FOXP2, retinoic acid, and language: a promising direction

Devanna et al. (2014) have demonstrated that FOXP2 mimics, and actually potentiates, retinoic acid (RA) induction of genes involved in neural differentiation. At the physiological level this effect results in an increase of neurite outgrowth and branching, and in a reduction of neuronal migration. The authors highlight the importance of RA signaling for brain growth and differentiation, and the relevance of FOXP2 for language. Specifically, the authors’ interest focuses on the upregulation of RARβ by FOXP2 in the striatum, where the primary pathology is located in people bearing a defective copy of FOXP2, known to give rise to language disorders (see Graham and Fisher, 2013 for review). Devanna et al.’s study adds to the literature showing that RA plays an important role in brain plasticity (Luo et al., 2009), learning and memory (Etchamendy et al., 2003; Jiang et al., 2012), and we find this research direction promising. In our opinion the link between RA, FOXP2, and language could be made more robust by taking advantage of information already available in the literature, which we wish to highlight here. In doing so, we hope to encourage further experimental testing in this area. Recently we have assembled a set of genes that we predict to be implicated in the refinement of the connectivity between sub-cortical and cortical structures, as well as the interface between brain growth and skull formation, and which may underlie our species-specific “language readiness” (Boeckx and Benitez-Burraco, 2014). Interestingly, in the context of Devanna et al.’s study, several of the genes belonging to our list are related to the RA signaling pathway, to FOXP2, or to both them. These links, if further explored and eventually mapped onto particular aspects of neural function and brain development could reinforce Devanna et al.’s findings and help us better understand the molecular underpinnings of human language. Our set of genes is centered on RUNX2, which controls different aspects of skull and brain development (Stein et al., 2004; Reale et al., 2013) and whose promoter region shows two derived alleles in modern humans (Perdomo-Sabogal et al., 2014). One of the RUNX2 targets is CRABPII (Wu et al., 2014), a RA signaling component highlighted by Devanna et al. Another target of RUNX2, and also a gene regulated by RA, is HES1 (Suh et al., 2008). The HES1 pathway is related to craniofacial development (Wen et al., 2013), the differentiation of GABAergic neurons, standardly regarded as critical for the maintenance of our species-specific cognitive profile (Long et al., 2013), and the development of dopaminergic neurons, routinely mentioned in the literature on motor behavior and vocal learning (Kameda et al., 2011). Moreover, HES1 is transcriptionally regulated by the SLIT/ROBO pathway (Borrell et al., 2012), which is impaired in language disorders and autism (Suda et al., 2011; St Pourcain et al., 2014; Tran et al., 2014) and which is implicated in the establishment of the vocal learning neural circuits in birds (Wang, 2011). Importantly, the SLIT/ROBO pathway interacts with FOXP2: both Vernes et al. (2007) and Konopka et al. (2009) have identified SLIT1 as a direct downstream target of FOXP2. Finally, among the RUNX2 targets identified by Kuhlwilm et al. (2013), two genes (NLGN1 and ITPR1) are both candidates for autism spectrum disorder and targets of RORA1, a major isoform of the RA-related orphan receptor-alpha (RORA) protein in the human brain, and also a candidate for autism (Sarachana and Hu, 2013). Interestingly, among the genes highlighted by Sarachana and Hu (2013) one also finds candidates for language disorders, like CYP19A1 (Anthoni et al., 2012), and several targets of FOXP2, like NTRK and A2BP1 (Konopka et al., 2009). The latter gene is also a target of the neural splicing factor FOX-1, related to many neurodevelopmental diseases and one of the FOXP2 targets that show strong signals of selection in modern humans (Ayub et al., 2013). Finally, another gene also highlighted by Devanna et al. is ASCL1, known to be involved in RA signaling. According to the authors, both FOXP2 and RA strongly downregulate ASCL1. We have found that ASCL1 regulates the DLX suite and the development of most neocortical GABAergic neurons (Letinic et al., 2002). We argued in Boeckx and Benitez-Burraco (2014) that DLX1 and DLX2 are likely to play an important role in the formation of a language-ready brain. Interestingly, Ascl1, Dlx1, Dlx2, and Foxp2’s target