Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Human-specific transcriptional regulation of CNS development genes by FOXP2

Abstract

The signalling pathways controlling both the evolution and development of language in the human brain remain unknown. So far, the transcription factor FOXP2 (forkhead box P2) is the only gene implicated in Mendelian forms of human speech and language dysfunction1,2,3. It has been proposed that the amino acid composition in the human variant of FOXP2 has undergone accelerated evolution, and this two-amino-acid change occurred around the time of language emergence in humans4,5. However, this remains controversial, and whether the acquisition of these amino acids in human FOXP2 has any functional consequence in human neurons remains untested. Here we demonstrate that these two human-specific amino acids alter FOXP2 function by conferring differential transcriptional regulation in vitro. We extend these observations in vivo to human and chimpanzee brain, and use network analysis to identify novel relationships among the differentially expressed genes. These data provide experimental support for the functional relevance of changes in FOXP2 that occur on the human lineage, highlighting specific pathways with direct consequences for human brain development and disease in the central nervous system (CNS). Because FOXP2 has an important role in speech and language in humans, the identified targets may have a critical function in the development and evolution of language circuitry in humans.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: FOXP2 and FOXP2 chimp differentially regulate genes in SH-SY5Y cells.
Figure 2: FOXP2 and FOXP2 chimp differentially transactivate target promoters independent of FOXP1 or FOXP4 interaction.
Figure 3: Visualization of one of the modules containing FOXP2 and FOXP2 chimp differentially expressed genes.

Accession codes

Primary accessions

Gene Expression Omnibus

Data deposits

Gene expression data have been deposited in the NCBI Gene Expression Omnibus (GEO; http://www.ncbi.nlm.nih.gov/geo) and are accessible using GEO series accession number GSE18142.

References

  1. 1

    Feuk, L. et al. Absence of a paternally inherited FOXP2 gene in developmental verbal dyspraxia. Am. J. Hum. Genet. 79, 965–972 (2006)

    CAS  Article  Google Scholar 

  2. 2

    Lai, C. S., Fisher, S. E., Hurst, J. A., Vargha-Khadem, F. & Monaco, A. P. A forkhead-domain gene is mutated in a severe speech and language disorder. Nature 413, 519–523 (2001)

    ADS  CAS  Article  Google Scholar 

  3. 3

    MacDermot, K. D. et al. Identification of FOXP2 truncation as a novel cause of developmental speech and language deficits. Am. J. Hum. Genet. 76, 1074–1080 (2005)

    CAS  Article  Google Scholar 

  4. 4

    Enard, W. et al. Molecular evolution of FOXP2, a gene involved in speech and language. Nature 418, 869–872 (2002)

    ADS  CAS  Article  Google Scholar 

  5. 5

    Zhang, J., Webb, D. M. & Podlaha, O. Accelerated protein evolution and origins of human-specific features: Foxp2 as an example. Genetics 162, 1825–1835 (2002)

    CAS  PubMed  PubMed Central  Google Scholar 

  6. 6

    Spiteri, E. et al. Identification of the transcriptional targets of FOXP2, a gene linked to speech and language, in developing human brain. Am. J. Hum. Genet. 81, 1144–1157 (2007)

    CAS  Article  Google Scholar 

  7. 7

    Vernes, S. C. et al. 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, 1232–1250 (2007)

    CAS  Article  Google Scholar 

  8. 8

    Li, S., Weidenfeld, J. & Morrisey, E. E. Transcriptional and DNA binding activity of the Foxp1/2/4 family is modulated by heterotypic and homotypic protein interactions. Mol. Cell. Biol. 24, 809–822 (2004)

    CAS  Article  Google Scholar 

  9. 9

    Oldham, M. C. et al. Functional organization of the transcriptome in human brain. Nature Neurosci. 11, 1271–1282 (2008)

    CAS  Article  Google Scholar 

  10. 10

    Zhang, B. & Horvath, S. A general framework for weighted gene co-expression network analysis. Stat. Appl. Genet. Mol. Biol. 4, 17 (2005)

    MathSciNet  Article  Google Scholar 

  11. 11

    Acampora, D. et al. Craniofacial, vestibular and bone defects in mice lacking the Distal-less-related gene Dlx5. Development 126, 3795–3809 (1999)

    CAS  PubMed  Google Scholar 

  12. 12

    Yoshihara, M., Adolfsen, B., Galle, K. T. & Littleton, J. T. Retrograde signaling by Syt 4 induces presynaptic release and synapse-specific growth. Science 310, 858–863 (2005)

    ADS  CAS  Article  Google Scholar 

  13. 13

    Brusse, E. et al. Spinocerebellar ataxia associated with a mutation in the fibroblast growth factor 14 gene (SCA27): A new phenotype. Mov. Disord. 21, 396–401 (2006)

    Article  Google Scholar 

  14. 14

    Holmes, S. E. et al. Expansion of a novel CAG trinucleotide repeat in the 5′ region of PPP2R2B is associated with SCA12. Nature Genet. 23, 391–392 (1999)

    CAS  Article  Google Scholar 

  15. 15

    Belton, E., Salmond, C. H., Watkins, K. E., Vargha-Khadem, F. & Gadian, D. G. Bilateral brain abnormalities associated with dominantly inherited verbal and orofacial dyspraxia. Hum. Brain Mapp. 18, 194–200 (2003)

    Article  Google Scholar 

  16. 16

    Shu, W. et al. Altered ultrasonic vocalization in mice with a disruption in the Foxp2 gene. Proc. Natl Acad. Sci. USA 102, 9643–9648 (2005)

