Region-specific Foxp2 deletions in cortex, striatum or cerebellum cannot explain vocalization deficits observed in spontaneous global knockouts

Bastiaan H A Urbanus,Saša Peter,Chris I De Zeeuw,Simon E Fisher

doi:10.1038/s41598-020-78531-8

Abstract

FOXP2 has been identified as a gene related to speech in humans, based on rare mutations that yield significant impairments in speech at the level of both motor performance and language comprehension. Disruptions of the murine orthologue Foxp2 in mouse pups have been shown to interfere with production of ultrasonic vocalizations (USVs). However, it remains unclear which structures are responsible for these deficits. Here, we show that conditional knockout mice with selective Foxp2 deletions targeting the cerebral cortex, striatum or cerebellum, three key sites of motor control with robust neural gene expression, do not recapture the profile of pup USV deficits observed in mice with global disruptions of this gene. Moreover, we observed that global Foxp2 knockout pups show substantive reductions in USV production as well as an overproduction of short broadband noise “clicks”, which was not present in the brain region-specific knockouts. These data indicate that deficits of Foxp2 expression in the cortex, striatum or cerebellum cannot solely explain the disrupted vocalization behaviours in global Foxp2 knockouts. Our findings raise the possibility that the impact of Foxp2 disruption on USV is mediated at least in part by effects of this gene on the anatomical prerequisites for vocalizing.

Highlights

FOXP2 has been identified as a gene related to speech in humans, based on rare mutations that yield significant impairments in speech at the level of both motor performance and language comprehension
We find that the mice in Emx1-Foxp[2] group, Rgs9-Foxp[2] group, and L7-Foxp[2] group are unaffected for all parameters tested, contrasting with phenotypes reported in global Foxp[2] knockout mouse p ups[9,10,20]
These findings indicate that the impact of Foxp[2] expression in the cerebral cortex, striatum as well as cerebellum is relatively limited in the context of pup ultrasonic vocalizations (USVs) production, and that complete inactivation of the gene in these sites is not sufficient to recapitulate phenotypic effects found in global knockouts

Summary

Introduction

FOXP2 has been identified as a gene related to speech in humans, based on rare mutations that yield significant impairments in speech at the level of both motor performance and language comprehension. Studies of a large three-generation British family (the KE family) identified a missense mutation of the human FOXP2 gene causing a severe speech and language disorder[1] Affected individuals in this family present with deficits in sequencing of oral movements, as well as impaired performance in expressive and receptive language tests[2]. R are[3], multiple independent point mutations disrupting FOXP2 have since been reported in additional cases of speech/language disorder[4,5,6] In line with these mutations, several different types of mouse models of Foxp[2] dysfunction have since been generated and used to investigate impacts on vocal and motor behaviours (reviewed by French and F isher[7]). When substantive effects on vocalization have been observed, it has remained unclear which neural circuit(s) may be responsible, and even whether the effects are brain-related or due to peripheral factors involving Foxp[2] activity in other tissues

Methods

Results

Conclusion