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Klaus H. Kaestner - One of the best experts on this subject based on the ideXlab platform.
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FOXA1 and foxa2 drive gastric differentiation and suppress squamous identity in nkx2 1 negative lung cancer
eLife, 2018Co-Authors: Soledad A Camolotto, Shrivatsav Pattabiraman, Timothy L Mosbruger, Alex Jones, Veronika K Belova, Grace Orstad, Mitchell Streiff, Lydia Salmond, Chris Stubben, Klaus H. KaestnerAbstract:Changes in cancer cell identity can alter malignant potential and therapeutic response. Loss of the pulmonary lineage specifier NKX2-1 augments the growth of KRAS-driven lung adenocarcinoma and causes pulmonary to gastric transdifferentiation. Here, we show that the transcription factors FOXA1 and FoxA2 are required for initiation of mucinous NKX2-1-negative lung adenocarcinomas in the mouse and for activation of their gastric differentiation program. FOXA1/2 deletion severely impairs tumor initiation and causes a proximal shift in cellular identity, yielding tumors expressing markers of the squamocolumnar junction of the gastrointestinal tract. In contrast, we observe downregulation of FOXA1/2 expression in the squamous component of both murine and human lung adenosquamous carcinoma. Using sequential in vivo recombination, we find that FOXA1/2 loss in established KRAS-driven neoplasia originating from SPC-positive alveolar cells induces keratinizing squamous cell carcinomas. Thus, NKX2-1, FOXA1 and FoxA2 coordinately regulate the growth and identity of lung cancer in a context-specific manner.
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FOXA1 and foxa2 are required for the maintenance of dopaminergic properties in ventral midbrain neurons at late embryonic stages
The Journal of Neuroscience, 2013Co-Authors: Simon R W Stott, Klaus H. Kaestner, Wei Lin, Emmanouil Metzakopian, Rene Hen, Siewlan AngAbstract:The maintained expression of transcription factors throughout the development of mesodiencephalic dopaminergic (mDA) neurons suggests multiple roles at various stages in development. Two members of the forkhead/winged helix transcription factor family, FOXA1 and Foxa2, have been recently shown to have an important influence in the early development of mDA neurons. Here we present data demonstrating that these genes are also involved in the later maintenance of the mDA system. We conditionally removed both genes in postmitotic mDA neurons using the dopamine transporter-cre mouse. Deletion of both FOXA1 and Foxa2 resulted in a significant reduction in the number of tyrosine hydroxylase (TH)-positive mDA neurons. The decrease was predominantly observed in the substantia nigra region of the mDA system, which led to a loss of TH+ fibers innervating the striatum. Further analysis demonstrated that the reduction in the number of TH+ cells in the mutant mice was not due to apoptosis or cell-fate change. Using reporter mouse lines, we found that the mDA neurons were still present in the ventral midbrain, but that they had lost much of their dopaminergic phenotype. The majority of these neurons remained in the ventral mesencephalon until at least 18 months of age. Chromatin immunoprecipitation suggested that the loss of the mDA phenotype is due to a reduction in the binding of the nuclear orphan receptor, Nurr-1 to the promoter region of TH. These results extend previous findings and demonstrate a later role for Foxa genes in regulating the maintenance of dopaminergic phenotype in mDA neurons.
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genome wide location analysis reveals distinct transcriptional circuitry by paralogous regulators FOXA1 and foxa2
PLOS Genetics, 2012Co-Authors: Irina M Bochkis, Jonathan Schug, Svitlana Kurinna, Sabrina A Stratton, Michelle Craig Barton, Klaus H. KaestnerAbstract:Gene duplication is a powerful driver of evolution. Newly duplicated genes acquire new roles that are relevant to fitness, or they will be lost over time. A potential path to functional relevance is mutation of the coding sequence leading to the acquisition of novel biochemical properties, as analyzed here for the highly homologous paralogs FOXA1 and Foxa2 transcriptional regulators. We determine by genome-wide location analysis (ChIP-Seq) that, although FOXA1 and Foxa2 share a large fraction of binding sites in the liver, each protein also occupies distinct regulatory elements in vivo. FOXA1-only sites are enriched for p53 binding sites and are frequently found near genes important to cell cycle regulation, while Foxa2-restricted sites show only a limited match to the forkhead consensus and are found in genes involved in steroid and lipid metabolism. Thus, FOXA1 and Foxa2, while redundant during development, have evolved divergent roles in the adult liver, ensuring the maintenance of both genes during evolution.
