Human-specific transcriptional regulation of CNS development genes by FOXP2
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ABSTRACT:
OTHER RELATED OMICS DATASETS IN: GSE18142
PROVIDER: PRJNA119431 | ENA |
REPOSITORIES: ENA
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Project description:The signaling pathways orchestrating both the evolution and development of language in the human brain remain unknown. To date, the transcription factor FOXP2 is the only gene implicated in Mendelian forms of human speech and language dysfunction1,2. It has been proposed, that the amino acid composition in the human variant of FOXP2 has undergone accelerated evolution, and this change occurred around the time of language emergence in humans3,4. However, this remains controversial, and whether the acquisition of these amino acids in human FOXP2 has any functional consequence in human neurons remains untested. Here, we demonstrate that these two amino acids confer new functionality in terms of differential transcriptional regulation, and extend these observations to in vivo brain, showing that several of the differential FOXP2 targets significantly overlap with genes different between human and chimpanzee brain. We also identify novel relationships among the differentially expressed genes with additional critical regulators of neuronal development. These data provide support for the functional relevance of changes that occur on the human lineage by showing that the two amino acids unique to human FOXP2 can lead to significant differences in gene expression patterns across brain evolution, with direct consequences for human brain development and disease. Since FOXP2 has an important role in the use of language in humans, the identified targets may have a critical function in the development and evolution of language circuitry in humans.
2009-11-12 | GSE18142 | GEO
Project description:The signalling pathways controlling both the evolution and development of language in the human brain remain unknown. So far, the transcription factor FOXP2 (forkhead box P2) is the only gene implicated in Mendelian forms of human speech and language dysfunction. It has been proposed that the amino acid composition in the human variant of FOXP2 has undergone accelerated evolution, and this two-amino-acid change occurred around the time of language emergence in humans. However, this remains controversial, and whether the acquisition of these amino acids in human FOXP2 has any functional consequence in human neurons remains untested. Here we demonstrate that these two human-specific amino acids alter FOXP2 function by conferring differential transcriptional regulation in vitro. We extend these observations in vivo to human and chimpanzee brain, and use network analysis to identify novel relationships among the differentially expressed genes. These data provide experimental support for the functional relevance of changes in FOXP2 that occur on the human lineage, highlighting specific pathways with direct consequences for human brain development and disease in the central nervous system (CNS). Because FOXP2 has an important role in speech and language in humans, the identified targets may have a critical function in the development and evolution of language circuitry in humans.
| S-EPMC2778075 | biostudies-literature
Project description:Mutations in FOXP2, a member of the forkhead family of transcription factors, are the only known cause of developmental speech and language disorders in humans. To date, there are no known targets of human FOXP2 in the nervous system. The identification of FOXP2 targets in the developing human brain therefore provides a unique tool with which to explore the development of human language and speech. Here we define FOXP2 targets in human basal ganglia (BG) and inferior frontal cortex (IFC) utilizing chromatin immunoprecipitation followed by microarray analysis (ChIP-chip) and validate the functional regulation of targets in vitro. ChIP-chip identified 285 FOXP2 targets in fetal human brain; significant overlap of targets in BG and IFC, indicate a core set of 34 transcriptional targets of FOXP2. We identified targets specific to the IFC or BG, not observed in lung, suggesting important regional and tissue differences in FOXP2 activity. Many target genes are known to play critical roles in specific aspects of CNS patterning or development, such as neurite outgrowth, as well as plasticity. Subsets of the FOXP2 transcriptional targets are either under positive selection in humans, or differentially expressed between human and chimpanzee brain. This is the first ChIP-chip study using human brain tissue, making the FOXP2 target genes identified in these studies important to understanding the pathways regulating speech and language in the developing human brain. These data provide the first insight into the functional network of genes directly regulated by FOXP2 in human brain and by evolutionary comparisons, highlight genes likely to be involved in the development of human higher order cognitive processes. Keywords: ChIP-chip
2007-12-31 | GSE8547 | GEO
Project description:To study the underlying mechanism of tumor initation driven by FOXP2, we performed transcriptome analysis of transformed NIH3T3 overexpressing FOXP2 or FOXP2-CEPD1 and control cells to explore the FOXP2-related transcriptome in tumorigenesis.
2019-05-08 | GSE114350 | GEO
Project description:In humans, mutations in the transcription factor encoding gene, FOXP2, are associated with language and Autism Spectrum (ASD) Disorders, the latter characterized by deficits in social interactions. However, little is known regarding the function of Foxp2 in male or female social behavior. Our previous studies in mice revealed high expression of Foxp2 within the medial subnucleus of the amygdala (MeA), a limbic brain region highly implicated in innate social behaviors such as mating, aggression, and parental care. Here, using a comprehensive panel of behavioral tests in male and female Foxp2+/- heterozygous mice, we investigated the role Foxp2 plays in MeA-linked innate social behaviors. We reveal significant deficits in olfactory processing, social interaction, mating, aggressive and parental behaviors. Interestingly, some of these deficits displayed in a sex-specific manner. To examine the consequences of Foxp2 loss of function specifically in the MeA, we conducted a proteomic analysis of microdissected MeA tissue and found sex differences in a host of proteins implicated in neuronal communication, connectivity and dopamine signaling. Consistent with this, we discovered that MeA Foxp2-lineage cells were responsive to dopamine with differences between males and females. Thus, our findings reveal a central and sex-specific role for Foxp2 in social behavior and MeA function.
