The Experts below are selected from a list of 55506 Experts worldwide ranked by ideXlab platform
Simon E Fisher - One of the best experts on this subject based on the ideXlab platform.
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FOXP2 loss of function increases striatal direct pathway inhibition via increased gaba release
Brain Structure & Function, 2018Co-Authors: Jonruben Van Rhijn, Simon E Fisher, Sonja C Vernes, Nael Nadif KasriAbstract:Heterozygous mutations of the Forkhead-box protein 2 (FOXP2) gene in humans cause childhood apraxia of speech. Loss of FOXP2 in mice is known to affect striatal development and impair motor skills. However, it is unknown if striatal excitatory/inhibitory balance is affected during development and if the imbalance persists into adulthood. We investigated the effect of reduced FOXP2 expression, via a loss-of-function mutation, on striatal medium spiny neurons (MSNs). Our data show that heterozygous loss of FOXP2 decreases excitatory (AMPA receptor-mediated) and increases inhibitory (GABA receptor-mediated) currents in D1 dopamine receptor positive MSNs of juvenile and adult mice. Furthermore, reduced FOXP2 expression increases GAD67 expression, leading to both increased presynaptic content and release of GABA. Finally, pharmacological blockade of inhibitory activity in vivo partially rescues motor skill learning deficits in heterozygous FOXP2 mice. Our results suggest a novel role for FOXP2 in the regulation of striatal direct pathway activity through managing inhibitory drive.
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Mapping of Human FOXP2 Enhancers Reveals Complex Regulation
Frontiers in molecular neuroscience, 2018Co-Authors: Martin Becker, Simon E Fisher, Paolo Devanna, Sonja C VernesAbstract:Mutations of the FOXP2 gene cause a severe speech and language disorder, providing a molecular window into the neurobiology of language. Individuals with FOXP2 mutations have structural and functional alterations affecting brain circuits that overlap with sites of FOXP2 expression, including regions of the cortex, striatum, and cerebellum. FOXP2 displays complex patterns of expression in the brain, as well as in non-neuronal tissues, suggesting that sophisticated regulatory mechanisms control its temporal-spatial expression. However, to date, little is known about the regulation of FOXP2 or the genomic elements that control its expression. Using chromatin conformation capture (3C), we mapped the human FOXP2 locus to identify putative enhancer regions that engage in long-range interactions with the promoter of this gene. We demonstrate the ability of the identified enhancer regions to drive gene expression. We also show regulation of the FOXP2 promoter and enhancer regions by candidate regulators - FOXP family and TBR1 transcription factors. These data point to regulatory elements that may contribute to the temporal- or tissue-specific expression patterns of human FOXP2. Understanding the upstream regulatory pathways controlling FOXP2 expression will bring new insight into the molecular networks contributing to human language and related disorders.
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Functional characterization of rare FOXP2 variants in neurodevelopmental disorder
Journal of Neurodevelopmental Disorders, 2016Co-Authors: Sara B. Estruch, Sarah A. Graham, Pelagia Deriziotis, Swathi M. Chinnappa, Simon E FisherAbstract:Background Heterozygous disruption of FOXP2 causes a rare form of speech and language impairment. Screens of the FOXP2 sequence in individuals with speech/language-related disorders have identified several rare protein-altering variants, but their phenotypic relevance is often unclear. FOXP2 encodes a transcription factor with a forkhead box DNA-binding domain, but little is known about the functions of protein regions outside this domain. Methods We performed detailed functional analyses of seven rare FOXP2 variants found in affected cases, including three which have not been previously characterized, testing intracellular localization, transcriptional regulation, dimerization, and interaction with other proteins. To shed further light on molecular functions of FOXP2, we characterized the interaction between this transcription factor and co-repressor proteins of the C-terminal binding protein (CTBP) family. Finally, we analysed the functional significance of the polyglutamine tracts in FOXP2, since tract length variations have been reported in cases of neurodevelopmental disorder. Results We confirmed etiological roles of multiple FOXP2 variants. Of three variants that have been suggested to cause speech/language disorder, but never before been characterized, only one showed functional effects. For the other two, we found no effects on protein function in any assays, suggesting that they are incidental to the phenotype. We identified a CTBP-binding region within the N-terminal portion of FOXP2. This region includes two amino acid substitutions that occurred on the human lineage following the split from chimpanzees. However, we did not observe any effects of these amino acid changes on CTBP binding or other core aspects of FOXP2 function. Finally, we found that FOXP2 variants with reduced polyglutamine tracts did not exhibit altered behaviour in cellular assays, indicating that such tracts are non-essential for core aspects of FOXP2 function, and that tract variation is unlikely to be a highly penetrant cause of speech/language disorder. Conclusions Our findings highlight the importance of functional characterization of novel rare variants in FOXP2 in assessing the contribution of such variants to speech/language disorder and provide further insights into the molecular function of the FOXP2 protein.