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foxa family members are crucial regulators of the hypertrophic chondrocyte differentiation program
Developmental Cell, 2012Co-Authors: Andreia M Ionescu, Klaus H. Kaestner, Elena Kozhemyakina, Claudia Nicolae, Bjorn Olsen, Andrew B LassarAbstract:Summary During endochondral ossification, small, immature chondrocytes enlarge to form hypertrophic chondrocytes, which express collagen X. In this work, we demonstrate that FoxA factors are induced during chondrogenesis, bind to conserved binding sites in the collagen X enhancer, and can promote the expression of a collagen X-luciferase reporter in both chondrocytes and fibroblasts. In addition, we demonstrate by both gain- and loss-of-function analyses that FoxA factors play a crucial role in driving the expression of both endogenous collagen X and other hypertrophic chondrocyte-specific genes. Mice engineered to lack expression of both FoxA2 and FoxA3 in their chondrocytes display defects in chondrocyte hypertrophy, alkaline phosphatase expression, and mineralization in their sternebrae and, in addition, exhibit postnatal dwarfism that is coupled to significantly decreased expression of both collagen X and MMP13 in their growth plates. Our findings indicate that FoxA family members are crucial regulators of the hypertrophic chondrocyte differentiation program.
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FOXA1 and foxa2 are essential for sexual dimorphism in liver cancer
Cell, 2012Co-Authors: Zhaoyu Li, Jonathan Schug, Geetu Tuteja, Klaus H. KaestnerAbstract:Summary Hepatocellular carcinoma (HCC) is sexually dimorphic in both rodents and humans, with significantly higher incidence in males, an effect that is dependent on sex hormones. The molecular mechanisms by which estrogens prevent and androgens promote liver cancer remain unclear. Here, we discover that sexually dimorphic HCC is completely reversed in FOXA1- and Foxa2-deficient mice after diethylnitrosamine-induced hepatocarcinogenesis. Coregulation of target genes by FOXA1/a2 and either the estrogen receptor (ERα) or the androgen receptor (AR) was increased during hepatocarcinogenesis in normal female or male mice, respectively, but was lost in FOXA1/2-deficient mice. Thus, both estrogen-dependent resistance to and androgen-mediated facilitation of HCC depend on FOXA1/2. Strikingly, single nucleotide polymorphisms at FOXA2 binding sites reduce binding of both FOXA2 and ERα to their targets in human liver and correlate with HCC development in women. Thus, Foxa factors and their targets are central for the sexual dimorphism of HCC.
Xin Xie - One of the best experts on this subject based on the ideXlab platform.
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chemical cocktails enable hepatic reprogramming of mouse fibroblasts with a single transcription factor
Stem cell reports, 2017Co-Authors: Ren Guo, Xin Wang, Wei Tang, Qianting Yuan, Lijian Hui, Xin XieAbstract:Summary Liver or hepatocytes transplantation is limited by the availability of donor organs. Functional hepatocytes independent of the donor sources may have wide applications in regenerative medicine and the drug industry. Recent studies have demonstrated that chemical cocktails may induce reprogramming of fibroblasts into a range of functional somatic cells. Here, we show that mouse fibroblasts can be transdifferentiated into the hepatocyte-like cells (iHeps) using only one transcription factor (TF) ( FOXA1 , Foxa2 , or Foxa3 ) plus a chemical cocktail. These iHeps show typical epithelial morphology, express multiple hepatocyte-specific genes, and acquire hepatocyte functions. Genetic lineage tracing confirms the fibroblast origin of these iHeps. More interestingly, these iHeps are expandable in vitro and can reconstitute the damaged hepatic tissues of the fumarylacetoacetate hydrolase-deficient ( Fah − / − ) mice. Our study provides a strategy to generate functional hepatocyte-like cells by using a single TF plus a chemical cocktail and is one step closer to generate the full-chemical iHeps.
