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Edward E Morrisey - One of the best experts on this subject based on the ideXlab platform.
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FOXP1 4 control epithelial cell fate during lung development and regeneration through regulation of anterior gradient 2
Development, 2012Co-Authors: Yi Wang, Joseph D Dekker, Yuzhen Zhang, Philip W. Tucker, Francesco J Demayo, Edward E MorriseyAbstract:The molecular pathways regulating cell lineage determination and regeneration in epithelial tissues are poorly understood. The secretory epithelium of the lung is required for production of mucus to help protect the lung against environmental insults, including pathogens and pollution, that can lead to debilitating diseases such as asthma and chronic obstructive pulmonary disease. We show that the transcription factors FOXP1 and Foxp4 act cooperatively to regulate lung secretory epithelial cell fate and regeneration by directly restricting the goblet cell lineage program. Loss of FOXP1/4 in the developing lung and in postnatal secretory epithelium leads to ectopic activation of the goblet cell fate program, in part, through de-repression of the protein disulfide isomerase anterior gradient 2 (Agr2). Forced expression of Agr2 is sufficient to promote the goblet cell fate in the developing airway epithelium. Finally, in a model of lung secretory cell injury and regeneration, we show that loss of FOXP1/4 leads to catastrophic loss of airway epithelial regeneration due to default differentiation of secretory cells into the goblet cell lineage. These data demonstrate the importance of FOXP1/4 in restricting cell fate choices during development and regeneration, thereby providing the proper balance of functional epithelial lineages in the lung.
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FOXP1 2 4 nurd interactions regulate gene expression and epithelial injury response in the lung via regulation of interleukin 6
Journal of Biological Chemistry, 2010Co-Authors: Ann L Chokas, Philip W. Tucker, Chinmay M Trivedi, Jonathan A Epstein, Edward E MorriseyAbstract:To determine the underlying mechanism of FOXP1/2/4-mediated transcriptional repression, a yeast two-hybrid screen was performed that identified p66beta, a transcriptional repressor and component of the NuRD chromatin-remodeling complex. We show that direct interactions between FOXP1/4 and p66beta are mediated by the CR2 domain within p66beta and the zinc finger/leucine zipper repression domain found in FOXP1/2/4. These direct interactions are functionally relevant as overexpression of p66beta in combination with Foxp factors cooperatively represses Foxp target gene expression, whereas loss of p66 and Foxp factors results in de-repression of endogenous Foxp target genes in lung epithelial cells. Moreover, the NuRD components HDAC1/2 associate in a macromolecular complex with Foxp proteins, and loss of expression or inhibition of HDAC1/2 activity leads to de-repression of Foxp target gene expression. Importantly, we show in vivo that FOXP1 and HDAC2 act cooperatively to regulate expression of the cytoprotective cytokine interleukin-6, which results in increased resistance to hyperoxic lung injury in FOXP1/HDAC2 compound mutant animals. These data reveal an important interaction between the Foxp transcription factors and the NuRD chromatin-remodeling complex that modulates transcriptional repression critical for the lung epithelial injury response.
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Foxp2 and FOXP1 cooperatively regulate lung and esophagus development.
Development (Cambridge England), 2007Co-Authors: Weiguo Shu, Yuzhen Zhang, Philip W. Tucker, Deying Zhou, Edward E MorriseyAbstract:The airways of the lung develop through a reiterative process of branching morphogenesis that gives rise to the intricate and extensive surface area required for postnatal respiration. The forkhead transcription factors Foxp2 and FOXP1 are expressed in multiple foregut-derived tissues including the lung and intestine. In this report, we show that loss of Foxp2 in mouse leads to defective postnatal lung alveolarization, contributing to postnatal lethality. Using in vitro and in vivo assays, we show that T1alpha, a lung alveolar epithelial type 1 cell-restricted gene crucial for lung development and function, is a direct target of Foxp2 and FOXP1. Remarkably, loss of a single FOXP1 allele in addition to complete loss of Foxp2 results in increased severity of morphological defects in mutant lungs and leads to perinatal loss of all Foxp2-/-;FOXP1+/- mice. Expression of N-myc and Hop, crucial regulators of lung development, is compromised in Foxp2-/-;FOXP1+/- mutants. In addition to the defects in lung development, esophageal muscle development is disrupted in Foxp2-/-;FOXP1+/- embryos, a tissue where Foxp2 and FOXP1 are co-expressed. These data identify Foxp2 and FOXP1 as crucial regulators of lung and esophageal development, underscoring the necessity of these transcription factors in the development of anterior foregut-derived tissues and demonstrating functional cooperativity between members of the FOXP1/2/4 family in tissues where they are co-expressed.
