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Molecular Networks of the FOXP2 Transcription Factor in the Brain

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Molecular Networks of the FOXP2 Transcription Factor in the Brain Review Molecular networks of the FOXP2 transcription factor in the brain Joery den Hoed1,2 , Karthikeyan Devaraju1 & Simon E Fisher1,3,* Abstract investigated contributions of common variation in FOXP2 to geneti- cally complex traits. For example, some studies of small samples The discovery of the FOXP2 transcription factor, and its implica- proposed that single nucleotide polymorphisms (SNPs) in the tion in a rare severe human speech and language disorder, has led FOXP2 gene are associated with schizophrenia risk (Spaniel et al, to two decades of empirical studies focused on uncovering its 2011; Li et al, 2013; Rao et al, 2017), but there is little evidence of roles in the brain using a range of in vitro and in vivo methods. replication (Yin et al, 2018). Large-scale systematic genome-wide Here, we discuss what we have learned about the regulation of association studies have identified significant associations of FOXP2, its downstream effectors, and its modes of action as a intronic FOXP2 SNPs with several traits, including attention-deficit/ transcription factor in brain development and function, providing hyperactivity disorder (ADHD) (Demontis et al, 2019) and risk- an integrated overview of what is currently known about the criti- taking behaviors (Clifton et al, 2018). Although rare disruptions in cal molecular networks. FOXP2 have been associated with changes in brain activity (Liegeois et al, 2003) and structure (Watkins et al, 2002; Liegeois Keywords FOXP2; molecular network; neurodevelopment; speech disorder; et al, 2016; Argyropoulos et al, 2019), common variation could not transcription factor be linked to task-based neural activations on language tasks Subject Categories Chromatin, Transcription & Genomics; Neuroscience (Udden et al, 2019) or neuroanatomical differences between indi- DOI 10.15252/embr.202152803 | Received 5 March 2021 | Revised 19 May viduals (Hoogman et al, 2014). 2021 | Accepted 23 June 2021 | Published online 14 July 2021 FOXP2 belongs to the forkhead box/winged-helix (FOX) family EMBO Reports (2021) 22:e52803 of proteins, a large group of transcription factors that share a highly conserved DNA-binding domain of ~ 80–100 amino acids, called the See the Glossary for abbreviations used in this article forkhead box (Weigel & Jackle, 1990; Hannenhalli & Kaestner, 2009) (following nomenclature guidelines, we use FOXP2 for humans, Foxp2 for mice, and FoxP2 for other species). There are 19 Introduction subclasses of FOX proteins, from FOXA to FOXS (Kaestner et al, 2000; Hannenhalli & Kaestner, 2009), with important roles in vari- FOXP2 was the first gene to be clearly linked to speech and ous biological processes, including cell differentiation, proliferation, language development. The initial finding was made through stud- and development (Hannenhalli & Kaestner, 2009; Zhang et al, ies of a large multi-generational family (the KE family) with a 2017). Although they all share a characteristic DNA-binding severe dominantly inherited developmental speech and language domain, different FOX proteins have distinct expression patterns disorder (MIM #602081) (Lai et al, 2001). All fifteen affected family and are involved in diverse mechanisms (Benayoun et al, 2011). members carried a heterozygous missense mutation (p.R553H) The FOXP subclass comprises four members, FOXP1–4 (Shu disrupting FOXP2. In the two decades since then, additional cases et al, 2001; Li et al, 2004). As well as the DNA-binding domain, of FOXP2-related speech and language disorders have been discov- FOXP proteins share a zinc finger and leucine zipper motif (Fig 1A) ered, both inherited and de novo (MacDermot et al, 2005; Feuk (Wang et al, 2003; Li et al, 2004). Moreover, FOXP1, FOXP2, and et al, 2006; Reuter et al, 2017), with childhood apraxia of speech FOXP4 contain long N-terminal glutamine-rich regions of unknown (also called developmental verbal dyspraxia) as a core phenotypic function (Wang et al, 2003; Li et al, 2004). A unique feature of the feature, characterized by difficulties in coordinating sequences of FOXP subclass is that they form homo- and heterodimers via the articulatory movements underlying proficient speech. In a subset of conserved leucine zipper, which appears essential for DNA binding individuals, broader phenotypes are observed including oral motor and transcription regulation (Li et al, 2004). They may even form deficits, global developmental delays, and/or autism spectrum oligomer complexes, as detected for FoxP1, FoxP2, and FoxP4 in disorder (Morgan et al, 2016). Beyond the well-documented conse- studies of zebra finch brain (Mendoza & Scharff, 2017). Formation quences of rare highly