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The language-related transcription factor FOXP2 is post-translationally modified with small ubiquitin-like modifiers
Scientific Reports, 2016Co-Authors: Sara B. Estruch, Sarah A. Graham, Pelagia Deriziotis, Simon E FisherAbstract:Mutations affecting the transcription factor FOXP2 cause a rare form of severe speech and language disorder. Although it is clear that sufficient FOXP2 expression is crucial for normal brain development, little is known about how this transcription factor is regulated. To investigate post-translational mechanisms for FOXP2 regulation, we searched for protein interaction partners of FOXP2 and identified members of the PIAS family as novel FOXP2 interactors. PIAS proteins mediate post-translational modification of a range of target proteins with small ubiquitin-like modifiers (SUMOs). We found that FOXP2 can be modified with all three human SUMO proteins and that PIAS1 promotes this process. An aetiological FOXP2 mutation found in a family with speech and language disorder markedly reduced FOXP2 SUMOylation. We demonstrate that FOXP2 is SUMOylated at a single major site, which is conserved in all FOXP2 vertebrate orthologues and in the paralogues FOXP1 and FOXP4. Abolishing this site did not lead to detectable changes in FOXP2 subcellular localization, stability, dimerization or transcriptional repression in cellular assays, but the conservation of this site suggests a potential role for SUMOylation in regulating FOXP2 activity in vivo .
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the forkhead transcription factor FOXP2 is required for regulation of p21waf1 cip1 in 143b osteosarcoma cell growth arrest
PLOS ONE, 2015Co-Authors: Duncan M Gascoyne, Simon E Fisher, Linden Lyne, Hayley Spearman, Rathi Puliyadi, Marta Perezalcantara, Les Coulton, Peter I Croucher, Alison H BanhamAbstract:Mutations of the forkhead transcription factor FOXP2 gene have been implicated in inherited speech-and-language disorders, and specific FOXP2 expression patterns in neuronal populations and neuronal phenotypes arising from FOXP2 disruption have been described. However, molecular functions of FOXP2 are not completely understood. Here we report a requirement for FOXP2 in growth arrest of the osteosarcoma cell line 143B. We observed endogenous expression of this transcription factor both transiently in normally developing murine osteoblasts and constitutively in human SAOS-2 osteosarcoma cells blocked in early osteoblast development. Critically, we demonstrate that in 143B osteosarcoma cells with minimal endogenous expression, FOXP2 induced by growth arrest is required for up-regulation of p21WAF1/CIP1. Upon growth factor withdrawal, FOXP2 induction occurs rapidly and precedes p21WAF1/CIP1 activation. Additionally, FOXP2 expression could be induced by MAPK pathway inhibition in growth-arrested 143B cells, but not in traditional cell line models of osteoblast differentiation (MG-63, C2C12, MC3T3-E1). Our data are consistent with a model in which transient upregulation of FOXP2 in pre-osteoblast mesenchymal cells regulates a p21-dependent growth arrest checkpoint, which may have implications for normal mesenchymal and osteosarcoma biology.
Sonja C Vernes - One of the best experts on this subject based on the ideXlab platform.
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FOXP2 loss of function increases striatal direct pathway inhibition via increased gaba release
Brain Structure & Function, 2018Co-Authors: Jonruben Van Rhijn, Simon E Fisher, Sonja C Vernes, Nael Nadif KasriAbstract:Heterozygous mutations of the Forkhead-box protein 2 (FOXP2) gene in humans cause childhood apraxia of speech. Loss of FOXP2 in mice is known to affect striatal development and impair motor skills. However, it is unknown if striatal excitatory/inhibitory balance is affected during development and if the imbalance persists into adulthood. We investigated the effect of reduced FOXP2 expression, via a loss-of-function mutation, on striatal medium spiny neurons (MSNs). Our data show that heterozygous loss of FOXP2 decreases excitatory (AMPA receptor-mediated) and increases inhibitory (GABA receptor-mediated) currents in D1 dopamine receptor positive MSNs of juvenile and adult mice. Furthermore, reduced FOXP2 expression increases GAD67 expression, leading to both increased presynaptic content and release of GABA. Finally, pharmacological blockade of inhibitory activity in vivo partially rescues motor skill learning deficits in heterozygous FOXP2 mice. Our results suggest a novel role for FOXP2 in the regulation of striatal direct pathway activity through managing inhibitory drive.