2021-07-07 | PXD026978 | Pride
Project description:FOXP2 is a forkhead transcription factor critical for normal development of language in humans, but little is known of its broader function and regulation during central nervous system (CNS) development. We report here that lef1, a member of the Lef/Tcf family of transcription factors activated by Wnt signaling, regulates foxP2 during embryogenesis, and we isolate novel foxP2 enhancers which are lef1-dependent.Loss, knock down, or inhibition of lef1 led to loss of foxP2 expression. We isolated DNA fragments from the foxP2 genomic region that function as enhancers to drive GFP expression in the CNS during development, including in the telencephalon, diencephalon, eye, tectum, and hindbrain. Three of these enhancers, foxP2-enhancerA.1, foxP2-enhancerB, and foxP2-enhancerD, contain putative Lef1 binding sites, and are regulated by lef1. However, two other genomic fragments containing Lef1 sites failed to function in vivo as enhancers. Chromatin immunoprecipitation confirmed that Lef1 binds to sites in foxP2-enhancerA.1 and foxP2-enhancerB.This work shows that lef1 is necessary for expression of foxP2 in the tectum, mid-hindbrain boundary, and hindbrain during CNS development, and is the first insight into the upstream regulation of foxP2 during development. We also demonstrate that in silico prediction of potential lef1 binding sites poorly predicts their ability to function in vivo as enhancers. The foxP2 enhancers we identified will allow dissection of foxP2's role during CNS development.
| S-EPMC2579431 | biostudies-literature
Project description:It has been proposed that two amino acid substitutions in the transcription factor FOXP2 have been positively selected during human evolution due to effects on aspects of speech and language. Here, we introduce these substitutions into the endogenous Foxp2 gene.of mice. Although these mice are generally healthy, they have qualitatively different ultrasonic vocalizations, decreased exploratory behavior and decreased dopamine concentrations in the brain suggesting an effect of the humanized Foxp2 allele on basal ganglia. In the striatum, a part of the basal ganglia that is affected in humans with a speech deficit due to one non-functional FOXP2 allele, we find that medium spiny neurons have increased dendrite lengths and increased synaptic plasticity. Since mice carrying one non-functional Foxp2 allele show opposite effects, this suggests that alterations in cortico-basal ganglia circuits might have been important for the evolution of speech and language in humans. In this particular experiment, we investigate the effects of human Foxp2 (Foxp2hum) and the non-functional Foxp2 allele on striatal gene expression in embryonic, young and adult mice. We determined genome-wide gene expression patterns in striatal biopsies from Foxp2hum/hum, Foxp2wt/ko and Foxp2wt/wt mice using high-density oligonucleotide arrays. The animals were derived from two independent FoxP2 knock-in strains and one knock-out strain. In total 71 animals were used, 29 males and 42 females. The mice ages were E16.5, P15, P18, P21 and P95 when sacrificed. The microarrays were processed in totally six batches.
2010-05-22 | E-GEOD-13588 | biostudies-arrayexpress
Project description:We observed different gene expression by overexpressing the transcription factor FOXP2 in U2OS cells compared to mock-transfected cells. Additionally, we found β-catenin as co-activator binding directly to FOXP2. Activation of Wnt signaling was changing the transcriptional activity of FOXP2. Other functional and regulatory elements were found within FOXP2 and were confirmed by RNA-Seq.
2020-06-01 | GSE138938 | GEO
Project description:It has been proposed that two amino acid substitutions in the transcription factor FOXP2 have been positively selected during human evolution due to effects on aspects of speech and language. Here, we introduce these substitutions into the endogenous Foxp2 gene.of mice. Although these mice are generally healthy, they have qualitatively different ultrasonic vocalizations, decreased exploratory behavior and decreased dopamine concentrations in the brain suggesting an effect of the humanized Foxp2 allele on basal ganglia. In the striatum, a part of the basal ganglia that is affected in humans with a speech deficit due to one non-functional FOXP2 allele, we find that medium spiny neurons have increased dendrite lengths and increased synaptic plasticity. Since mice carrying one non-functional Foxp2 allele show opposite effects, this suggests that alterations in cortico-basal ganglia circuits might have been important for the evolution of speech and language in humans. In this particular experiment, we investigate the effects of human Foxp2 (Foxp2hum) and the non-functional Foxp2 allele on striatal gene expression in embryonic, young and adult mice.
2009-03-02 | GSE13588 | GEO
Project description:Alterations to corticostriatal glutamatergic function are early pathophysiological changes associated with Huntington?s disease (HD). The factors that regulate the maintenance of corticostriatal glutamatergic synapses post-developmentally are not well understood. Recently, the striatum-enriched transcription factor Foxp2 was implicated in the development of these synapses. Here we show that, in mice, overexpression of Foxp2 in the adult striatum of two models of HD leads to rescue of HD-associated behaviors, while knockdown of Foxp2 in wild-type mice leads to development of HD-associated behaviors. We note that Foxp2 encodes the longest polyglutamine repeat protein in the human reference genome, and we show that it can be sequestered into aggregates with polyglutamine-expanded mutant Huntingtin protein (mHTT). Foxp2 overexpression in HD model mice leads to altered expression of several genes associated with synaptic function, genes which present new targets for normalization of corticostriatal dysfunction in HD.
2017-12-05 | GSE104990 | GEO