The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Edward E Morrisey - One of the best experts on this subject based on the ideXlab platform.
-
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.
-
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.
-
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.
-
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.
-
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.
Alexander Y Rudensky - One of the best experts on this subject based on the ideXlab platform.
-
transcription factor foxp1 regulates FOXP3 chromatin binding and coordinates regulatory t cell function
Nature Immunology, 2019Co-Authors: Catherine Konopacki, Yuri Pritykin, Yury P Rubtsov, Christina S Leslie, Alexander Y RudenskyAbstract:Regulatory T cells (Treg cells), whose differentiation and function are controlled by transcription factor FOXP3, express the closely related family member Foxp1. Here we explored Foxp1 function in Treg cells. We found that a large number of FOXP3-bound genomic sites in Treg cells were occupied by Foxp1 in both Treg cells and conventional T cells (Tconv cells). In Treg cells, Foxp1 markedly increased FOXP3 binding to these sites. Foxp1 deficiency in Treg cells resulted in their impaired function and competitive fitness, associated with markedly reduced CD25 expression and interleukin-2 (IL-2) responsiveness, diminished CTLA-4 expression and increased SATB1 expression. The characteristic expression patterns of CD25, FOXP3 and CTLA-4 in Treg cells were fully or partially rescued by strong IL-2 signaling. Our studies suggest that Foxp1 serves an essential non-redundant function in Treg cells by enforcing FOXP3-mediated regulation of gene expression and enabling efficient IL-2 signaling in these cells. The transcription factor Foxp1 regulates the quiescence of naive T cells. Rudensky and colleagues show that Foxp1 has a role that is cooperative and synergistic with that of FOXP3 in regulatory T cells, distinct from its roles in conventional CD4+ T cells.
-
transcription factor foxp1 regulates FOXP3 chromatin binding and coordinates regulatory t cell function
Nature Immunology, 2019Co-Authors: Catherine Konopacki, Yuri Pritykin, Yury P Rubtsov, Christina S Leslie, Alexander Y RudenskyAbstract:Regulatory T cells (Treg cells), whose differentiation and function are controlled by transcription factor FOXP3, express the closely related family member Foxp1. Here we explored Foxp1 function in Treg cells. We found that a large number of FOXP3-bound genomic sites in Treg cells were occupied by Foxp1 in both Treg cells and conventional T cells (Tconv cells). In Treg cells, Foxp1 markedly increased FOXP3 binding to these sites. Foxp1 deficiency in Treg cells resulted in their impaired function and competitive fitness, associated with markedly reduced CD25 expression and interleukin-2 (IL-2) responsiveness, diminished CTLA-4 expression and increased SATB1 expression. The characteristic expression patterns of CD25, FOXP3 and CTLA-4 in Treg cells were fully or partially rescued by strong IL-2 signaling. Our studies suggest that Foxp1 serves an essential non-redundant function in Treg cells by enforcing FOXP3-mediated regulation of gene expression and enabling efficient IL-2 signaling in these cells.
-
Transcription factor FOXP3 and its protein partners form a complex regulatory network
Nature Immunology, 2012Co-Authors: Dipayan Rudra, Christina Leslie, Ashutosh Chaudhry, Paul Deroos, Aaron Arvey, Robert M Samstein, David R Goodlett, Rachel E Niec, Scott A Shaffer, Alexander Y RudenskyAbstract:The transcription factor FOXP3 is indispensible for the differentiation and function of regulatory T cells (T(reg) cells). To gain insights into the molecular mechanisms of FOXP3-mediated gene expression, we purified FOXP3 complexes and explored their composition. Biochemical and mass-spectrometric analyses revealed that FOXP3 forms multiprotein complexes of 400-800 kDa or larger and identified 361 associated proteins, ∼30% of which were transcription related. FOXP3 directly regulated expression of a large proportion of the genes encoding its cofactors. Some transcription factor partners of FOXP3 facilitated its expression. Functional analysis of the cooperation of FOXP3 with one such partner, GATA-3, provided additional evidence for a network of transcriptional regulation afforded by FOXP3 and its associates to control distinct aspects of T(reg) cell biology.
-
cutting edge tcr stimulation is sufficient for induction of FOXP3 expression in the absence of dna methyltransferase 1
Journal of Immunology, 2009Co-Authors: Steven Z Josefowicz, Chris Wilson, Alexander Y RudenskyAbstract:TCR signaling is important for regulatory T cell (Tr) development. Using a genetic model of DNA methyltransferase 1 (Dnmt1) deficiency, we observed highly efficient FOXP3 induction following TCR stimulation, suggesting a dominant role for TCR signaling in FOXP3 induction. In the absence of Dnmt1, FOXP3 induction in thymic and peripheral FOXP3-negative T cells was maximized upon TCR engagement, and the provision of TGF-β was dispensable for FOXP3 expression. In addition, CD4-Cre × dnmt1fl/fl mice harbored sizeable thymic and peripheral populations of CD8+FOXP3+ cells, suggesting that Dnmt1 activity is required for restricting FOXP3 expression to the CD4 T cell lineage. Our results suggest that the TCR signal is sufficient for transcriptional activation of FOXP3 in the absence of maintenance DNA methylation and that TGF-β facilitates FOXP3 induction in part by opposing cell cycle-dependent Dnmt1 recruitment, leading to locus inactivation.