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Chemical Cocktails Enable Hepatic Reprogramming of Mouse Fibroblasts with a Single Transcription Factor
Elsevier, 2017Co-Authors: Ren Guo, Xin Wang, Wei Tang, Qianting Yuan, Lijian Hui, Xin XieAbstract:Summary: Liver or hepatocytes transplantation is limited by the availability of donor organs. Functional hepatocytes independent of the donor sources may have wide applications in regenerative medicine and the drug industry. Recent studies have demonstrated that chemical cocktails may induce reprogramming of fibroblasts into a range of functional somatic cells. Here, we show that mouse fibroblasts can be transdifferentiated into the hepatocyte-like cells (iHeps) using only one transcription factor (TF) (FOXA1, Foxa2, or Foxa3) plus a chemical cocktail. These iHeps show typical epithelial morphology, express multiple hepatocyte-specific genes, and acquire hepatocyte functions. Genetic lineage tracing confirms the fibroblast origin of these iHeps. More interestingly, these iHeps are expandable in vitro and can reconstitute the damaged hepatic tissues of the fumarylacetoacetate hydrolase-deficient (Fah−/−) mice. Our study provides a strategy to generate functional hepatocyte-like cells by using a single TF plus a chemical cocktail and is one step closer to generate the full-chemical iHeps. : In this article, Xie and colleagues show that mouse fibroblasts can be transdifferentiated into the hepatocyte-like cells (iHeps) using only one transcription factor plus a chemical cocktail. Genetic lineage tracing confirms the fibroblast origin of these iHeps. These iHeps are expandable in vitro and can reconstitute the damaged hepatic tissues of the fumarylacetoacetate hydrolase-deficient mice. Keywords: reprogramming, hepatic transdifferentiation, hepatocyte, induced hepatocyte, chemically induced hepatocyte, fibroblast, chemical cocktail, regenerative medicin
Jeffrey A. Whitsett - One of the best experts on this subject based on the ideXlab platform.
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FOXM1 stimulates progression of lung adenomas into mucinous adenocarcinomas.
2017Co-Authors: David Milewski, Vladimir Ustiyan, Vladimir V Kalinichenko, David Balli, Hendrik Dienemann, Arne Warth, Kai Breuhahn, Jeffrey A. Whitsett, Tanya V KalinAbstract:Schematic drawing shows that FOXF1 induces expression of cell-cycle regulatory and mucinous genes, including Agr2, causing increased tumor cell proliferation and mucinous phenotype. FOXM1 directly activates transcription of Agr2. Both FOXM1 and AGR2 are critical for PIMA growth, invasion and progression of lung adenomas into aggressive mucinous adenocarcinomas.
