People who carry rare heterozygous mutations disrupting the FOXP2 gene have problems mastering the complex sequences of mouth movements needed for speech, along with deficits in many aspects of expressive and receptive language. The gene encodes a highly conserved transcription factor that helps regulate development and function of neuronal subpopulations in a wide range of non-speaking vertebrates, although evidence suggests that its role(s) may have been modified during human evolution.
It is emphasised that FOXP2 is not the mythical “gene for speech”, but represents one piece of a complex puzzle. I will describe how FOXP2 can be used as a unique window into key neurogenetic pathways via an array of complementary approaches. For example, using functional genomic screening of human neurons grown in the laboratory, we identified the CNTNAP2 gene (a member of the neurexin superfamily) as a downstream target directly regulated by FOXP2. Intriguingly, we found that CNTNAP2 is itself associated with common cases of language impairment; this target has also been implicated in language delays of autistic children. High-throughput screening has enabled us to isolate additional putative targets of FOXP2, including multiple genes involved in neurite outgrowth and synaptic plasticity. Moving to animal models of FOXP2 dysfunction, we have shown that point mutations implicated in human speech deficits yield impaired motor-skill learning in mutant mice. Electrophysiological recording suggests that this may be mediated by altered plasticity of Foxp2-expressing circuitry. Together with findings from other model systems, these data indicate that the contributions of FOXP2 to human speech and language are built on evolutionarily ancient roles in neural circuits involved in sensorimotor integration and motor-skill learning.
Overall, this work demonstrates how we can begin to bridge gaps between molecules, neurons and the brain, helping us to build more sophisticated models of the relationships between genes, speech and language.
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