    ADS  CAS  Article  Google Scholar 

  17. 17

    Van Camp, G. et al. A new autosomal recessive form of Stickler syndrome is caused by a mutation in the COL9A1 gene. Am. J. Hum. Genet. 79, 449–457 (2006)

    CAS  Article  Google Scholar 

  18. 18

    Uhlenberg, B. et al. Mutations in the gene encoding gap junction protein α12 (connexin 46.6) cause Pelizaeus-Merzbacher-like disease. Am. J. Hum. Genet. 75, 251–260 (2004)

    CAS  Article  Google Scholar 

  19. 19

    Johnson, M. B. et al. Functional and evolutionary insights into human brain development through global transcriptome analysis. Neuron 62, 494–509 (2009)

    CAS  Article  Google Scholar 

  20. 20

    Prabhakar, S., Noonan, J. P., Paabo, S. & Rubin, E. M. Accelerated evolution of conserved noncoding sequences in humans. Science 314, 786 (2006)

    CAS  Article  Google Scholar 

  21. 21

    Dorus, S. et al. Accelerated evolution of nervous system genes in the origin of Homo sapiens. Cell 119, 1027–1040 (2004)

    CAS  Article  Google Scholar 

  22. 22

    Enard, W. et al. A humanized version of Foxp2 affects cortico-basal ganglia circuits in mice. Cell 137, 961–971 (2009)

    CAS  Article  Google Scholar 

  23. 23

    Kumar, S. & Hedges, S. B. A molecular timescale for vertebrate evolution. Nature 392, 917–920 (1998)

    ADS  CAS  Article  Google Scholar 

  24. 24

    King, M. C. & Wilson, A. C. Evolution at two levels in humans and chimpanzees. Science 188, 107–116 (1975)

    ADS  CAS  Article  Google Scholar 

  25. 25

    Enard, W. et al. Intra- and interspecific variation in primate gene expression patterns. Science 296, 340–343 (2002)

    ADS  CAS  Article  Google Scholar 

  26. 26

    Caceres, M. et al. Elevated gene expression levels distinguish human from non-human primate brains. Proc. Natl Acad. Sci. USA 100, 13030–13035 (2003)

    ADS  CAS  Article  Google Scholar 

  27. 27

    Coppola, G. et al. Gene expression study on peripheral blood identifies progranulin mutations. Ann. Neurol. 64, 92–96 (2008)

    CAS  Article  Google Scholar 

  28. 28

    Konopka, G., Tekiela, J., Iverson, M., Wells, C. & Duncan, S. A. Junctional adhesion molecule-A is critical for the formation of pseudocanaliculi and modulates E-cadherin expression in hepatic cells. J. Biol. Chem. 282, 28137–28148 (2007)

    CAS  Article  Google Scholar 

  29. 29

    Wohlschlegel, J. A. Identification of SUMO-conjugated proteins and their SUMO attachment sites using proteomic mass spectrometry. Methods Mol. Biol. 497, 33–49 (2009)

    CAS  Article  Google Scholar 

  30. 30

    Elias, J. E. & Gygi, S. P. Target-decoy search strategy for increased confidence in large-scale protein identifications by mass spectrometry. Nature Methods 4, 207–214 (2007)

    CAS  Article  Google Scholar 

  31. 31

    Coppola, G., Winden, K., Konopka, G., Gao, F. & Geschwind, D. H. Expression and network analysis of Illumina microarray data. Nature Protocols 10.1038/nprot.2009.215 (2009)

Download references

Acknowledgements

We thank M. Oldham for generating the Illumina microarray mask file; J. Ou and E. Spiteri for performing site-directed mutagenesis; L. Chen for technical assistance; and L. Kawaguchi for laboratory management. Human tissue was obtained from the NICHD Brain and Tissue Bank for Developmental Disorders at the University of Maryland (NICHD Contract numbers N01-HD-4-3368 and N01-HD-4-3383). The role of the NICHD Brain and Tissue Bank is to distribute tissue, and therefore cannot endorse the studies performed or the interpretation of results. This work was supported by grant R21MH075028, R37MH60233-06A1 (D.H.G.), T32HD007032, an A.P. Giannini Foundation Medical Research Fellowship, and a NARSAD Young Investigator Award (G.K.), T32MH073526 (K.W.) NIH/NCRR grant RR00165 and a James S. McDonnell Foundation grant, JSMF 21002093 (T.M.P).

Author Contributions G.K. and D.H.G. designed the study, analysed the data and wrote the paper; G.K. performed all of the experiments; J.M.B. made contributions to an earlier phase of the project including generating cell lines, immunoblotting and qRT–PCR; K.W. performed statistical analysis and weighted gene coexpression network analysis; G.C. conducted promoter analysis and G.C. and F.G. analysed the microarray data; Z.O.J. and J.A.W. performed mass spectrometry; S.P. performed some of the qRT–PCR; T.M.P. performed tissue dissections and provided non-human primate samples; all authors discussed the results and commented on the manuscript.

Author information

Affiliations

Authors

Corresponding authors

Correspondence to Genevieve Konopka or Daniel H. Geschwind.

Supplementary information

Supplementary Information

This file contains Supplementary Figures 1-6 with Legends and Supplementary Tables 1-10. (PDF 882 kb)

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Konopka, G., Bomar, J., Winden, K. et al. Human-specific transcriptional regulation of CNS development genes by FOXP2. Nature 462, 213–217 (2009). https://doi.org/10.1038/nature08549

Download citation

Further reading

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing