DLX5/6GABAergic expression affects social vocalization: implications for human evolution

Abstract

DLX5 and DLX6 are two closely related transcription factors involved in brain development and in GABAergic differentiation. The DLX5/6 locus is regulated by FoxP2, a gene involved in language evolution and has been associated to neurodevelopmental disorders and mental retardation. Targeted inactivation of Dlx5/6 in mouse GABAergic neurons (Dlx5/6VgatCre mice) results in behavioural and metabolic phenotypes notably increasing lifespan by 33%.Here, we show that Dlx5/6VgatCre mice present an hyper-vocalization and hyper-socialization phenotype. While only 7% of control mice emitted more than 700 vocalizations/10min, 30% and 56% of heterozygous or homozygous Dlx5/6VgatCre mice emitted more than 700 and up to 1400 calls/10min with longer, uninterrupted, call sequences and a higher proportion of complex and modulated calls. Hyper-vocalizing animals were more sociable: the time they spent in dynamic interactions with an unknown visitor was more than doubled compared to low-vocalizing individuals.We then compared the DLX5/6 genomic regions from Neanderthal and modern humans to examine if DLX5/6 GABAergic expression could have been involved in human social evolution. We identify an introgressed Neanderthal haplotype (DLX5/6-N-Haplotype) present in 12.6% of European individuals that covers DLX5/6 coding and regulatory sequences. The DLX5/6-N-Haplotype is not significantly associated to Autism Spectrum Disorders (ASDs) but includes the binding site for GTF2I, a gene associated to Williams-Beuren syndrome, a neurodevelopmental disorder characterized by hyper-sociability and hyper-vocalization. Interestingly, the DLX5/6-N-Haplotype is significantly underrepresented in semi-supercentenarians (>105y of age), a well-established human model of healthy ageing and longevity, suggesting its potential involvement in the co-evolution of longevity, sociability and speech.

Human Cerebral Organoid Implantation Alleviated the Neurological Deficits of Traumatic Brain Injury in Mice

“…The transcription factor Foxp2 is involved in setting up the neuronal circuitry for vocal learning in mammals and is thought to have played a special role in the evolution of human speech and language [34]. And it is also associated with inherited dyspraxia and poor control of the facial musculature [35]. Satb2, an uplayer marker [36], was detected at this time point as well (Figure 1(j)).…”

Self-Domestication: From Analogy to Homology via Genomics

“…We expect future work to continue revealing the relevance of genes implicated in neurodevelopmental disorders to understand domesticated phenotypes (for a salient recent example, see 126 ). Of note, Levi 127 found that the protein coded for by a gene on the WBSCR (GTF2I) binds a locus associated with DLX5/6, a region of the genome associated with a hypersocialization and hypervocalization in mice. Likewise, genes regulated by genes on WBSCR (such as those studied in 56 ) deserve closer attention.…”