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FoxP2 expression in avian vocal learners and non-learners.
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2004Co-Authors: Sebastian Haesler, Edward E Morrisey, Kazuhiro Wada, A. Nshdejan, Thierry Lints, Eric D. Jarvis, Constance ScharffAbstract:Most vertebrates communicate acoustically, but few, among them humans, dolphins and whales, bats, and three orders of birds, learn this trait. FOXP2 is the first gene linked to human speech and has been the target of positive selection during recent primate evolution. To test whether the expression pattern of FOXP2 is consistent with a role in learned vocal communication, we cloned zebra finch FoxP2 and its close relative FOXP1 and compared mRNA and protein distribution in developing and adult brains of a variety of avian vocal learners and non-learners, and a crocodile. We found that the protein sequence of zebra finch FoxP2 is 98% identical with mouse and human FOXP2. In the avian and crocodilian forebrain, FoxP2 was expressed predominantly in the striatum, a basal ganglia brain region affected in patients with FOXP2 mutations. Strikingly, in zebra finches, the striatal nucleus Area X, necessary for vocal learning, expressed more FoxP2 than the surrounding tissue at post-hatch days 35 and 50, when vocal learning occurs. In adult canaries, FoxP2 expression in Area X differed seasonally; more FoxP2 expression was associated with times when song becomes unstable. In adult chickadees, strawberry finches, song sparrows, and Bengalese finches, Area X expressed FoxP2 to different degrees. Non-telencephalic regions in both vocal learning and non-learning birds, and in crocodiles, were less variable in expression and comparable with regions that express FOXP2 in human and rodent brains. We conclude that differential expression of FoxP2 in avian vocal learners might be associated with vocal plasticity.
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transcriptional and dna binding activity of the FOXP1 2 4 family is modulated by heterotypic and homotypic protein interactions
Molecular and Cellular Biology, 2004Co-Authors: Shanru Li, Joel Weidenfeld, Edward E MorriseyAbstract:FOXP1, Foxp2, and Foxp4 are large multidomain transcriptional regulators belonging to the family of winged-helix DNA binding proteins known as the Fox family. FOXP1 and Foxp2 have been shown to act as transcriptional repressors, while regulatory activity of the recently identified Foxp4 has not been determined. Given the importance of this Fox gene subfamily in neural and lung development, we sought to elucidate the mechanisms by which FOXP1, Foxp2, and Foxp4 repress gene transcription. We show that like FOXP1 and Foxp2, Foxp4 represses transcription. Analysis of the N-terminal repression domain in FOXP1, Foxp2, and Foxp4 shows that this region contains two separate and distinct repression subdomains that are highly homologous termed subdomain 1 and subdomain 2. However, subdomain 2 is not functional in Foxp4. Screening for proteins that interact with subdomains 1 and 2 of Foxp2 using yeast two-hybrid analysis revealed that subdomain 2 binds to C-terminal binding protein 1, which can synergistically repress transcription with FOXP1 and Foxp2, but not Foxp4. Subdomain 1 contains a highly conserved leucine zipper similar to that found in N-myc and confers homo- and heterodimerization to the FOXP1/2/4 family members. These interactions are dependent on the conserved leucine zipper motif. Finally, we show that the integrity of this subdomain is essential for DNA binding, making FOXP1, Foxp2, and Foxp4 the first Fox proteins that require dimerization for DNA binding. These data reveal a complex regulatory mechanism underlying FOXP1, Foxp2, and Foxp4 activity, demonstrating that FOXP1, Foxp2, and Foxp4 are the first Fox proteins reported whose activity is regulated by homo- and heterodimerization.