penetrant genetic disruptions, studies have of FOXP homo- and heterodimers in any particular tissue/cell type 1 Language and Genetics Department, Max Planck Institute for Psycholinguistics, Nijmegen, The Netherlands 2 International Max Planck Research School for Language Sciences, Max Planck Institute for Psycholinguistics, Nijmegen, The Netherlands 3 Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, The Netherlands *Corresponding author. Tel: +31 24 3521441; E-mail: [email protected] ª 2021 The Authors. Published under the terms of the CC BY 4.0 license EMBO reports 22:e52803 | 2021 1 of 15 EMBO reports Joery den Hoed et al Glossary ADHD attention-deficit/hyperactivity disorder NR2F nuclear receptor subfamily 2, group F BCL11B B-cell lymphoma/leukemia 11B NuRD nucleosome remodeling and histone deacetylase BRET bioluminescence resonance energy transfer PAX6 paired box protein 6 CASK calcium/calmodulin-dependent serine protein pcw post-conception week kinase 3 PIAS protein inhibitor of activated STAT CHD chromodomain-helicase-DNA-binding protein POU3F2 POU class 3 homeobox 2 ChIP chromatin immunoprecipitation PTM post-translational modification CNTNAP2/CASPR2 contactin-associated protein-like 2 RAR retinoic acid receptor CTBP C-terminal-binding protein RELN reelin DISC1 disrupted in schizophrenia 1 ROR RAR-related orphan receptor FOXP forkhead box/winged-helix protein SATB special AT-rich binding protein GATAD2B GATA zinc finger domain-containing 2B SNP single nucleotide polymorphism GRIN2A glutamate ionotropic receptor NMDA type SOX5 SRY (sex determining region Y)-box 5 subunit 2A SRPX2 sushi repeat-containing protein X-linked 2 GSK3b glycogen-synthase kinase 3 beta SUMO small ubiquitin-like modifier HDAC histone deacetylase TBR T-box, brain Int. protein interactors TCF/LEF T-cell factor/lymphoid enhancer-binding factor LZ leucine zipper TF transcription factor MET MET proto-oncogene, receptor tyrosine kinase VLDLR very-low-density lipoprotein receptor MRI magnetic resonance imaging WNT wingless-related MMTV integration site 1 MTA metastasis-associated protein WNT3 wnt family member 3 NEDD9 neural precursor cell expressed developmentally YY1 yin yang 1 downregulated protein 9 ZBTB20 zinc finger and BTB domain-containing 20 NEUROD neurogenic differentiation 1 ZF zinc finger NFI nuclear factor 1 ZMYM2 zinc finger MYM-type protein 2 NGN2 neurogenin 2 is likely mediated by expression and availability of the different et al, 2016). Mice that are heterozygous for the mutation originally FOXP proteins, providing potential for more complex regulation of identified in the KE family display reduced motor-skill learning downstream pathways. (Groszer et al, 2008) and produce shorter sequences of ultrasonic While FOXP3 expression and function is largely limited to the vocalizations with less complex syntax (Chabout et al, 2016), as immune system (Fontenot et al, 2003), FOXP1, FOXP2, and FOXP4 compared to wild-type littermates. Foxp2 expression in the mouse are expressed in various tissues throughout the body, including the cortex, striatum, and cerebellum modulates different aspects of brain, where they show distinctive, yet partially overlapping, motor function, as demonstrated by conditional homozygous knock- expression patterns (human fetal and post-natal expression of outs targeting these structures (French et al, 2019). However, selec- FOXP1, FOXP2, and FOXP4 based on BrainSpan expression data: tive deletion of the gene in each of these brain regions does not Fig 1B and C. For a detailed review on the expression patterns of significantly alter production of ultrasonic vocalizations (Urbanus FOXP genes in the brain, see (Co et al, 2020)). FOXP1 expression is et al, 2020). Interestingly, while selective deletion of Foxp2 in the enriched in layers III-IV of the cerebral cortex (Ferland et al, 2003; mouse cortex does not appear to impact development of cortical Hisaoka et al, 2010), as well as the thalamus, striatum, and CA1 structures during embryogenesis (Co et al, 2019; Kast et al, 2019), subregion of the hippocampus (Ferland et al, 2003). Main sites of cortical-specific knockouts are reported to nonetheless show altered FOXP2 expression include layers IV-VI of the cerebral cortex (Fer- social behaviors (Co et al, 2019; Medvedeva et al, 2019). When land et al, 2003; Lai et al, 2003; Campbell et al, 2009; Hisaoka et al, mouse Foxp2 is constitutively replaced by a partially humanized 2010), the striatum (Ferland et al, 2003; Lai et al, 2003; Campbell version, medium spiny neurons in the striatum show increases in et al, 2009; Garcia-Calero et al, 2016), the posterior and lateral thala- dendrite length and synaptic plasticity (Enard et al, 2009), consis- mic nuclei (Ferland et al, 2003; Lai et al, 2003; Campbell et al, tent with multiple studies implicating the gene in development and 2009), the
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