The FOXP2-Driven Network in Developmental Disorders and Neurodegeneration

Abstract

The transcription repressor FOXP2 is a crucial player in nervous system evolution and development of humans and songbirds. In order to provide an additional insight into its functional role we compared target gene expression levels between human neuroblastoma cells (SH-SY5Y) stably overexpressing FOXP2 cDNA of either humans or the common chimpanzee, Rhesus monkey, and marmoset, respectively. RNA-seq led to identification of 27 genes with differential regulation under the control of human FOXP2, which were previously reported to have FOXP2-driven and/or songbird song-related expression regulation. RT-qPCR and Western blotting indicated differential regulation of additional 13 new target genes in response to overexpression of human FOXP2. These genes may be directly regulated by FOXP2 considering numerous matches of established FOXP2-binding motifs as well as publicly available FOXP2-ChIP-seq reads within their putative promoters. Ontology analysis of the new and reproduced targets, along with their interactors in a network, revealed an enrichment of terms relating to cellular signaling and communication, metabolism and catabolism, cellular migration and differentiation, and expression regulation. Notably, terms including the words “neuron” or “axonogenesis” were also enriched. Complementary literature screening uncovered many connections to human developmental (autism spectrum disease, schizophrenia, Down syndrome, agenesis of corpus callosum, trismus-pseudocamptodactyly, ankyloglossia, facial dysmorphology) and neurodegenerative diseases and disorders (Alzheimer’s, Parkinson’s, and Huntington’s diseases, Lewy body dementia, amyotrophic lateral sclerosis). Links to deafness and dyslexia were detected, too. Such relations existed for single proteins (e.g., DCDC2, NURR1, PHOX2B, MYH8, and MYH13) and groups of proteins which conjointly function in mRNA processing, ribosomal recruitment, cell–cell adhesion (e.g., CDH4), cytoskeleton organization, neuro-inflammation, and processing of amyloid precursor protein. Conspicuously, many links pointed to an involvement of the FOXP2-driven network in JAK/STAT signaling and the regulation of the ezrin–radixin–moesin complex. Altogether, the applied phylogenetic perspective substantiated FOXP2’s importance for nervous system development, maintenance, and functioning. However, the study also disclosed new regulatory pathways that might prove to be useful for understanding the molecular background of the aforementioned developmental disorders and neurodegenerative diseases.

The promoter regions of intellectual disability-associated genes are uniquely enriched in LTR sequences of the MER41 primate-specific endogenous retrovirus: an evolutionary connection between immunity and cognition

“…We thus sought to determine whether YY1 could potentially represent a molecular link between FOXP2 and the immune/MER41/cognition pathway we identified. To this aim, we explored data obtained from a recent work attempting to identify a set of FOXP2 targets that are specific to human FOXP2 in neurons (Oswald et al, 2017). More precisely, data from this study were obtained by: i) a meta-analysis of previous works reporting on FOXP2 neuronal targets (based notably on Chip-Seq analyses of the neuronal cell line SH-SY5Y) (Enard et al, 2009;Hilliard et al, 2012;Konopka et al, 2009;Spiteri et al, 2007;Vernes et al, 2007Vernes et al, , 2011 and ii) a comparison of neuronal genes that are targeted by human FOXP2 vs non-human primates orthologs of FOXP2 in the neuronal cell line SH-SY5Y (Oswald et al, 2017).…”

“…Our results 6 indicate a possible evolutionary advantage to humans in the immune/MER41/cognition pathway. Finally, since FOXP2 is currently known as a relevant TF regulating aspects of brain development and functions which are important for the execution of speech-related motor programs (Konopka et al, 2009;Oswald et al, 2017;Spiteri et al, 2007;Vernes et al, 2007Vernes et al, , 2011, we searched genomics and proteomics databases to map a putative functional interactome linking FOXP2 and the immune TFs binding MER41 LTRs. This way, we were able to unravel a HERV-driven evolutionary-determined connection between cognition and immunity with a potential impact on language evolution and the pathophysiology of ID.…”

“…Mapping of the protein and functional network linking FOXP2 to immune TFs that bind MER41 LTRs in the promoter regions of cognition-related (ID-associated) genes.A survey of the human proteome was performed on the BioGRID database(Chatr-aryamontri et al, 2015) in order to map protein-protein interactions between FOXP2, STAT1, STAT3, NFKB1, YY1 and the molecules identified as being human-specifically regulated by FOXP2 in the neuronal cell line SH-SY-5Y(Oswald et al, 2017). Ellipse shapes highlighted in yellow represent FOXP2, its protein partner YY1 and the 3 immune TFs that bind MER41 LTRs in the promoter regions of cognition-related (ID-associated) genes (namely STAT1, STAT3 and NFKB1).…”

Genomics of Speech and Language Disorders

“…A study identified 27 genes with differential regulation under human FOXP2 control. RT-qPCR and western blot studies showed the differential regulation of 13 additional target genes in response to human over-expression of FOXP2 [82] . The functional deficiency of FOXP2 affects both expressive and receptive language with a central characteristic of the abnormal articulation [7] .…”

“…The functional deficiency of FOXP2 affects both expressive and receptive language with a central characteristic of the abnormal articulation [7] . Its function at central nervous system has been proven by neuroimaging studies and animal models, participating in cell signaling and communication, metabolism, migration, differentiation, and expression regulation [82,83] .…”