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Human-specific transcriptional regulation of CNS development genes by FOXP2


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.

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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.

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Gene Expression Omnibus

Data deposits

Gene expression data have been deposited in the NCBI Gene Expression Omnibus (GEO; and are accessible using GEO series accession number GSE18142.


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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.

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Correspondence to Genevieve Konopka or Daniel H. Geschwind.

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

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