FOXP2 as a molecular window into speech and language

Abstract

Rare mutations of the FOXP2 transcription factor gene cause a monogenic syndrome characterized by impaired speech development and linguistic deficits. Recent genomic investigations indicate that its downstream neural targets make broader impacts on common language impairments, bridging clinically distinct disorders. Moreover, the striking conservation of both FoxP2 sequence and neural expression in different vertebrates facilitates the use of animal models to study ancestral pathways that have been recruited towards human speech and language. Intriguingly, reduced FoxP2 dosage yields abnormal synaptic plasticity and impaired motor-skill learning in mice, and disrupts vocal learning in songbirds. Converging data indicate that Foxp2 is important for modulating the plasticity of relevant neural circuits. This body of research represents the first functional genetic forays into neural mechanisms contributing to human spoken language.

Insights into the Genetic Foundations of Human Communication

“…Similarly to children acquiring spoken language, juvenile zebra finches learn their vocalizations incrementally during a critical period by imitating an adult (Bolhuis et al 2010). The neural circuitry underlying vocal learning appears to be partly shared by humans and songbirds, despite these species being separated by large evolutionary distances, pointing to a deep homology (Fisher and Scharff 2009;Scharff and Petri 2011). Furthermore, the zebra finch genome has been sequenced, and sophisticated genetic experiments are possible in this species, such as the identification of neural molecules regulated by vocal behavior (Hilliard et al 2012), and the manipulation of the expression levels of genes of interest during the critical song-learning period (Haesler et al 2007).…”

“…The first gene implicated in a developmental communication disorder was discovered through studies of a large UK pedigree, known as the KE family, in which approximately half of the individuals are affected by CAS (Table 1), accompanied by difficulties in expressive and receptive language abilities, affecting both oral and written language (Watkins et al 1999;Fisher et al 1998;Fisher and Scharff 2009). Affected members of the family carry a heterozygous missense mutation in the FOXP2 gene, which encodes a transcription factor that regulates expression of other genes (Lai et al 2001).…”

“…A framework for bridging the gap between genetics and behavior is provided by a decade of research into FOXP2 (Fisher and Scharff 2009;Graham and Fisher 2013). It is still not fully understood why disruption of one copy of this gene should lead to a severe speech and language disorder, but considerable progress has been made in elucidating both molecular-level effects and consequences for higher-level brain function.…”

“…The role of FOXP2 in the development of neural circuitry has been further investigated using several mutant mouse lines (Fisher and Scharff 2009;French and Fisher 2014). Mice lacking functional Foxp2 (the rodent ortholog of human FOXP2) have developmental delays and severe motor impairments, dying at 3-4 weeks after birth (French and Fisher 2014).…”

“…Additional studies with mutant mice have highlighted deficits in the processing and integration of auditory information (Kurt et al 2009;Kurt et al 2012). In both humans and mice, FOXP2 is expressed in brain regions including the striatum, cerebellum, thalamus and cortex (Ferland et al 2003;Lai et al 2003;Fisher and Scharff 2009). The profile of language impairments observed in individuals with FOXP2 disruptions may represent a compound disorder resulting from reduction in levels of this transcription factor in multiple brain areas involved in speech and language.…”