-
single cell analysis of normal and FOXP3 mutant human t cells FOXP3 expression without regulatory t cell development
Proceedings of the National Academy of Sciences of the United States of America, 2006Co-Authors: Marc A Gavin, Paul Deroos, Evan G Houston, Asbjorg Straypedersen, Elizabeth L Ocheltree, William Ho, Troy R Torgerson, Philip D. Greenberg, Hans D. Ochs, Alexander Y RudenskyAbstract:Forkhead winged-helix transcription factor FOXP3 serves as the dedicated mediator of the genetic program governing CD25+CD4+ regulatory T cell (Tr) development and function in mice. In humans, its role in mediating Tr development has been controversial. Furthermore, the fate of Tr precursors in FOXP3 deficiency has yet to be described. Making use of flow cytometric detection of human FOXP3, we have addressed the relationship between FOXP3 expression and human Tr development. Unlike murine FOXP3− T cells, a small subset of human CD4+ and CD8+ T cells transiently up-regulated FOXP3 upon in vitro stimulation. Induced FOXP3, however, did not alter cell-surface phenotype or suppress T helper 1 cytokine expression. Furthermore, only ex vivo FOXP3+ Tr cells persisted after prolonged culture, suggesting that induced FOXP3 did not activate a Tr developmental program in a significant number of cells. FOXP3 flow cytometry was also used to further characterize several patients exhibiting symptoms of immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) with or without FOXP3 mutations. Most patients lacked FOXP3-expressing cells, further solidifying the association between FOXP3 deficiency and immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome. Interestingly, one patient bearing a FOXP3 mutation enabling expression of stable FOXP3mut protein exhibited FOXP3mut-expressing cells among a subset of highly activated CD4+ T cells. This observation raises the possibility that the severe autoimmunity in FOXP3 deficiency can be attributed, in part, to aggressive T helper cells that have developed from Tr precursors.
G. Bussy - One of the best experts on this subject based on the ideXlab platform.
-
New insight in ARX-mutated patients' language specific impairment and underlying FOXP1 dysregulation
European Journal of Paediatric Neurology, 2017Co-Authors: A. Curie, G. Friocourt, S. Bertrand, F. Rochefort, N. Loaëc, A. Reboul, T. Nazir, A. Brun-laurisse, A. Cheylus, G. BussyAbstract:Objective: The ARX (Aristaless Related homeoboX) gene encodes a transcription factor which mutations have been associated with syndromes ranging from severe neuronal migration defects such as lissencephaly, to mild or moderate forms of X-linked Intellectual Disability (ID) without apparent brain abnormalities. The most frequent ARX mutation (c.429_452dup24), a duplication of 24 base pairs, constitutes a recognizable clinical syndrome with ARX patients exhibiting ID, without primary motor impairment, but with a very specific upper limb distal motor apraxia associated with a pathognomonic hand-grip. Furthermore, patients also exhibit language impairment and an obvious difficulty to execute oro-lingual praxis. The aim of the present study was to better characterize language abnormalities in ARX c.429_452dup24 patients. Methods: We collected data on 16 French ARX patients, and 16 age- and IQ-matched controls (Fragile X (FraX) patients). Given the similarities between ARX mutated patients and FOXP2-mutated patients, we investigated the molecular relationship between Arx and Foxp2. Results: ARX patients have structural language impairments in both receptive and expressive aspects of language compared to FraX patients: phonetic feature recognition, receptive (ECOSSE test for sentence comprehension) and expressive (TCG-R for sentence production) morphosyntactic skills and oro-lingual dyspraxia (movements of the face, tongue, and lips) were significantly more impaired in ARX patients. FraX patients made words more complex and they were less impaired in their ability to articulate words. On the contrary, language pragmatic analysis showed that ARXdup24 patients had significantly better interactional skills than FraX. patients. Interestingly, we found that although Arx has no effect on Foxp2 expression, Arx was found to activate Foxp1 expression, and that the c.429_452dup24 mutation alters the expression of this gene. Foxp1 is known to heterodimerize with Foxp2 and has been involved in language defects. Conclusion: These data uncover a novel role of ARX in language development, probably through the regulation of Foxp1.
Jorge Babul - One of the best experts on this subject based on the ideXlab platform.