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genome wide characterisation of FOXA1 binding sites reveals several mechanisms for regulating neuronal differentiation in midbrain dopamine cells
Journal of Cell Science, 2015Co-Authors: Emmanouil Metzakopian, Jeffrey A. Whitsett, Kamal Bouhali, Matias Alvarezsaavedra, David J Picketts, Siewlan AngAbstract:Midbrain dopamine neuronal progenitors develop into heterogeneous subgroups of neurons, such as substantia nigra pars compacta, ventral tegmental area and retrorubal field, that regulate motor control, motivated and addictive behaviours. The development of midbrain dopamine neurons has been extensively studied, and these studies indicate that complex cross-regulatory interactions between extrinsic and intrinsic molecules regulate a precise temporal and spatial programme of neurogenesis in midbrain dopamine progenitors. To elucidate direct molecular interactions between multiple regulatory factors during neuronal differentiation in mice, we characterised genome-wide binding sites of the forkhead/winged helix transcription factor FOXA1, which functions redundantly with Foxa2 to regulate the differentiation of mDA neurons. Interestingly, our studies identified a rostral brain floor plate Neurog2 enhancer that requires direct input from Otx2, FOXA1, Foxa2 and an E-box transcription factor for its transcriptional activity. Furthermore, the chromatin remodelling factor Smarca1 was shown to function downstream of FOXA1 and Foxa2 to regulate differentiation from immature to mature midbrain dopaminergic neurons. Our genome-wide FOXA1-bound cis-regulatory sequences from ChIP-Seq and FOXA1/2 candidate target genes from RNA-Seq analyses of embryonic midbrain dopamine cells also provide an excellent resource for probing mechanistic insights into gene regulatory networks involved in the differentiation of midbrain dopamine neurons.
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FOXA1 and foxa2 function both upstream of and cooperatively with lmx1a and lmx1b in a feedforward loop promoting mesodiencephalic dopaminergic neuron development
Developmental Biology, 2009Co-Authors: Wei Lin, Nan Gao, Jeffrey A. Whitsett, Emmanouil Metzakopian, Yannis E Mavromatakis, Nikolaos Balaskas, Hiroshi Sasaki, James Briscoe, Martyn Goulding, Klaus H. KaestnerAbstract:Mesodiencephalic dopaminergic neurons control voluntary movement and reward based behaviours. Their dysfunction can lead to neurological disorders, including Parkinson's disease. These neurons are thought to arise from progenitors in the floor plate of the caudal diencephalon and midbrain. Members of the Foxa family of forkhead/winged helix transcription factor, FOXA1 and Foxa2, have previously been shown to regulate neuronal specification and differentiation of mesodiencephalic progenitors. However, FOXA1 and Foxa2 are also expressed earlier during regional specification of the rostral brain. In this paper, we have examined the early function of FOXA1 and Foxa2 using conditional mutant mice. Our studies show that FOXA1 and Foxa2 positively regulate Lmx1a and Lmx1b expression and inhibit Nkx2.2 expression in mesodiencephalic dopaminergic progenitors. Subsequently, FOXA1 and Foxa2 function cooperatively with Lmx1a and Lmx1b to regulate differentiation of mesodiencephalic dopaminergic neurons. Chromatin immunoprecipitation experiments indicate that Nkx2.2 and TH genes are likely direct targets of FOXA1 and Foxa2 in mesodiencephalic dopaminergic cells in vivo. FOXA1 and Foxa2 also inhibit GABAergic neuron differentiation by repressing the Helt gene in the ventral midbrain. Our data therefore provide new insights into the specification and differentiation of mesodiencephalic dopaminergic neurons and identifies FOXA1 and Foxa2 as essential regulators in these processes.
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FOXA1 and foxa2 regulate multiple phases of midbrain dopaminergic neuron development in a dosage dependent manner
Development, 2007Co-Authors: Anna L M Ferri, Hiroshi Sasaki, Yannis E Mavromatakis, Julie C Wang, Jeffrey A. WhitsettAbstract:The role of transcription factors in regulating the development of midbrain dopaminergic (mDA) neurons is intensively studied owing to the involvement of these neurons in diverse neurological disorders. Here we demonstrate novel roles for the forkhead/winged helix transcription factors FOXA1 and Foxa2 in the specification and differentiation of mDA neurons by analysing the phenotype of FOXA1 and Foxa2 single- and double-mutant mouse embryos. During specification, FOXA1 and Foxa2 regulate the extent of neurogenesis in mDA progenitors by positively regulating Ngn2 (Neurog2) expression. Subsequently, FOXA1 and Foxa2 regulate the expression of Nurr1 (Nr4a2) and engrailed 1 in immature neurons and the expression of aromatic l-amino acid decarboxylase and tyrosine hydroxylase in mature neurons during early and late differentiation of midbrain dopaminergic neurons. Interestingly, genetic evidence indicates that these functions require different gene dosages of FOXA1 and Foxa2. Altogether, our results demonstrate that FOXA1 and Foxa2 regulate multiple phases of midbrain dopaminergic neuron development in a dosage-dependent manner.