Satoshi Inoue - One of the best experts on this subject based on the ideXlab platform.
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Integrative Analysis of FOXP1 Function Reveals a Tumor-Suppressive Effect in Prostate Cancer
Molecular endocrinology (Baltimore Md.), 2014Co-Authors: Ken-ichi Takayama, Takashi Suzuki, Shuichi Tsutsumi, Tetsuya Fujimura, Satoru Takahashi, Yukio Homma, Tomohiko Urano, Hiroyuki Aburatani, Satoshi InoueAbstract:The transcriptional network of the androgen receptor (AR), a key molecule of prostate cancer, is frequently modulated by interactions with other transcriptional factors such as forkhead box protein A1 (FOXA1). However, global regulatory mechanisms of AR signaling mediated by such factors have not been well investigated. Here we conducted a chromatin immunoprecipitation sequence analysis, which revealed that another FOX family, FOXP1, is specifically regulated by both AR and FOXA1. We also found that FOXP1 acts as a tumor suppressor in prostate cancer through inhibiting cell proliferation and migration. We generated an extensive global map of FOXP1 binding sites and found that FOXP1 is directly involved in AR-mediated transcription. We demonstrated that FOXP1 has a repressive effect on AR-induced transcriptional activity or histone modification in enhancer regions. Moreover, by a global analysis of androgen-mediated transcriptional networks, we observed enrichment of FOXP1 binding genes in the gene cluster...
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FOXP1 and estrogen signaling in breast cancer.
Vitamins and hormones, 2013Co-Authors: Nobuhiro Ijichi, Kazuhiro Ikeda, Kuniko Horie-inoue, Satoshi InoueAbstract:Breast cancers are considered to be primarily regulated by estrogen signaling pathways because estrogen-dependent proliferation is observed in the majority of breast cancer cases. Thus, hormone therapy using antiestrogen drugs such as tamoxifen is effective for breast cancers expressing estrogen receptor α (ERα). However, acquired resistance during the endocrine therapy is a critical unresolved problem in breast cancer. Recently, a forkhead transcription factor FOXA1 has been reported to play an important role in the regulation of ERα-mediated transcription and proliferation of breast cancer. Interestingly, immunohistochemical analysis of breast cancer specimens has revealed that nuclear immunoreactivities of FOXP1 as well as those of FOXA1 are positively correlated with hormone receptor status, including ERα and progesterone receptor. In particular, the double-positive immunoreactivities of FOXP1 and FOXA1 are significantly associated with a favorable prognosis for survival of breast cancer patients receiving adjuvant tamoxifen therapy. The functions of FOXP1 and FOXA1 have been characterized in cultured cells; further, similar to FOXA1, FOXP1 is assumed to be a critical transcription factor for ERα signaling, and both forkhead transcription factors can serve as predictive factors for acquired endocrine resistance in breast cancer.
