A Humanized Version of Foxp2 Affects Cortico-Basal Ganglia Circuits in Mice

Abstract

It has been proposed that two amino acid substitutions in the transcription factor FOXP2 have been positively selected during human evolution due to effects on aspects of speech and language. Here, we introduce these substitutions into the endogenous Foxp2 gene of mice. Although these mice are generally healthy, they have qualitatively different ultrasonic vocalizations, decreased exploratory behavior and decreased dopamine concentrations in the brain suggesting that the humanized Foxp2 allele affects basal ganglia. In the striatum, a part of the basal ganglia affected in humans with a speech deficit due to a nonfunctional FOXP2 allele, we find that medium spiny neurons have increased dendrite lengths and increased synaptic plasticity. Since mice carrying one nonfunctional Foxp2 allele show opposite effects, this suggests that alterations in cortico-basal ganglia circuits might have been important for the evolution of speech and language in humans.

Relaxed genetic control of cortical organization in human brains compared with chimpanzees

“…However, the clear differences in behavioral and cognitive development between enculturated apes and humans point to particular neural specializations that make the human brain-but not the brain of great apes-extremely responsive to exogenous influences. In this light, several comparative studies have shown molecular and microstructural specializations in the human brain indicating an increased level of synaptic plasticity (21,22), which might be linked to increased learning abilities.…”

Tracing the origin of our species through palaeogenomics

“…The gene FOXP2 evolves specifically in the human lineage and has two point mutations that are present in the genomes of humans, Neanderthals and Denisovans, and that distinguish them from the other primates [17]. When the FOXP2 gene of mice was humanized, i.e., these two human-specific mutations were introduced in the mouse gene, effects on the neuronal plasticity of the basal ganglions were observed, suggesting that these mutations could have played a role in the evolution of language in the human lineage [18]. On the other hand, mutations affecting non-coding regions of the gene FOXP2 are different in the genomes of humans, Denisovans and Neanderthals [19].…”

Insights into the Genetic Foundations of Human Communication

“…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).…”