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compensatory roles of FOXA1 and foxa2 during lung morphogenesis
Journal of Biological Chemistry, 2005Co-Authors: Huajing Wan, Klaus H. Kaestner, Sharon Dingle, Valerie Besnard, Siewlan Ang, Susan E Wert, Mildred T Stahlman, Jeffrey A. WhitsettAbstract:FOXA1 and Foxa2 are closely related family members of the Foxa group of transcription factors that are coexpressed in subsets of respiratory epithelial cells throughout lung morphogenesis. Shared patterns of expression, conservation of DNA binding, and transcriptional activation domains indicate that they may serve complementary functions in the regulation of gene expression during lung morphogenesis. Whereas branching morphogenesis of the fetal lung occurs normally in the Foxa2Delta/Delta and FOXA1-/- mice, deletion of both FOXA1 and Foxa2 (in Foxa2Delta/Delta, FOXA1-/- mice) inhibited cell proliferation, epithelial cell differentiation, and branching. Dilation of terminal lung tubules and decreased branching were observed as early as embryonic day 12.5. FOXA1 and Foxa2 regulated Shh (sonic hedgehog) and Shh-dependent genes in the respiratory epithelial cells that influenced the expression of genes in the pulmonary mesenchyme that are required for branching morphogenesis. Epithelial cell differentiation, as indicated by lack of expression of surfactant protein B, surfactant protein C, the Clara cell secretory protein, and Foxj1, was inhibited. Foxa family members regulate signaling and transcriptional programs required for morphogenesis and cell differentiation during formation of the lung.
Mahmood M Hussain - One of the best experts on this subject based on the ideXlab platform.
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circadian regulation of intestinal lipid absorption by apolipoprotein aiv involves forkhead transcription factors a2 and o1 and microsomal triglyceride transfer protein
Journal of Biological Chemistry, 2013Co-Authors: Xiaoyue Pan, Jahangir Iqbal, Mohamed Khalid Munshi, Joyce Queiroz, Alaa Sirwi, Shrenik Shah, Abdullah Younus, Mahmood M HussainAbstract:Abstract We have shown previously that Clock, microsomal triglyceride transfer protein (MTP), and nocturnin are involved in the circadian regulation of intestinal lipid absorption. Here, we clarified the role of apolipoprotein AIV (apoAIV) in the diurnal regulation of plasma lipids and intestinal lipid absorption in mice. Plasma triglyceride in apoAIV−/− mice showed diurnal variations similar to apoAIV+/+ mice; however, the increases in plasma triglyceride at night were significantly lower in these mice. ApoAIV−/− mice absorbed fewer lipids at night and showed blunted response to daytime feeding. To explain reasons for these lower responses, we measured MTP expression; intestinal MTP was low at night, and its induction after food entrainment was less in apoAIV−/− mice. Conversely, apoAIV overexpression increased MTP mRNA in hepatoma cells, indicating transcriptional regulation. Mechanistic studies revealed that sequences between −204/−775 bp in the MTP promoter respond to apoAIV and that apoAIV enhances expression of FoxA2 and FoxO1 transcription factors and their binding to the identified cis elements in the MTP promoter at night. Knockdown of FoxA2 and FoxO1 abolished apoAIV-mediated MTP induction. Similarly, knockdown of apoAIV in differentiated Caco-2 cells reduced MTP, FoxA2, and FoxO1 mRNA levels, cellular MTP activity, and media apoB. Moreover, FoxA2 and FoxO1 expression showed diurnal variations, and their expression was significantly lower in apoAIV−/− mice. These data indicate that apoAIV modulates diurnal changes in lipid absorption by regulating forkhead transcription factors and MTP and that inhibition of apoAIV expression might reduce plasma lipids.
