is encoded by the FOXP2 gene[1], located on human chromosome 7 (7q31, at the SPCH1 locus).[2][3] FOXP2 orthologs [4] have also been identified in all mammals for which complete genome data are available. The FOXP2 protein contains a forkhead-box DNA-binding domain, making it a member of the FOX group of transcription factors, involved in regulation of gene expression. In addition to this characteristic forkhead-box domain, the protein contains a polyglutamine tract, a zinc finger and a leucine zipper.

In humans, mutations of FOXP2 cause a severe speech and language disorder.[1][5] Versions of FOXP2 exist in similar forms in distantly related vertebrates; functional studies of the gene in mice[6] and in songbirds[7] indicate that it is important for modulating plasticity of neural circuits.[8] Outside the brain FOXP2 has also been implicated in development of other tissues such as the lung and gut.[9] FOXP2 directly regulates a large number of downstream target genes.[10][11]

One particular target that is directly downregulated by FOXP2 in human neurons is the CNTNAP2 gene, a member of the neurexin family; variants in this target gene have been associated with common forms of language impairment.[12] Two amino-acid substitutions distinguish the human FOXP2 protein from that found in chimpanzees.[13] Evidence from genetically manipulated mice[14] and human neuronal cell models[15] suggests that these changes affect the neural functions of FOXP2.

Contents

Function

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.[16] 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.[9]

Different studies of FOXP2 in songbirds suggest that FOXP2 may regulate genes involved in neuroplasticity: During song learning FOXP2 is upregulated in brain regions critical for song learning in young zebra finches. Knockdown of FOXP2 in Area X of the basal ganglia of these birds results in incomplete and inaccurate song imitation.[7] Similarly, in adult canaries higher FOXP2 levels also correlate with song changes.[17] In addition, levels of FOXP2 in adult zebra finches are significantly lower when males direct their song to females than when they sing song in other contexts.[18] 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.[19]

FOXP2 has also been implicated in the development of bat echolocation.[20]

Clinical significance

Several cases of developmental verbal dyspraxia in humans have been linked to mutations in the FOXP2 gene.[21] Such individuals have little or no cognitive handicaps but are unable to correctly perform the coordinated movements required for speech. fMRI analysis of these individuals performing silent verb generation and spoken word repetition tasks showed underactivation of Broca's area and the putamen, brain centers thought to be involved in language tasks. Because of this, FOXP2 has been dubbed the "speech and 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).[19] Scientists have also looked for associations between FOXP2 and autism and both positive and negative findings have been reported.[22][23]

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:

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).

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.[24][25] 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."[26] Aside from a polyglutamine tract, 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.[13][27][28] A recent extraction of DNA from Neanderthal bones indicates that Neanderthals had the same version (allele) of the FOXP2 gene as modern humans.[29]

Some researchers have speculated that the two amino acid differences between chimps and humans led to the evolution of language in humans.[13] Others, however, have been unable to find a clear association between species with learned vocalizations and similar mutations in FOXP2.[24][25] 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; a reduction in dopamine levels and changes in the morphology of certain nerve cells are also observed.[14] It may also be, based on general observations of development and songbird results, that any difference between humans and non-humans would be due to regulatory sequence divergence (affecting where and when FOXP2 is expressed) rather than the two amino acid differences mentioned above.[19]

Discovery

The human gene was identified through molecular investigations of an unusual family known as the KE family. Researchers in London discovered that around half of the family members - fifteen individuals across three generations - suffered from severe speech and language deficits.[30] 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 (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.[31]

In the mid-1990's 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.[2] This scan confirmed autosomal dominant monogenic inheritance and localized the gene responsible to a small section of chromosome 7.[2] 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.[3] 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 chromosome 5. The site of breakage of chromosome 7 was located within the SPCH1 region.[3]

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.[1] Using a combination of bioinformatics and RNA 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 that was shared by all the affected individuals, but absent from unaffected members and a large panel of controls from the general population.[1] This mutation yields an amino-acid substitution at a crucial point of the DNA-binding domain of the FOXP2 protein, disrupting its function.[32] Further screening of the gene has since identified multiple additional cases of FOXP2 disruption, including different point mutations[5] and chromosomal rearrangements,[33] providing further evidence that damage to one copy of this gene is sufficient to derail speech and language development.

