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FOXP transcription factors in vertebrate brain development, function, and disorders

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Abstract FOXP transcription factors are an evolutionarily ancient protein subfamily coordinating the development of several organ systems in the vertebrate body. Association of their genes with neurodevelopmental disorders has sparked particular interest in their expression patterns and functions in the brain. Here, FOXP1, FOXP2, and FOXP4 are expressed in distinct cell type‐specific spatiotemporal patterns in multiple regions, including the cortex, hippocampus, amygdala, basal ganglia, thalamus, and cerebellum. These varied sites and timepoints of expression have complicated efforts to link FOXP1 and FOXP2 mutations to their respective developmental disorders, the former affecting global neural functions and the latter specifically affecting speech and language. However, the use of animal models, particularly those with brain region‐ and cell type‐specific manipulations, has greatly advanced our understanding of how FOXP expression patterns could underlie disorder‐related phenotypes. While many questions remain regarding FOXP expression and function in the brain, studies to date have illuminated the roles of these transcription factors in vertebrate brain development and have greatly informed our understanding of human development and disorders. This article is categorized under: Nervous System Development > Vertebrates: General Principles Gene Expression and Transcriptional Hierarchies > Gene Networks and Genomics Nervous System Development > Vertebrates: Regional Development
Shared structural domains of human FOXP proteins. Shared protein domains of human FOXP1, FOXP2, and FOXP4 are shown using information from UniProtKB. FH, forkhead; LZ, leucine zipper; polyQ, polyglutamine tract; ZF, zinc finger
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Summary of reported behavioral findings in Foxp1 and Foxp2 mouse experimental systems. Behavior deficits in whole‐brain Nestin‐Cre; Foxp1 cKO mice (a), Foxp1 heterozygous mice (b), Emx1‐Cre; Foxp1 cKO mice (c), Foxp2 mutant or heterozygous mice (d), Neurod6/Nex‐Cre; Foxp2 cKO mice, (f) Emx1‐Cre; Foxp2 cKO mice, Rgs9‐Cre; Foxp2 cKO mice (g), and Pcp2/L7‐Cre; Foxp2 cKO mice (h). Highlighted areas within brain schematics indicate brain regions with targeted deletion of Foxp1 or Foxp2 within mouse strains. *(d) represents different mouse strains that have whole‐body, heterozygous loss‐of‐function mutations in Foxp2 that include the following strains: Foxp2‐R552H‐KI, Foxp2‐R552H‐ENU, Foxp2‐S31X, and Foxp2‐ex7‐KO mice
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Structural and functional brain abnormalities in affected KE family members. (a) Brain regions containing sites of altered gray matter in KE family members affected by FOXP2 mutation. Regions altered in two or more structural MRI studies are shown. (b) Brain regions containing sites of altered neural activation in PET or fMRI studies of affected KE family members. MRI, magnetic resonance imaging; PET, Positron emission tomography
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FOXP1 and FOXP2 expression patterns in mammalian and zebra finch brain. Expression patterns of FOXP1 and FOXP2 in mammalian brain (left) and zebra finch brain (right) with major motor‐ and vocalization‐related circuits highlighted. CB, cerebellum; CTX, cortex; DLM, medial nucleus of dorsolateral thalamus; DM, dorsomedial nucleus of midbrain; DTZ, dorsal thalamic zone; HP, hippocampus, lMAN, lateral magnocellular nucleus of anterior nidopallium; M, mesopallium; nXIIts, tracheosyringeal subdivision of the hypoglossal nucleus; RA, arcopallial vocal nucleus; STR, striatum; THAL, thalamus
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Expression patterns of FOXPs over human brain development. Using RNA‐seq data from the BrainSpan Atlas of the Developing Human Brain (Li, Santpere, et al., 2018; Miller et al., ), log‐transformed reads per kilobase of transcript per million mapped reads (RPKM) values were plotted at each timepoint for FOXP1, FOXP2, and FOXP4 within distinct brain regions. Dotted line indicates last prenatal timepoint
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Cell type‐specific expression of FOXP transcription factors in forebrain regions. (a) Visualization of adult mouse single‐cell RNA‐seq data from Saunders et al. (). Visualization of Foxp1, Foxp2, and Foxp4 expression within the frontal and posterior cortex, striatum, and hippocampus using the DropViz tool (http://dropviz.org). Expression is shown in black with enriched clusters shaded in color. DG, dentate gyrus; Endo, endothelial cells; Entor, entorhinal cortex; L, layer; SPN, spiny projection neuron; Sub, subiculum. (b) Adult human cortical scRNA‐seq data showing the expression of FOXP1, FOXP2, and FOXP4 within the medial temporal gyrus from the Allen Brain Atlas tool (https://celltypes.brain‐map.org/rnaseq/human). Red indicates high expression, black indicates no expression. Ex, excitatory neurons; Int, interneurons; L, layer
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Nervous System Development > Vertebrates: Regional Development
Gene Expression and Transcriptional Hierarchies > Gene Networks and Genomics
Nervous System Development > Vertebrates: General Principles