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circadian regulation of intestinal lipid absorption by apolipoprotein aiv involves forkhead transcription factors a2 and o1 and microsomal triglyceride transfer protein
Journal of Biological Chemistry, 2013Co-Authors: Xiaoyue Pan, Jahangir Iqbal, Mohamed Khalid Munshi, Joyce Queiroz, Alaa Sirwi, Shrenik Shah, Abdullah Younus, Mahmood M HussainAbstract:We have shown previously that Clock, microsomal triglyceride transfer protein (MTP), and nocturnin are involved in the circadian regulation of intestinal lipid absorption. Here, we clarified the role of apolipoprotein AIV (apoAIV) in the diurnal regulation of plasma lipids and intestinal lipid absorption in mice. Plasma triglyceride in apoAIV−/− mice showed diurnal variations similar to apoAIV+/+ mice; however, the increases in plasma triglyceride at night were significantly lower in these mice. ApoAIV−/− mice absorbed fewer lipids at night and showed blunted response to daytime feeding. To explain reasons for these lower responses, we measured MTP expression; intestinal MTP was low at night, and its induction after food entrainment was less in apoAIV−/− mice. Conversely, apoAIV overexpression increased MTP mRNA in hepatoma cells, indicating transcriptional regulation. Mechanistic studies revealed that sequences between −204/−775 bp in the MTP promoter respond to apoAIV and that apoAIV enhances expression of FoxA2 and FoxO1 transcription factors and their binding to the identified cis elements in the MTP promoter at night. Knockdown of FoxA2 and FoxO1 abolished apoAIV-mediated MTP induction. Similarly, knockdown of apoAIV in differentiated Caco-2 cells reduced MTP, FoxA2, and FoxO1 mRNA levels, cellular MTP activity, and media apoB. Moreover, FoxA2 and FoxO1 expression showed diurnal variations, and their expression was significantly lower in apoAIV−/− mice. These data indicate that apoAIV modulates diurnal changes in lipid absorption by regulating forkhead transcription factors and MTP and that inhibition of apoAIV expression might reduce plasma lipids. Background: The role of apoAIV in the diurnal regulation of plasma lipids is unknown. Results: Plasma lipids, lipid absorption, and MTP, FoxO1, and FoxA2 levels are lower at night and at mealtime in apoAIV−/− mice. Conclusion: ApoAIV increases intestinal lipid absorption by modulating the expression of MTP involving FoxA2 and FoxO1. Significance: Inhibition of intestinal apoAIV expression might reduce plasma lipids.
Nan Gao - One of the best experts on this subject based on the ideXlab platform.
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FOXA1 deletion in luminal epithelium causes prostatic hyperplasia and alteration of differentiated phenotype
Laboratory Investigation, 2014Co-Authors: David J Degraff, Nan Gao, Mary K Herrick, Magdalena M Grabowska, Tom C Case, William J Hayward, Douglas W Strand, Justin M Cates, Simon W Hayward, Michael A WalterAbstract:The forkhead box (Fox) superfamily of transcription factors has essential roles in organogenesis and tissue differentiation. FOXA1 and Foxa2 are expressed during prostate budding and ductal morphogenesis, whereas FOXA1 expression is retained in adult prostate epithelium. Previous characterization of prostatic tissue rescued from embryonic FOXA1 knockout mice revealed FOXA1 to be essential for ductal morphogenesis and epithelial maturation. However, it is unknown whether FOXA1 is required to maintain the differentiated status in adult prostate epithelium. Here, we employed the PBCre4 transgenic system and determined the impact of prostate-specific FOXA1 deletion in adult murine epithelium. PBCre4/FOXA1^loxp/loxp mouse prostates showed progressive florid hyperplasia with extensive cribriform patterning, with the anterior prostate being most affected. Immunohistochemistry studies show mosaic FOXA1 KO consistent with PBCre4 activity, with FOXA1 KO epithelial cells specifically exhibiting altered cell morphology, increased proliferation, and elevated expression of basal cell markers. Castration studies showed that, while PBCre4/FOXA1^loxp/loxp prostates did not exhibit altered sensitivity in response to hormone ablation compared with control prostates, the number of FOXA1-positive cells in mosaic FOXA1 KO prostates was significantly reduced compared with FOXA1-negative cells following castration. Unexpectedly, gene expression profile analyses revealed that FOXA1 deletion caused abnormal expression of seminal vesicle-associated genes in KO prostates. In summary, these results indicate FOXA1 expression is required for the maintenance of prostatic cellular differentiation.