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mapping the distribution of language related genes foxp1 FOXP2 and cntnap2 in the brains of vocal learning bat species
The Journal of Comparative Neurology, 2018Co-Authors: Pedro Rodenascuadrado, Paolo Devanna, Janine Mengede, Laura Baas, Tobias Schmid, Michael M Yartsev, Uwe Firzlaff, Sonja C VernesAbstract:Genes including FOXP2, FOXP1, and CNTNAP2, have been implicated in human speech and language phenotypes, pointing to a role in the development of normal language-related circuitry in the brain. Although speech and language are unique to humans a comparative approach is possible by addressing language-relevant traits in animal systems. One such trait, vocal learning, represents an essential component of human spoken language, and is shared by cetaceans, pinnipeds, elephants, some birds and bats. Given their vocal learning abilities, gregarious nature, and reliance on vocalizations for social communication and navigation, bats represent an intriguing mammalian system in which to explore language-relevant genes. We used immunohistochemistry to detail the distribution of FOXP2, FoxP1, and Cntnap2 proteins, accompanied by detailed cytoarchitectural histology in the brains of two vocal learning bat species; Phyllostomus discolor and Rousettus aegyptiacus. We show widespread expression of these genes, similar to what has been previously observed in other species, including humans. A striking difference was observed in the adult P. discolor bat, which showed low levels of FOXP2 expression in the cortex that contrasted with patterns found in rodents and nonhuman primates. We created an online, open-access database within which all data can be browsed, searched, and high resolution images viewed to single cell resolution. The data presented herein reveal regions of interest in the bat brain and provide new opportunities to address the role of these language-related genes in complex vocal-motor and vocal learning behaviors in a mammalian model system.
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Mapping of Human FOXP2 Enhancers Reveals Complex Regulation
Frontiers in molecular neuroscience, 2018Co-Authors: Martin Becker, Simon E Fisher, Paolo Devanna, Sonja C VernesAbstract:Mutations of the FOXP2 gene cause a severe speech and language disorder, providing a molecular window into the neurobiology of language. Individuals with FOXP2 mutations have structural and functional alterations affecting brain circuits that overlap with sites of FOXP2 expression, including regions of the cortex, striatum, and cerebellum. FOXP2 displays complex patterns of expression in the brain, as well as in non-neuronal tissues, suggesting that sophisticated regulatory mechanisms control its temporal-spatial expression. However, to date, little is known about the regulation of FOXP2 or the genomic elements that control its expression. Using chromatin conformation capture (3C), we mapped the human FOXP2 locus to identify putative enhancer regions that engage in long-range interactions with the promoter of this gene. We demonstrate the ability of the identified enhancer regions to drive gene expression. We also show regulation of the FOXP2 promoter and enhancer regions by candidate regulators - FOXP family and TBR1 transcription factors. These data point to regulatory elements that may contribute to the temporal- or tissue-specific expression patterns of human FOXP2. Understanding the upstream regulatory pathways controlling FOXP2 expression will bring new insight into the molecular networks contributing to human language and related disorders.
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FOXP2 drives neuronal differentiation by interacting with retinoic acid signaling pathways
Frontiers in cellular neuroscience, 2014Co-Authors: Paolo Devanna, Jeroen Middelbeek, Sonja C VernesAbstract:FOXP2 was the first gene shown to cause a Mendelian form of speech and language disorder. Although developmentally expressed in many organs, loss of a single copy of FOXP2 leads to a phenotype that is largely restricted to orofacial impairment during articulation and linguistic processing deficits. Why perturbed FOXP2 function affects specific aspects of the developing brain remains elusive. We investigated the role of FOXP2 in neuronal differentiation and found that FOXP2 drives molecular changes consistent with neuronal differentiation in a human model system. We identified a network of FOXP2 regulated genes related to retinoic acid signaling and neuronal differentiation. FOXP2 also produced phenotypic changes associated with neuronal differentiation including increased neurite outgrowth and reduced migration. Crucially, cells expressing FOXP2 displayed increased sensitivity to retinoic acid exposure. This suggests a mechanism by which FOXP2 may be able to increase the cellular differentiation response to environmental retinoic acid cues for specific subsets of neurons in the brain. These data demonstrate that FOXP2 promotes neuronal differentiation by interacting with the retinoic acid signaling pathway and regulates key processes required for normal circuit formation such as neuronal migration and neurite outgrowth. In this way, FOXP2, which is found only in specific subpopulations of neurons in the brain, may drive precise neuronal differentiation patterns and/or control localization and connectivity of these FOXP2 positive cells.
