Human-specific transcriptional regulation of CNS development genes by FOXP2

Abstract

The signaling pathways orchestrating both the evolution and development of language in the human brain remain unknown. To date, 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 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 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. Since 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.

Insights into the Genetic Foundations of Human Communication

“…However, given that it is a transcription factor, genes regulated by FOXP2 could have roles in other forms of language disorder. Several studies have together identified thousands of genes that are potentially regulated by FOXP2 in at least one tissue or developmental timepoint Vernes et al 2007Vernes et al , 2011Konopka et al 2009). One early study (Vernes et al 2008) chose to follow up specifically on CNTNAP2, which encodes a neuronal cell-surface transmembrane protein.…”

“…Several studies have therefore attempted to identify such neural targets. However, there is limited overlap between datasets, and the crucial targets of FOXP2 with regard to language disorder remain unclear Vernes et al 2007;Vernes et al 2011;Konopka et al 2009). One key set of FOXP2 targets may be those involved in neurite outgrowth.…”

“…The expression pattern of this gene is broadly conserved in vertebrates, although it remains possible that there may have been subtle alterations in our lineage (Lai et al 2003;Ferland et al 2003;Teramitsu et al 2004). It is highly likely that there are differences in sets of downstream targets in different species, and that such changes may have been influential in driving evolutionary differences in hominin neurodevelopment, but the crucial changes with regard to language have not yet been clearly identified (Nelson et al 2013;Konopka et al 2009). Two amino acid substitutions in FOXP2 occurred in the human lineage since the split from chimpanzees, against a generally low background of amino acid change during vertebrate evolution (Enard et al 2002;Enard 2011).…”

“…Two amino acid substitutions in FOXP2 occurred in the human lineage since the split from chimpanzees, against a generally low background of amino acid change during vertebrate evolution (Enard et al 2002;Enard 2011). There is evidence that these substitutions affect target regulation and synaptic plasticity, but the molecular mechanism of these effects is still unknown (Konopka et al 2009;Enard et al 2009;ReimersKipping et al 2011). Interestingly, a selective sweep may have occurred at the FOXP2 locus within the last 200,000 years, but is not explained by the amino acid substitutions and may instead relate to non-coding changes affecting FOXP2 regulation, or may be a false-positive finding (Coop et al 2008;Maricic et al 2013;Graham and Fisher 2013).…”

“…Several studies have identified putative members of this FOXP2 molecular network (Coutinho et al 2011;Clovis et al 2012;Shi et al 2013;Spiteri et al 2007;Vernes et al 2007;Konopka et al 2009;Vernes et al 2011;Li et al 2004;Chokas et al 2010;Sakai et al 2011;Zhou et al 2008). In previous sections we have discussed the relationship of the FOXP2 target, CNTNAP2, and the FOXP2 interacting proteins, TBR1 and FOXP1, to communication disorders.…”