Foxp2 Regulates Gene Networks Implicated in Neurite Outgrowth in the Developing Brain

Abstract

Forkhead-box protein P2 is a transcription factor that has been associated with intriguing aspects of cognitive function in humans, non-human mammals, and song-learning birds. Heterozygous mutations of the human FOXP2 gene cause a monogenic speech and language disorder. Reduced functional dosage of the mouse version (Foxp2) causes deficient cortico-striatal synaptic plasticity and impairs motor-skill learning. Moreover, the songbird orthologue appears critically important for vocal learning. Across diverse vertebrate species, this well-conserved transcription factor is highly expressed in the developing and adult central nervous system. Very little is known about the mechanisms regulated by Foxp2 during brain development. We used an integrated functional genomics strategy to robustly define Foxp2-dependent pathways, both direct and indirect targets, in the embryonic brain. Specifically, we performed genome-wide in vivo ChIP–chip screens for Foxp2-binding and thereby identified a set of 264 high-confidence neural targets under strict, empirically derived significance thresholds. The findings, coupled to expression profiling and in situ hybridization of brain tissue from wild-type and mutant mouse embryos, strongly highlighted gene networks linked to neurite development. We followed up our genomics data with functional experiments, showing that Foxp2 impacts on neurite outgrowth in primary neurons and in neuronal cell models. Our data indicate that Foxp2 modulates neuronal network formation, by directly and indirectly regulating mRNAs involved in the development and plasticity of neuronal connections.

Intronic miRNA miR-3666 Modulates its Host Gene FOXP2 Functions in Neurodevelopment and May Contribute to Pathogenesis of Neurological Disorders Schizophrenia and Autism

“…We also studied FOXP2 interactions using STRING [36,37] (Figure 3a), BioGRID [38] and IntAct [64]. For a more extensive study, we referred scientific literature [60][61][62][63][64][65][66][67][68][69] and took into consideration some genes that were not common targets but play important roles in the nervous system or in pathogenesis of neurological disorders (for example, CNTNAP2 and BDNF) and showed potential in being indirectly co-regulated by FOXP2 and miR-3666 through common target genes. Therefore, a total of 30 genes were selected for developing our models (Supplementary Table S4).…”

Insights into the Genetic Foundations of Human Communication

“…However, given that it is a transcription factor, genes regulated by FOXP2 could have roles in other forms of language disorder. Several studies have together identified thousands of genes that are potentially regulated by FOXP2 in at least one tissue or developmental timepoint Vernes et al 2007Vernes et al , 2011Konopka et al 2009). One early study (Vernes et al 2008) chose to follow up specifically on CNTNAP2, which encodes a neuronal cell-surface transmembrane protein.…”

“…Several studies have therefore attempted to identify such neural targets. However, there is limited overlap between datasets, and the crucial targets of FOXP2 with regard to language disorder remain unclear Vernes et al 2007;Vernes et al 2011;Konopka et al 2009). One key set of FOXP2 targets may be those involved in neurite outgrowth.…”

“…One key set of FOXP2 targets may be those involved in neurite outgrowth. Genes in this category were found to be enriched among putative targets in embryonic mouse brain, leading to the discovery that neurons from mice that completely lack Foxp2 exhibit reduced neurite outgrowth, which could impair neuronal connectivity in the developing brain (Vernes et al 2011).…”

“…Several studies have identified putative members of this FOXP2 molecular network (Coutinho et al 2011;Clovis et al 2012;Shi et al 2013;Spiteri et al 2007;Vernes et al 2007;Konopka et al 2009;Vernes et al 2011;Li et al 2004;Chokas et al 2010;Sakai et al 2011;Zhou et al 2008). In previous sections we have discussed the relationship of the FOXP2 target, CNTNAP2, and the FOXP2 interacting proteins, TBR1 and FOXP1, to communication disorders.…”