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molecular networks implicated in speech related disorders FOXP2 regulates the srpx2 upar complex
Human Molecular Genetics, 2010Co-Authors: Patrice Roll, Sonja C Vernes, Nadine Bruneau, Jennifer Cillario, Annick Massacrier, Magali PonsolelenfantAbstract:It is a challenge to identify the molecular networks contributing to the neural basis of human speech. Mutations in transcription factor FOXP2 cause difficulties mastering fluent speech (developmental verbal dyspraxia, DVD), whereas mutations of sushi-repeat protein SRPX2 lead to epilepsy of the rolandic (sylvian) speech areas, with DVD or with bilateral perisylvian polymicrogyria. Pathophysiological mechanisms driven by SRPX2 involve modified interaction with the plasminogen activator receptor (uPAR). Independent chromatin-immunoprecipitation microarray screening has identified the uPAR gene promoter as a potential target site bound by FOXP2. Here, we directly tested for the existence of a transcriptional regulatory network between human FOXP2 and the SRPX2/uPAR complex. In silico searches followed by gel retardation assays identified specific efficient FOXP2-binding sites in each of the promoter regions of SRPX2 and uPAR. In FOXP2-transfected cells, significant decreases were observed in the amounts of both SRPX2 (43.6%) and uPAR (38.6%) native transcripts. Luciferase reporter assays demonstrated that FOXP2 expression yielded a marked inhibition of SRPX2 (80.2%) and uPAR (77.5%) promoter activity. A mutant FOXP2 that causes DVD (p.R553H) failed to bind to SRPX2 and uPAR target sites and showed impaired down-regulation of SRPX2 and uPAR promoter activity. In a patient with polymicrogyria of the left rolandic operculum, a novel FOXP2 mutation (p.M406T) was found in the leucine-zipper (dimerization) domain. p.M406T partially impaired the FOXP2 regulation of SRPX2 promoter activity, whereas that of the uPAR promoter remained unchanged. Together with recently described FOXP2-CNTNAP2 and SRPX2/uPAR links, the FOXP2-SRPX2/uPAR network provides exciting insights into molecular pathways underlying speech-related disorders.
Annick Massacrier - One of the best experts on this subject based on the ideXlab platform.
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molecular networks implicated in speech related disorders FOXP2 regulates the srpx2 upar complex
Human Molecular Genetics, 2010Co-Authors: Patrice Roll, Sonja C Vernes, Nadine Bruneau, Jennifer Cillario, Annick Massacrier, Magali PonsolelenfantAbstract:It is a challenge to identify the molecular networks contributing to the neural basis of human speech. Mutations in transcription factor FOXP2 cause difficulties mastering fluent speech (developmental verbal dyspraxia, DVD), whereas mutations of sushi-repeat protein SRPX2 lead to epilepsy of the rolandic (sylvian) speech areas, with DVD or with bilateral perisylvian polymicrogyria. Pathophysiological mechanisms driven by SRPX2 involve modified interaction with the plasminogen activator receptor (uPAR). Independent chromatin-immunoprecipitation microarray screening has identified the uPAR gene promoter as a potential target site bound by FOXP2. Here, we directly tested for the existence of a transcriptional regulatory network between human FOXP2 and the SRPX2/uPAR complex. In silico searches followed by gel retardation assays identified specific efficient FOXP2-binding sites in each of the promoter regions of SRPX2 and uPAR. In FOXP2-transfected cells, significant decreases were observed in the amounts of both SRPX2 (43.6%) and uPAR (38.6%) native transcripts. Luciferase reporter assays demonstrated that FOXP2 expression yielded a marked inhibition of SRPX2 (80.2%) and uPAR (77.5%) promoter activity. A mutant FOXP2 that causes DVD (p.R553H) failed to bind to SRPX2 and uPAR target sites and showed impaired down-regulation of SRPX2 and uPAR promoter activity. In a patient with polymicrogyria of the left rolandic operculum, a novel FOXP2 mutation (p.M406T) was found in the leucine-zipper (dimerization) domain. p.M406T partially impaired the FOXP2 regulation of SRPX2 promoter activity, whereas that of the uPAR promoter remained unchanged. Together with recently described FOXP2-CNTNAP2 and SRPX2/uPAR links, the FOXP2-SRPX2/uPAR network provides exciting insights into molecular pathways underlying speech-related disorders.