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FOXP1 is an androgen responsive transcription factor that negatively regulates androgen receptor signaling in prostate cancer cells
Biochemical and Biophysical Research Communications, 2008Co-Authors: Ken-ichi Takayama, Kazuhiro Ikeda, Satoshi Inoue, Tomohiko Urano, Kuniko Horieinoue, Kayoko Murakami, Yoshihide Hayashizaki, Yasuyoshi OuchiAbstract:Androgen and androgen receptor (AR) play important roles in the formation and the progression of prostate cancer. AR activates its target genes by recruiting various coregulators and transcriptional factors. Here we show that the FOXP1 forkhead transcription factor is a novel androgen-regulated gene. By sequencing DNA fragments obtained from chromatin immunoprecipitation (ChIP), a bona-fide AR binding site (ARBS) is identified in an intron region of FOXP1 gene. FOXP1 can be induced by androgen in hormone-sensitive prostate cancer LNCaP cells at both mRNA and protein levels. In particular, a smaller FOXP1 variant, FOXP1D, is upregulated in response to androgen. Notably, we demonstrate that FOXP1 directly interacts with AR and negatively regulates AR signaling ligand-dependently, as exemplified by the transcriptional repression of PSA gene regulated by androgen-dependent FOXP1 recruitment on its enhancer region. We show that several other forkhead transcription factors are also androgen-responsive in LNCaP cells. Our study provides a new insight to the function of forkhead transcription factors that modulates AR signaling as an androgen-regulated transcriptional factor, which would contribute to the tumorigenesis of prostate cancer.
Anthony P Monaco - One of the best experts on this subject based on the ideXlab platform.
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identification of FOXP1 deletions in three unrelated patients with mental retardation and significant speech and language deficits
Human Mutation, 2010Co-Authors: Denise Horn, Johannes Kapeller, Nuria Riverabrugues, Ute Moog, Bettina Lorenzdepiereux, Maja Hempel, Janine Wagenstaller, Alex J T Gawthrope, Anthony P Monaco, Michael BoninAbstract:Mental retardation affects 2-3% of the population and shows a high heritability. Neurodevelopmental disorders that include pronounced impairment in language and speech skills occur less frequently. For most cases, the molecular basis of mental retardation with or without speech and language disorder is unknown due to the heterogeneity of underlying genetic factors. We have used molecular karyotyping on 1523 patients with mental retardation to detect copy number variations (CNVs) including deletions or duplications. These studies revealed three heterozygous overlapping deletions solely affecting the forkhead box P1 (FOXP1) gene. All three patients had moderate mental retardation and significant language and speech deficits. Since our results are consistent with a de novo occurrence of these deletions, we considered them as causal although we detected a single large deletion including FOXP1 and additional genes in 4104 ancestrally matched controls. These findings are of interest with regard to the structural and functional relationship between FOXP1 and FOXP2. Mutations in FOXP2 have been previously related to monogenic cases of developmental verbal dyspraxia. Both FOXP1 and FOXP2 are expressed in songbird and human brain regions that are important for the developmental processes that culminate in speech and language. ©2010 Wiley-Liss, Inc.
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Identification of FOXP1 deletions in three unrelated patients with mental retardation and significant speech and language deficits
Human Mutation, 2010Co-Authors: Denise Horn, Johannes Kapeller, Ute Moog, Maja Hempel, Janine Wagenstaller, Alex J T Gawthrope, Núria Rivera-brugués, Bettina Lorenz-depiereux, Sebastian Eck, Anthony P MonacoAbstract:Mental retardation affects 2-3% of the population and shows a high heritability. Neurodevelopmental disorders that include pronounced impairment in language and speech skills occur less frequently. For most cases, the molecular basis of mental retardation with or without speech and language disorder is unknown due to the heterogeneity of underlying genetic factors. We have used molecular karyotyping on 1523 patients with mental retardation to detect copy number variations (CNVs) including deletions or duplications. These studies revealed three heterozygous overlapping deletions solely affecting the forkhead box P1 (FOXP1) gene. All three patients had moderate mental retardation and significant language and speech deficits. Since our results are consistent with a de novo occurrence of these deletions, we considered them as causal although we detected a single large deletion including FOXP1 and additional genes in 4104 ancestrally matched controls. These findings are of interest with regard to the structural and functional relationship between FOXP1 and FOXP2. Mutations in FOXP2 have been previously related to monogenic cases of developmental verbal dyspraxia. Both FOXP1 and FOXP2 are expressed in songbird and human brain regions that are important for the developmental processes that culminate in speech and language.