Interactions

FOXP2 has been shown to interact with CTBP1.[34]

See also

References

  1. ↑ 1.0 1.1 1.2 1.3 Lai CSL, Fisher SE, Hurst JA, Vargha-Khadem F, Monaco AP (2001). "A forkhead-domain gene is mutated in a severe speech and language disorder". Nature 413 (6855): 519–23. doi:10.1038/35097076. PMID 11586359. 
  2. ↑ 2.0 2.1 2.2 Fisher SE, Vargha-Khadem F, Watkins KE, Monaco AP, Pembrey ME (1998). "Localisation of a gene implicated in a severe speech and language disorder". Nature Genet. 18 (2): 168–70. doi:10.1038/ng0298-168. PMID 9462748. 
  3. ↑ 3.0 3.1 3.2 Lai CS, Fisher SE, Hurst JA, Levy ER, Hodgson S, Fox M, Jeremiah S, Povey S, Jamison DC, Green ED, Vargha-Khadem F, Monaco AP (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. PMID 10880297. 
  4. ↑ "OrthoMaM phylogenetic marker: FOXP2 coding sequence". http://www.orthomam.univ-montp2.fr/orthomam/data/cds/detailMarkers/ENSG00000128573_FOXP2.xml. 
  5. ↑ 5.0 5.1 MacDermot KD, Bonora E, Sykes N, Coupe AM, Lai CS, Vernes SC, Vargha-Khadem F, McKenzie F, Smith RL, Monaco AP, Fisher SE (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. PMID 15877281. 
  6. ↑ Groszer M, Keays DA, Deacon RM, de Bono JP, Prasad-Mulcare S, Gaub S, Baum MG, French CA, Nicod J, Coventry JA, Enard W, Fray M, Brown SD, Nolan PM, Pääbo S, Channon KM, Costa RM, Eilers J, Ehret G, Rawlins JN, Fisher SE (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. PMID 18328704. 
  7. ↑ 7.0 7.1 Haesler S, Rochefort C, Georgi B, Licznerski P, Osten P, Scharff C (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. PMID 18052609. 
  8. ↑ Fisher SE, Scharff C (2009). "FOXP2 as a molecular window into speech and language". Trends Genet. 25 (4): 166–77. doi:10.1016/j.tig.2009.03.002. PMID 19304338. 
  9. ↑ 9.0 9.1 Shu W, Lu MM, Zhang Y, Tucker PW, Zhou D, Morrisey EE (2007). "Foxp2 and Foxp1 cooperatively regulate lung and esophagus development". Development 134 (10): 1991–2000. doi:10.1242/dev.02846. PMID 17428829. 
  10. ↑ Spiteri E, Konopka G, Coppola G, Bomar J, Oldham M, Ou J, Vernes SC, Fisher SE, Ren B, Geschwind DH (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. PMID 17999357. 
  11. ↑ Vernes SC, Spiteri E, Nicod J, Groszer M, Taylor JM, Davies KE, Geschwind DH, Fisher SE (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. PMID 17999362. 
  12. ↑ Vernes SC, Newbury DF, Abrahams BS, Winchester L, Nicod J, Groszer M, Alarcón M, Oliver PL, Davies KE, Geschwind DH, Monaco AP, Fisher SE (2008). "A functional genetic link between distinct developmental language disorders". N. Engl. J. Med. 359 (22): 2337–45. doi:10.1056/NEJMoa0802828. PMID 18987363. PMC 2756409. http://content.nejm.org/cgi/content/abstract/359/22/2337. 
  13. ↑ 13.0 13.1 13.2 Enard W, Przeworski M, Fisher SE, Lai CS, Wiebe V, Kitano T, Monaco AP, Pääbo S (2002). "Molecular evolution of FOXP2, a gene involved in speech and language". Nature 418 (6900): 869–72. doi:10.1038/nature01025. PMID 12192408. 
  14. ↑ 14.0 14.1 Enard W, Gehre S, Hammerschmidt K, et al. (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. 
  15. ↑ Konopka G, Bomar JM, Winden K, Coppola G, Jonsson ZO, Gao F, Peng S, Preuss TM, Wohlschlegel JA, Geschwind DH (2009). "Human-specific transcriptional regulation of CNS development genes by FOXP2". Nature 462 (7270): 213–217. doi:10.1038/nature08549. PMID 19907493. 
  16. ↑ Shu W, Cho JY, Jiang Y, Zhang M, Weisz D, Elder GA, Schmeidler J, De Gasperi R, Sosa MA, Rabidou D, Santucci AC, Perl D, Morrisey E, Buxbaum JD (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. PMID 15983371. 
  17. ↑ Haesler S, Wada K, Nshdejan A, Morrisey EE, Lints T, Jarvis ED, Scharff C (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. 
  18. ↑ 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. PMID 16837586. 
  19. ↑ 19.0 19.1 19.2 Sean B Carroll (July 2005). "Evolution at Two Levels: On Genes and Form". PLoS Biol. 3 (7): e245. doi:10.1371/journal.pbio.0030245. PMID 16000021. PMC 1174822. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1174822. 