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Molecular networks implicated in speech-related disorders: FOXP2 regulates the SRPX2/uPAR complex
Human molecular genetics, 2010Co-Authors: Patrice Roll, Sonja C Vernes, Nadine Bruneau, Jennifer Cillario, Magali Ponsole-lenfant, Annick Massacrier, Gabrielle Rudolf, Manal Khalife, Edouard Hirsch, Simon E FisherAbstract:It is a challenge to identify the molecular networks contributing to the neural basis of human speech. Mutations in transcription factor FOXP2 cause difficulties mastering fluent speech (developmental verbal dyspraxia, DVD), whereas mutations of sushi-repeat protein SRPX2 lead to epilepsy of the rolandic (sylvian) speech areas, with DVD or with bilateral perisylvian polymicrogyria. Pathophysiological mechanisms driven by SRPX2 involve modified interaction with the plasminogen activator receptor (uPAR). Independent chromatin-immunoprecipitation microarray screening has identified the uPAR gene promoter as a potential target site bound by FOXP2. Here, we directly tested for the existence of a transcriptional regulatory network between human FOXP2 and the SRPX2/uPAR complex. In silico searches followed by gel retardation assays identified specific efficient FOXP2-binding sites in each of the promoter regions of SRPX2 and uPAR. In FOXP2-transfected cells, significant decreases were observed in the amounts of both SRPX2 (43.6%) and uPAR (38.6%) native transcripts. Luciferase reporter assays demonstrated that FOXP2 expression yielded a marked inhibition of SRPX2 (80.2%) and uPAR (77.5%) promoter activity. A mutant FOXP2 that causes DVD (p.R553H) failed to bind to SRPX2 and uPAR target sites and showed impaired down-regulation of SRPX2 and uPAR promoter activity. In a patient with polymicrogyria of the left rolandic operculum, a novel FOXP2 mutation (p.M406T) was found in the leucine-zipper (dimerization) domain. p.M406T partially impaired the FOXP2 regulation of SRPX2 promoter activity, whereas that of the uPAR promoter remained unchanged. Together with recently described FOXP2-CNTNAP2 and SRPX2/uPAR links, the FOXP2-SRPX2/uPAR network provides exciting insights into molecular pathways underlying speech-related disorders.
Stephanie A. White - One of the best experts on this subject based on the ideXlab platform.
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beyond critical period learning striatal FOXP2 affects the active maintenance of learned vocalizations in adulthood
eNeuro, 2019Co-Authors: Nancy F Day, Jonathan B Heston, Taylor G Hobbs, Stephanie A. WhiteAbstract:In humans, mutations in the transcription factor forkhead box P2 (FOXP2) result in language disorders associated with altered striatal structure. Like speech, birdsong is learned through social interactions during maturational critical periods, and it relies on auditory feedback during initial learning and on-going maintenance. Hearing loss causes learned vocalizations to deteriorate in adult humans and songbirds. In the adult songbird brain, most FOXP2-enriched regions (e.g., cortex, thalamus) show a static expression level, but in the striatal song control nucleus, area X, FOXP2 is regulated by singing and social context: when juveniles and adults sing alone, its levels drop, and songs are more variable. When males sing to females, FOXP2 levels remain high, and songs are relatively stable: this "on-line" regulation implicates FOXP2 in ongoing vocal processes, but its role in the auditory-based maintenance of learned vocalization has not been examined. To test this, we overexpressed FOXP2 in both hearing and deafened adult zebra finches and assessed effects on song sung alone versus songs directed to females. In intact birds singing alone, no changes were detected between songs of males expressing FOXP2 or a GFP construct in area X, consistent with the marked stability of mature song in this species. In contrast, songs of males overexpressing FOXP2 became more variable and were less preferable to females, unlike responses to songs of GFP-expressing control males. In deafened birds, song deteriorated more rapidly following FOXP2 overexpression relative to GFP controls. Together, these experiments suggest that behavior-driven FOXP2 expression and auditory feedback interact to precisely maintain learned vocalizations.
