Mice carrying a humanized Foxp2 knock-in allele show region-specific shifts of striatal Foxp2 expression levels

Abstract

Genetic and clinical studies of speech and language disorders are providing starting points to unravel underlying neurobiological mechanisms. The gene encoding the transcription factor FOXP2 has been the first example of a gene involved in the development and evolution of this human-specific trait. A number of autosomal-dominant FOXP2 mutations are associated with developmental speech and language deficits indicating that gene dosage plays an important role in the disorder. Comparative genomics studies suggest that two human-specific amino acid substitutions in FOXP2 might have been positively selected during human evolution. A knock-in mouse model carrying these two amino acid changes in the endogenous mouse Foxp2 gene (Foxp2^hum/hum) shows profound changes in striatum-dependent behaviour and neurophysiology, supporting a functional role for these changes. However, how this affects Foxp2 expression patterns in different striatal regions and compartments has not been assessed. Here, we characterized Foxp2 protein expression patterns in adult striatal tissue in Foxp2^hum/hum mice. Consistent with prior reports in wildtype mice, we find that striatal neurons in Foxp2^hum/hum mice and wildtype littermates express Foxp2 in a range from low to high levels. However, we observe a shift towards more cells with higher Foxp2 expression levels in Foxp2^hum/hum mice, significantly depending on the striatal region and the compartment. As potential behavioural readout of these shifts in Foxp2 levels across striatal neurons, we employed a morphine sensitization assay. While we did not detect differences in morphine-induced hyperlocomotion during acute treatment, there was an attenuated hyperlocomotion plateau during sensitization in Foxp2^hum/hum mice. Taken together, these results suggest that the humanized Foxp2 allele in a mouse background is associated with a shift in striatal Foxp2 protein expression pattern.

Keywords: Evolution; Expression; Foxp2; Striatum; Striosome.