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Assessing the impact of FOXP1 mutations on developmental verbal dyspraxia
European Journal of Human Genetics, 2009Co-Authors: Sonja C Vernes, Anthony P Monaco, Kay D Macdermot, Simon E FisherAbstract:Neurodevelopmental disorders that disturb speech and language are highly heritable. Isolation of the underlying genetic risk factors has been hampered by complexity of the phenotype and potentially large number of contributing genes. One exception is the identification of rare heterozygous mutations of the FOXP2 gene in a monogenic syndrome characterised by impaired sequencing of articulatory gestures, disrupting speech (developmental verbal dyspraxia, DVD), as well as multiple deficits in expressive and receptive language. The protein encoded by FOXP2 belongs to a divergent subgroup of forkhead-box transcription factors, with a distinctive DNA-binding domain and motifs that mediate hetero- and homodimerisation. FOXP1, the most closely related member of this subgroup, can directly interact with FOXP2 and is co-expressed in neural structures relevant to speech and language disorders. Moreover, investigations of songbird orthologues indicate that combinatorial actions of the two proteins may play important roles in vocal learning, leading to the suggestion that human FOXP1 should be considered a strong candidate for involvement in DVD. Thus, in this study, we screened the entire coding region of FOXP1 (exons and flanking intronic sequence) for nucleotide changes in a panel of probands used earlier to detect novel mutations in FOXP2 . A non-synonymous coding change was identified in a single proband, yielding a proline-to-alanine change (P215A). However, this was also found in a random control sample. Analyses of non-coding SNP changes did not find any correlation with affection status. We conclude that FOXP1 mutations are unlikely to represent a major cause of DVD.
Denise Horn - One of the best experts on this subject based on the ideXlab platform.
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FOXP1 mutations cause intellectual disability and a recognizable phenotype
American Journal of Medical Genetics Part A, 2013Co-Authors: Anna K. Le Fevre, Christopher W Carr, Denise Horn, Sharelle Taylor, Neva H. Malek, Omar A. Abdul-rahman, Sherindan O'donnell, Trent Burgess, Marie Shaw, Jozef GeczAbstract:Mutations in FOXP1, located at 3p13, have been reported in patients with global developmental delay (GDD), intellectual disability (ID), and speech defects. Mutations in FOXP2, located at 7q31, are well known to cause developmental speech and language disorders, particularly developmental verbal dyspraxia (DVD). FOXP2 has been shown to work co-operatively with FOXP1 in mouse development. An overlap in FOXP1 and FOXP2 expression, both in the songbird and human fetal brain, has suggested that FOXP1 may also have a role in speech and language disorders. We report on a male child with a 0.19 MB intragenic deletion that is predicted to result in haploinsufficiency of FOXP1. Review of our patient and others reported in the literature reveals an emerging phenotype of GDD/ID with moderate to severe speech delay where expressive speech is most severely affected. DVD appears not to be a distinct feature in this group. Facial features include a broad forehead, downslanting palpebral fissures, a short nose with broad tip, relative or true macrocephaly, a frontal hair upsweep and prominent digit pads. Autistic traits and other behavioral problems are likely to be associated with haploinsufficiency of FOXP1. Congenital malformations may be associated.