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differential FOXP2 and foxp1 expression in a vocal learning nucleus of the developing budgerigar
Developmental Neurobiology, 2015Co-Authors: Osceola Whitney, Stephanie A. White, Tawni Voyles, Erina Hara, Qianqian Chen, Timothy F WrightAbstract:The forkhead domain FOXP2 and FOXP1 transcription factors are implicated in several cognitive disorders with language deficits, notably autism, and thus play a central role in learned vocal motor behavior in humans. Although a similar role for FOXP2 and FoxP1 is proposed for other vertebrate species, including songbirds, the neurodevelopmental expression of these genes are unknown in a species with lifelong vocal learning abilities. Like humans, budgerigars (Melopsittacus undulatus) learn new vocalizations throughout their entire lifetime. Like songbirds, budgerigars have distinct brain nuclei for vocal learning, which include the magnocellular nucleus of the medial striatum (MMSt), a basal ganglia region that is considered developmentally and functionally analogous to Area X in songbirds. Here, we used in situ hybridization and immunohistochemistry to investigate FOXP2 and FoxP1 expression in the MMSt of juvenile and adult budgerigars. We found FOXP2 mRNA and protein expression levels in the MMSt that were lower than the surrounding striatum throughout development and adulthood. In contrast, FoxP1 mRNA and protein had an elevated MMSt/striatum expression ratio as birds matured, regardless of their sex. These results show that life-long vocal plasticity in budgerigars is associated with persistent low-level FOXP2 expression in the budgerigar MMSt, and suggests the possibility that FoxP1 plays an organizational role in the neurodevelopment of vocal motor circuitry. Thus, developmental regulation of the FOXP2 and FoxP1 genes in the basal ganglia appears essential for vocal mimicry in a range of species that possess this relatively rare trait.
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behavior linked FOXP2 regulation enables zebra finch vocal learning
The Journal of Neuroscience, 2015Co-Authors: Jonathan B Heston, Stephanie A. WhiteAbstract:Mutations in the FOXP2 transcription factor cause an inherited speech and language disorder, but how FOXP2 contributes to learning of these vocal communication signals remains unclear. FOXP2 is enriched in corticostriatal circuits of both human and songbird brains. Experimental knockdown of this enrichment in song control neurons of the zebra finch basal ganglia impairs tutor song imitation, indicating that adequate FOXP2 levels are necessary for normal vocal learning. In unmanipulated birds, vocal practice acutely downregulates FOXP2, leading to increased vocal variability and dynamic regulation of FOXP2 target genes. To determine whether this behavioral regulation is important for song learning, here, we used viral-driven overexpression of FOXP2 to counteract its downregulation. This manipulation disrupted the acute effects of song practice on vocal variability and caused inaccurate song imitation. Together, these findings indicate that dynamic behavior-linked regulation of FOXP2, rather than absolute levels, is critical for vocal learning.
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expression analysis of the speech related genes foxp1 and FOXP2 and their relation to singing behavior in two songbird species
The Journal of Experimental Biology, 2013Co-Authors: Qianqian Chen, Jonathan B Heston, Zachary D Burkett, Stephanie A. WhiteAbstract:Humans and songbirds are among the rare animal groups that exhibit socially learned vocalizations: speech and song, respectively. These vocal-learning capacities share a reliance on audition and cortico-basal ganglia circuitry, as well as neurogenetic mechanisms. Notably, the transcription factors Forkhead box proteins 1 and 2 (FoxP1, FOXP2) exhibit similar expression patterns in the cortex and basal ganglia of humans and the zebra finch species of songbird, among other brain regions. Mutations in either gene are associated with language disorders in humans. Experimental knock-down of FOXP2 in the basal ganglia song control region Area X during song development leads to imprecise copying of tutor songs. Moreover, FOXP2 levels decrease naturally within Area X when zebra finches sing. Here, we examined neural expression patterns of FoxP1 and FOXP2 mRNA in adult Bengalese finches, a songbird species whose songs exhibit greater sequence complexity and increased reliance on audition for maintaining their quality. We found that FoxP1 and FOXP2 expression in Bengalese finches is similar to that in zebra finches, including strong mRNA signals for both factors in multiple song control nuclei and enhancement of FoxP1 in these regions relative to surrounding brain tissue. As with zebra finches, when Bengalese finches sing, FOXP2 is behaviorally downregulated within basal ganglia Area X over a similar time course, and expression negatively correlates with the amount of singing. This study confirms that in multiple songbird species, FoxP1 expression highlights song control regions, and regulation of FOXP2 is associated with motor control of song.