  20. ↑ Li G, Wang J, Rossiter SJ, Jones G, Zhang S (2007). "Accelerated FoxP2 evolution in echolocating bats". PLoS ONE 2 (9): e900. doi:10.1371/journal.pone.0000900. PMID 17878935. 
  21. ↑ Vargha-Khadem F, Gadian DG, Copp A, Mishkin M (2005). "FOXP2 and the neuroanatomy of speech and language". Nature Reviews Neuroscience 6 (2): 131–137. doi:10.1038/nrn1605. PMID 15685218. 
  22. ↑ Scherer SW, et al. (2003). "Human chromosome 7: DNA sequence and biology". Science 300 (5620): 767–772. doi:10.1126/science.1083423. PMID 12690205. 
  23. ↑ Newbury DF, Bonora E, Lamb JA, Fisher SE, Lai CS, Baird G, Jannoun L, Slonims V, Stott CM, Merricks MJ, Bolton PF, Bailey AJ, Monaco AP (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. PMID 11894222. 
  24. ↑ 24.0 24.1 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. 
  25. ↑ 25.0 25.1 Scharff C, Haesler S (2004). "An evolutionary perspective on FoxP2: strictly for the birds?". Curr Opin Neurobiol 15 (6): 694–703. doi:10.1016/j.conb.2005.10.004. PMID 16266802. 
  26. ↑ Accelerated FoxP2 Evolution in Echolocating Bats
  27. ↑ Teramitsu I, Kudo LC, London SE, Geschwind DH, White SA (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. 
  28. ↑ Haesler S, Wada K, Nshdejan A,Morrisey EE, Lints T, Jarvis ED, Scharff C (2004). "FoxP2 expression in avian vocal learners and non-learners". J Neurosci. 24 (24): 3164–75. doi:10.1523/JNEUROSCI.4369-03.2004. PMID 15056696. 
  29. ↑ Krause J, Lalueza-Fox C, Orlando L, Enard W, Green RE, Burbano HA, Hublin JJ, Hänni C, Fortea J, de la Rasilla M, Bertranpetit J, Rosas A, Pääbo S (November 2007). "The derived FOXP2 variant of modern humans was shared with Neandertals". Curr. Biol. 17 (21): 1908–12. doi:10.1016/j.cub.2007.10.008. PMID 17949978. Lay summary – New York Times (2007-10-19).  See also Antonio Benítez-Burraco, Víctor M. Longa, Guillermo Lorenzo, Juan Uriagereka (November 2008). "Also sprach Neanderthalis... Or Did She?". Biolinguistics 2 (2): 225–232. http://www.biolinguistics.eu/index.php/biolinguistics/article/view/50/67. 
  30. ↑ Hurst JA, Baraitser M, Auger E, Graham F, Norell S (1990). "An extended family with a dominantly inherited speech disorder". Dev. Med. Child Neurol. 32 (4): 352–5. PMID 2332125. 
  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. http://arjournals.annualreviews.org/doi/pdf/10.1146/annurev.neuro.26.041002.131144. 
  32. ↑ Vernes SC, Nicod J, Elahi FM, Coventry JA, Kenny N, Coupe AM, Bird LE, Davies KE, Fisher SE (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. http://hmg.oxfordjournals.org/cgi/reprint/15/21/3154.pdf. 
  33. ↑ Feuk L, Kalervo A, Lipsanen-Nyman M, Skaug J, Nakabayashi K, Finucane B, Hartung D, Innes M, Kerem B, Nowaczyk MJ, Rivlin J, Roberts W, Senman L, Summers A, Szatmari P, Wong V, Vincent JB, Zeesman S, Osborne LR, Cardy JO, Kere J, Scherer SW, Hannula-Jouppi K (2006). "Absence of a paternally inherited FOXP2 gene in developmental verbal dyspraxia". Am. J. Hum. Genet. 79 (5): 965–72. doi:10.1086/508902. PMID 17033973. PMC 1698557. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1698557. 
  34. ↑ Li, Shanru; Weidenfeld Joel, Morrisey Edward E (Jan. 2004). "Transcriptional and DNA binding activity of the Foxp1/2/4 family is modulated by heterotypic and homotypic protein interactions". Mol. Cell. Biol. (United States) 24 (2): 809–22. doi:10.1128/MCB.24.2.809-822.2004. ISSN 0270-7306. PMID 14701752. 

External links

Animal communication
Concepts
Animal training · Animal language · Animal cognition · Bioacoustics · Ethology · Evolutionary linguistics · FOXP2 · Talking animals · Origin of language · Human-animal communication
Animal-specific
Bird vocalization · Talking birds · Great ape language (Yerkish) · Whale song · Dog communication
Related topics
Category:Talking birds · Category:Apes from language studies