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FOXA1 and foxa2 maintain the metabolic and secretory features of the mature β cell
The Journal of Clinical Endocrinology and Metabolism, 2010Co-Authors: Nan Gao, Nicolai M Doliba, Jonathan Schug, Olga Smirnova, Franz M Matschinsky, John Le Lay, Wei Qin, Alan J Fox, Klaus H. KaestnerAbstract:FOXA1 and Foxa2 play both redundant and distinct roles in early pancreas development. We demonstrate here that inducible ablation of both transcription factors in mature mouse beta-cells leads to impaired glucose homeostasis and insulin secretion. The defects in both glucose-stimulated insulin secretion and intracellular calcium oscillation are more pronounced than those in beta-cells lacking only Foxa2. Unexpectedly, in contrast to the severe reduction of beta-cell-enriched factors contributing to metabolic and secretory pathways, expression of a large number of genes that are involved in neural differentiation and function is significantly elevated. We further demonstrate that expression of carbohydrate response element-binding protein (ChREBP or Mlxipl), an important transcriptional regulator of carbohydrate metabolism, is significantly affected in compound FOXA1/a2 mutant beta-cells. ChREBP expression is directly controlled by FOXA1 and Foxa2 in both the fetal endocrine pancreas as well as mature islets. These data demonstrate that FOXA1 and Foxa2 play crucial roles in the development and maintenance of beta-cell-specific secretory and metabolic pathways.
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FOXA1 and foxa2 function both upstream of and cooperatively with lmx1a and lmx1b in a feedforward loop promoting mesodiencephalic dopaminergic neuron development
Developmental Biology, 2009Co-Authors: Wei Lin, Nan Gao, Jeffrey A. Whitsett, Emmanouil Metzakopian, Yannis E Mavromatakis, Nikolaos Balaskas, Hiroshi Sasaki, James Briscoe, Martyn Goulding, Klaus H. KaestnerAbstract:Mesodiencephalic dopaminergic neurons control voluntary movement and reward based behaviours. Their dysfunction can lead to neurological disorders, including Parkinson's disease. These neurons are thought to arise from progenitors in the floor plate of the caudal diencephalon and midbrain. Members of the Foxa family of forkhead/winged helix transcription factor, FOXA1 and Foxa2, have previously been shown to regulate neuronal specification and differentiation of mesodiencephalic progenitors. However, FOXA1 and Foxa2 are also expressed earlier during regional specification of the rostral brain. In this paper, we have examined the early function of FOXA1 and Foxa2 using conditional mutant mice. Our studies show that FOXA1 and Foxa2 positively regulate Lmx1a and Lmx1b expression and inhibit Nkx2.2 expression in mesodiencephalic dopaminergic progenitors. Subsequently, FOXA1 and Foxa2 function cooperatively with Lmx1a and Lmx1b to regulate differentiation of mesodiencephalic dopaminergic neurons. Chromatin immunoprecipitation experiments indicate that Nkx2.2 and TH genes are likely direct targets of FOXA1 and Foxa2 in mesodiencephalic dopaminergic cells in vivo. FOXA1 and Foxa2 also inhibit GABAergic neuron differentiation by repressing the Helt gene in the ventral midbrain. Our data therefore provide new insights into the specification and differentiation of mesodiencephalic dopaminergic neurons and identifies FOXA1 and Foxa2 as essential regulators in these processes.