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Striatal FOXP2 Is Actively Regulated during Songbird Sensorimotor Learning
PloS one, 2010Co-Authors: Ikuko Teramitsu, Amy Poopatanapong, Salvatore Torrisi, Stephanie A. WhiteAbstract:Mutations in the FOXP2 transcription factor lead to language disorders with developmental onset. Accompanying structural abnormalities in cortico-striatal circuitry indicate that at least a portion of the behavioral phenotype is due to organizational deficits. We previously found parallel FOXP2 expression patterns in human and songbird cortico/pallio-striatal circuits important for learned vocalizations, suggesting that FOXP2's function in birdsong may generalize to speech.We used zebra finches to address the question of whether FOXP2 is additionally important in the post-organizational function of these circuits. In both humans and songbirds, vocal learning depends on auditory guidance to achieve and maintain optimal vocal output. We tested whether deafening prior to or during the sensorimotor phase of song learning disrupted FOXP2 expression in song circuitry. As expected, the songs of deafened juveniles were abnormal, however basal FOXP2 levels were unaffected. In contrast, when hearing or deaf juveniles sang for two hours in the morning, FOXP2 was acutely down-regulated in the striatal song nucleus, area X. The extent of down-regulation was similar between hearing and deaf birds. Interestingly, levels of FOXP2 and singing were correlated only in hearing birds.Hearing appears to link FOXP2 levels to the amount of vocal practice. As juvenile birds spent more time practicing than did adults, their FOXP2 levels are likely to be low more often. Behaviorally-driven reductions in the mRNA encoding this transcription factor could ultimately affect downstream molecules that function in vocal exploration, especially during sensorimotor learning.
Constance Scharff - One of the best experts on this subject based on the ideXlab platform.
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CNTNAP2 is a direct FOXP2 target in vitro and in vivo in zebra finches: complex regulation by age and activity
Genes brain and behavior, 2017Co-Authors: Iris Adam, Ezequiel Mendoza, Ursula Kobalz, Sandra Wohlgemuth, Constance ScharffAbstract:Mutations of FOXP2 are associated with altered brain structure, including the striatal part of the basal ganglia, and cause a severe speech and language disorder. Songbirds serve as a tractable neurobiological model for speech and language research. Experimental downregulation of FOXP2 in zebra finch Area X, a nucleus of the striatal song control circuitry, affects synaptic transmission and spine densities. It also renders song learning and production inaccurate and imprecise, similar to the speech impairment of patients carrying FOXP2 mutations. Here we show that experimental downregulation of FOXP2 in Area X using lentiviral vectors leads to reduced expression of CNTNAP2, a FOXP2 target gene in humans. In addition, natural downregulation of FOXP2 by age or by singing also downregulated CNTNAP2 expression. Furthermore, we report that FOXP2 binds to and activates the avian CNTNAP2 promoter in vitro. Taken together these data establish CNTNAP2 as a direct FOXP2 target gene in songbirds, likely affecting synaptic function relevant for song learning and song maintenance.
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FOXP2 directly regulates the reelin receptor VLDLR developmentally and by singing
Molecular and cellular neurosciences, 2016Co-Authors: Iris Adam, Ezequiel Mendoza, Ursula Kobalz, Sandra Wohlgemuth, Constance ScharffAbstract:Mutations of the transcription factor FOXP2 cause a severe speech and language disorder. In songbirds, FOXP2 is expressed in the medium spiny neurons (MSNs) of the avian basal ganglia song nucleus, Area X, which is crucial for song learning and adult song performance. Experimental downregulation of FOXP2 in Area X affects spine formation, prevents neuronal plasticity induced by social context and impairs song learning. Direct target genes of FOXP2 relevant for song learning and song production are unknown. Here we show that a lentivirally mediated FOXP2 knockdown in Area X of zebra finches downregulates the expression of VLDLR, one of the two reelin receptors. Zebra finch FOXP2 binds to the promoter of VLDLR and activates it, establishing VLDLR as a direct FOXP2 target. Consistent with these findings, VLDLR expression is co-regulated with FOXP2 as a consequence of adult singing and during song learning. We also demonstrate that knockdown of FOXP2 affects glutamatergic transmission at the corticostriatal MSN synapse. These data raise the possibility that the regulatory relationship between FOXP2 and VLDLR guides structural plasticity towards the subset of FOXP2-positive MSNs in an activity dependent manner via the reelin pathway.