-
intrinsically disordered regions of the dna binding domain of human foxp1 facilitate domain swapping
Journal of Molecular Biology, 2020Co-Authors: Exequiel Medina, Pablo Villalobos, Elizabeth A Komives, George L Hamilton, Hugo Sanabria, Cesar A Ramirezsarmiento, Jorge BabulAbstract:Abstract Forkhead box P (FoxP) proteins are unique transcription factors that spatiotemporally regulate gene expression by tethering two chromosome loci together via functional domain-swapped dimers formed through their DNA-binding domains. Further, the differential kinetics on this dimerization mechanism underlie an intricate gene regulation network at physiological conditions. Nonetheless, poor understanding of the structural dynamics and steps of the association process impedes to link the functional domain swapping to human-associated diseases. Here, we have characterized the DNA-binding domain of human FoxP1 by integrating single-molecule Forster resonance energy transfer and hydrogen–deuterium exchange mass spectrometry data with molecular dynamics simulations. Our results confirm the formation of a previously postulated domain-swapped (DS) FoxP1 dimer in solution and reveal the presence of highly populated, heterogeneous, and locally disordered dimeric intermediates along the dimer dissociation pathway. The unique features of FoxP1 provide a glimpse of how intrinsically disordered regions can facilitate domain swapping oligomerization and other tightly regulated association mechanisms relevant in biological processes.
-
Three-Dimensional Domain Swapping Changes the Folding Mechanism of the Forkhead Domain of FoxP1
Biophysical Journal, 2016Co-Authors: Exequiel Medina, Cristóbal Córdova, Pablo Villalobos, Javiera Reyes, César A. Ramírez-sarmiento, Elizabeth A Komives, Jorge BabulAbstract:Abstract The forkhead family of transcription factors (Fox) controls gene transcription during key processes such as regulation of metabolism, embryogenesis, and immunity. Structurally, Fox proteins feature a conserved DNA-binding domain known as forkhead. Interestingly, solved forkhead structures of members from the P subfamily (FoxP) show that they can oligomerize by three-dimensional domain swapping, whereby structural elements are exchanged between adjacent subunits, leading to an intertwined dimer. Recent evidence has largely stressed the biological relevance of domain swapping in FoxP, as several disease-causing mutations have been related to impairment of this process. Here, we explore the equilibrium folding and binding mechanism of the forkhead domain of wild-type FoxP1, and of two mutants that hinder DNA-binding (R53H) and domain swapping (A39P), using size-exclusion chromatography, circular dichroism, and hydrogen-deuterium exchange mass spectrometry. Our results show that domain swapping of FoxP1 occurs at micromolar protein concentrations within hours of incubation and is energetically favored, in contrast to classical domain-swapping proteins. Also, DNA-binding mutations do not significantly affect domain swapping. Remarkably, equilibrium unfolding of dimeric FoxP1 follows a three-state N 2 ↔ 2I ↔ 2U folding mechanism in which dimer dissociation into a monomeric intermediate precedes protein unfolding, in contrast to the typical two-state model described for most domain-swapping proteins, whereas the A39P mutant follows a two-state N ↔ U folding mechanism consistent with the second transition observed for dimeric FoxP1. Also, the free-energy change of the N ↔ U in A39P FoxP1 is ∼2 kcal⋅mol −1 larger than the I ↔ U transition of both wild-type and R53H FoxP1. Finally, hydrogen-deuterium exchange mass spectrometry reveals that the intermediate strongly resembles the native state. Our results suggest that domain swapping in FoxP1 is at least partially linked to monomer folding stability and follows an unusual three-state folding mechanism, which might proceed via transient structural changes rather than requiring complete protein unfolding as do most domain-swapping proteins.
Philip W. Tucker - One of the best experts on this subject based on the ideXlab platform.
-
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.
-
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.
-
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.
-
multiple domains define the expression and regulatory properties of foxp1 forkhead transcriptional repressors
Journal of Biological Chemistry, 2003Co-Authors: Bin Wang, Danjuan Lin, Philip W. TuckerAbstract:The Foxp subfamily of forkhead/HNF3 transcription factors has recently been recognized because of its involvement in autoimmune disease, speech and language disorders, and lung development. Domains unique to this subfamily include a divergent DNA-binding winged helix, a leucine zipper, a zinc finger, and a polyglutamine tract. Little is known about the properties of these proteins that are fundamental to their function as transcription factors nor how the Foxp sequence motifs regulate their transcriptional regulatory properties. We report here a structure/function analysis of the Foxp1 protein. We have analyzed the alternative splice isoforms 1A and 1C and also report the cloning and characterization of a novel isoform Foxp1D that lacks the polyglutamine domain. We have isolated the preferred DNA-binding sites for Foxp1 transcription factors. Foxp1A, C, and D isoforms and the related Foxp2 protein repress gene transcription via binding to this consensus site or to a naturally occurring site within the SV40 and the interleukin-2 promoters. In some cases the strength of Foxp1 repression is mediated by the polyglutamine domain. Unlike previously characterized forkhead factors, Foxp1 proteins can form homodimers or heterodimers with subfamily members. The dimerization domain was localized to an evolutionarily conserved C2H2 zinc finger and leucine zipper motif. Finally, we demonstrate that Foxp1, although broadly expressed, is further regulated by tissue-specific alternative splicing of these functionally important sequence domains. These results suggest that Foxp1 proteins have diverse functional roles in different cell and tissue types.