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Dynamic regulation of Pdx1 enhancers by FOXA1 and Foxa2 is essential for pancreas development
Genes & Development, 2008Co-Authors: Nan Gao, John Lelay, Marko Z. Vatamaniuk, Sebastian Rieck, Joshua R. Friedman, Klaus H. KaestnerAbstract:The onset of pancreas development in the foregut endoderm is marked by activation of the homeobox gene Pdx1 (IPF1). Pdx1 is essential for the expansion of the pancreatic primordium and the development of endocrine islets. The control of Pdx1 expression has been only partially elucidated. We demonstrate here that the winged-helix transcription factors FOXA1 and Foxa2 co-occupy multiple regulatory domains in the Pdx1 gene. Compound conditional ablation of both FOXA1 and Foxa2 in the pancreatic primordium results in complete loss of Pdx1 expression and severe pancreatic hypoplasia. Mutant mice exhibit hyperglycemia with severely disrupted acinar and islet development, and die shortly after birth. Assessment of developmental markers in the mutant pancreas revealed a failure in the expansion of the pancreatic anlage, a blockage of exocrine and endocrine cell differentiation, and an arrest at the primitive duct stage. Comparing their relative developmental activity, we find that Foxa2 is the major regulator in promoting pancreas development and cell differentiation. Using chromatin immunoprecipitations (ChIP) and ChIP sequencing (ChIPSeq) of fetal pancreas and islet chromatin, we demonstrate that FOXA1 and Foxa2 predominantly occupy a distal enhancer at �6.4 kb relative to the transcriptional start site in the Pdx1 gene. In addition, occupancy of the well-characterized proximal Pdx1 enhancer by FOXA1 and Foxa2 is developmental stage-dependent. Thus, the regulation of Pdx1 expression by FOXA1 and Foxa2 is a key early event controlling the expansion and differentiation of the pancreatic primordia.
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forkhead box a1 regulates prostate ductal morphogenesis and promotes epithelial cell maturation
Development, 2005Co-Authors: Nan Gao, Janni Mirosevich, Kenichiro Ishii, Satoru Kuwajima, Stacey R Oppenheimer, Richard L Roberts, Ming Jiang, Scott B Shappell, Richard M Caprioli, Markus StoffelAbstract:We have previously shown that a forkhead transcription factor FOXA1 interacts with androgen signaling and controls prostate differentiated response. Here, we show the mouse FOXA1 expression marks the entire embryonic urogenital sinus epithelium (UGE), contrasting with Shh and Foxa2, which are restricted to the basally located cells during prostate budding. The FOXA1-deficient mouse prostate shows a severely altered ductal pattern that resembles primitive epithelial cords surrounded by thick stromal layers. Characterization of these mutant cells indicates a population of basal-like cells similar to those found in the embryonic UGE, whereas no differentiated or mature luminal epithelial cells are found in FOXA1-deficient epithelium. These phenotypic changes are accompanied with molecular aberrations, including focal epithelial activation of Shh and elevated Foxa2 and Notch1 in the null epithelium. Perturbed epithelial-stromal interactions induced by FOXA1-deficient epithelium is evident, as demonstrated by the expansion of surrounding smooth muscle and elevated levels of stromal factors (Bmp4, Fgf7, Fgf10 and Gli). The prostatic homeobox protein Nkx3.1, a known proliferation inhibitor, was downregulated in FOXA1-deficient epithelial cells, while several prostate-specific androgen-regulated markers, including a novel FOXA1 target, are absent in the null prostate. These data indicate that FOXA1 plays a pivotal role in controlling prostate morphogenesis and cell differentiation.