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FOXP2 in songbirds
Current opinion in neurobiology, 2014Co-Authors: Sandra Wohlgemuth, Iris Adam, Constance ScharffAbstract:Humans with mutations in the transcription factor FOXP2 display a severe speech disorder. Songbirds are a powerful model system to study FOXP2. Like humans, songbirds communicate via vocalizations that are imitatively learned during critical periods and this learning is influenced by social factors and relies on functionally lateralized neural circuits. During the past five years significant progress has been made moving from a descriptive to a more mechanistic understanding of how FOXP2 functions in songbirds. Current evidence from molecular and electrophysiological studies indicates that FOXP2 is important for shaping synaptic plasticity of specific neuron populations. One future goal will be to identify the transcriptional regulation orchestrated by FOXP2 and its associated molecular network that brings about these physiological effects. This will be key to further unravel how FOXP2 influences synaptic function and thereby contributes to auditory guided vocal motor behavior in the songbird model.
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diminished FOXP2 levels affect dopaminergic modulation of corticostriatal signaling important to song variability
Neuron, 2013Co-Authors: Malavika Murugan, Constance Scharff, Stephen C Harward, Richard MooneyAbstract:Mutations of the FOXP2 gene impair speech and language development in humans and shRNA-mediated suppression of the avian ortholog FOXP2 disrupts song learning in juvenile zebra finches. How diminished FOXP2 levels affect vocal control and alter the function of neural circuits important to learned vocalizations remains unclear. Here we show that FOXP2 knockdown in the songbird striatum disrupts developmental and social modulation of song variability. Recordings in anesthetized birds show that FOXP2 knockdown interferes with D1R-dependent modulation of activity propagation in a corticostriatal pathway important to song variability, an effect that may be partly attributable to reduced D1R and DARPP-32 protein levels. Furthermore, recordings in singing birds reveal that FOXP2 knockdown prevents social modulation of singing-related activity in this pathway. These findings show that reduced FOXP2 levels interfere with the dopaminergic modulation of vocal variability, which may impede song and speech development by disrupting reinforcement learning mechanisms.
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young and intense FOXP2 immunoreactivity in area x varies with age song stereotypy and singing in male zebra finches
Frontiers in Neural Circuits, 2013Co-Authors: Christopher K Thompson, Ezequiel Mendoza, Fabian Schwabe, Alexander Schoof, Jutta Gampe, Christelle Rochefort, Constance ScharffAbstract:FOXP2 is a transcription factor functionally relevant for learned vocalizations in humans and songbirds. In songbirds, FOXP2 mRNA expression in the medium spiny neurons of the basal ganglia song nucleus Area X is developmentally regulated and varies with singing conditions in different social contexts. How individual neurons in Area X change FOXP2 expression across development and in social contexts is not known, however. Here we address this critical gap in our understanding of FOXP2 as a link between neuronal networks and behavior. We used a statistically unbiased analysis of FOXP2-immunoreactivity (IR) on a neuron-by-neuron basis and found a bimodal distribution of FOXP2-IR neurons in Area X: weakly-stained and intensely-stained. The density of intensely-stained FOXP2-IR neurons was 10 times higher in juveniles than in adults, exponentially decreased with age, and was negatively correlated with adult song stability. Three-week old neurons labeled with BrdU were more than five times as likely to be intensely-stained than weakly-stained. The density of FOXP2-IR putative migratory neurons with fusiform-shaped nuclei substantially decreased as birds aged. The density of intensely-stained FOXP2-IR neurons was not affected by singing whereas the density of weakly-stained FOXP2-IR neurons was. Together, these data indicate that young Area X medium spiny neurons express FOXP2 at high levels and decrease expression as they become integrated into existing neural circuits. Once integrated, levels of FOXP2 expression correlate with singing behavior. Together, these findings raise the possibility that FOXP2 levels may orchestrate song learning and song stereotypy in adults by a common mechanism.