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identification of FOXP1 deletions in three unrelated patients with mental retardation and significant speech and language deficits
Human Mutation, 2010Co-Authors: Denise Horn, Johannes Kapeller, Nuria Riverabrugues, Ute Moog, Bettina Lorenzdepiereux, Maja Hempel, Janine Wagenstaller, Alex J T Gawthrope, Anthony P Monaco, Michael BoninAbstract:Mental retardation affects 2-3% of the population and shows a high heritability. Neurodevelopmental disorders that include pronounced impairment in language and speech skills occur less frequently. For most cases, the molecular basis of mental retardation with or without speech and language disorder is unknown due to the heterogeneity of underlying genetic factors. We have used molecular karyotyping on 1523 patients with mental retardation to detect copy number variations (CNVs) including deletions or duplications. These studies revealed three heterozygous overlapping deletions solely affecting the forkhead box P1 (FOXP1) gene. All three patients had moderate mental retardation and significant language and speech deficits. Since our results are consistent with a de novo occurrence of these deletions, we considered them as causal although we detected a single large deletion including FOXP1 and additional genes in 4104 ancestrally matched controls. These findings are of interest with regard to the structural and functional relationship between FOXP1 and FOXP2. Mutations in FOXP2 have been previously related to monogenic cases of developmental verbal dyspraxia. Both FOXP1 and FOXP2 are expressed in songbird and human brain regions that are important for the developmental processes that culminate in speech and language. ©2010 Wiley-Liss, Inc.
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Identification of FOXP1 deletions in three unrelated patients with mental retardation and significant speech and language deficits
Human Mutation, 2010Co-Authors: Denise Horn, Johannes Kapeller, Ute Moog, Maja Hempel, Janine Wagenstaller, Alex J T Gawthrope, Núria Rivera-brugués, Bettina Lorenz-depiereux, Sebastian Eck, Anthony P MonacoAbstract:Mental retardation affects 2-3% of the population and shows a high heritability. Neurodevelopmental disorders that include pronounced impairment in language and speech skills occur less frequently. For most cases, the molecular basis of mental retardation with or without speech and language disorder is unknown due to the heterogeneity of underlying genetic factors. We have used molecular karyotyping on 1523 patients with mental retardation to detect copy number variations (CNVs) including deletions or duplications. These studies revealed three heterozygous overlapping deletions solely affecting the forkhead box P1 (FOXP1) gene. All three patients had moderate mental retardation and significant language and speech deficits. Since our results are consistent with a de novo occurrence of these deletions, we considered them as causal although we detected a single large deletion including FOXP1 and additional genes in 4104 ancestrally matched controls. These findings are of interest with regard to the structural and functional relationship between FOXP1 and FOXP2. Mutations in FOXP2 have been previously related to monogenic cases of developmental verbal dyspraxia. Both FOXP1 and FOXP2 are expressed in songbird and human brain regions that are important for the developmental processes that culminate in speech and language.
Sonja C Vernes - One of the best experts on this subject based on the ideXlab platform.
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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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Assessing the impact of FOXP1 mutations on developmental verbal dyspraxia
European Journal of Human Genetics, 2009Co-Authors: Sonja C Vernes, Anthony P Monaco, Kay D Macdermot, Simon E FisherAbstract:Neurodevelopmental disorders that disturb speech and language are highly heritable. Isolation of the underlying genetic risk factors has been hampered by complexity of the phenotype and potentially large number of contributing genes. One exception is the identification of rare heterozygous mutations of the FOXP2 gene in a monogenic syndrome characterised by impaired sequencing of articulatory gestures, disrupting speech (developmental verbal dyspraxia, DVD), as well as multiple deficits in expressive and receptive language. The protein encoded by FOXP2 belongs to a divergent subgroup of forkhead-box transcription factors, with a distinctive DNA-binding domain and motifs that mediate hetero- and homodimerisation. FOXP1, the most closely related member of this subgroup, can directly interact with FOXP2 and is co-expressed in neural structures relevant to speech and language disorders. Moreover, investigations of songbird orthologues indicate that combinatorial actions of the two proteins may play important roles in vocal learning, leading to the suggestion that human FOXP1 should be considered a strong candidate for involvement in DVD. Thus, in this study, we screened the entire coding region of FOXP1 (exons and flanking intronic sequence) for nucleotide changes in a panel of probands used earlier to detect novel mutations in FOXP2 . A non-synonymous coding change was identified in a single proband, yielding a proline-to-alanine change (P215A). However, this was also found in a random control sample. Analyses of non-coding SNP changes did not find any correlation with affection status. We conclude that FOXP1 mutations are unlikely to represent a major cause of DVD.
