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Chunyan Zhou - One of the best experts on this subject based on the ideXlab platform.
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ISL1, a novel regulator of CCNB1, CCNB2 and c-MYC genes, promotes gastric cancer cell proliferation and tumor growth.
Oncotarget, 2016Co-Authors: Qiong Shi, Weiping Wang, Ping Chen, Zhuqing Jia, Chunyan ZhouAbstract:// Qiong Shi 1, * , Weiping Wang 1, * , Zhuqing Jia 1 , Ping Chen 1 , Kangtao Ma 1 , Chunyan Zhou 1 1 Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education of China, Peking University, Beijing, P.R. China * These authors contributed equally to this work Correspondence to: Chunyan Zhou, email: chunyanzhou@bjmu.edu.cn Keywords: ISL1, gastric cancer, proliferation, CCNB, c-MYC Received: October 05, 2015 Accepted: April 22, 2016 Published: May 10, 2016 ABSTRACT I slet-1 ( ISL1 ) belongs to the LIM homeodomain transcription factor family, which is specifically expressed in certain tissue types only. Previously, we reported that ISL1 is aberrantly overexpressed in gastric cancer (GC). However, its role in GC is not clear. Here, we report that ISL1 is aberrantly upregulated not only in human gastric carcinoma tissues but also in some GC cell lines. Upregulated ISL1 expression enhanced xenografted gastric carcinoma development, while ISL1 knockdown inhibited GC growth in nude mice. ISL1 overexpression promoted GC cell proliferation, colony formation, and cell growth in soft agar, and facilitated cell cycle transition in GC cells, demonstrated an increase in the proportion of cells in the G 2 /M and S phases and a decrease in the proportion of cells in the G 1 phase. Furthermore, we provide evidence that ISL1 is a novel regulator of the cyclin B1 ( CCNB1 ), cyclin B2 ( CCNB2 ) and c-myc ( c-MYC ) genes. ISL1 activated the expression of these genes in GC cells by binding to the conserved binding sites on their promoters or enhancers. The expression levels of the genes were decreased in response to ISL1 knockdown. Therefore, ISL1 may serve as a potential therapeutic target in GC.
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ISL1 and JMJD3 synergistically control cardiac differentiation of embryonic stem cells
Nucleic Acids Research, 2016Co-Authors: Yang Wang, Weiping Wang, Ping Chen, Zhuqing Jia, Chen Guo, Danny Reinberg, Chunyan ZhouAbstract:ISL1 is expressed in cardiac progenitor cells and plays critical roles in cardiac lineage differentiation and heart development. Cardiac progenitor cells hold great potential for clinical and translational applications. However, the mechanisms underlying ISL1 function in cardiac progenitor cells have not been fully elucidated. Here we uncover a hierarchical role of ISL1 in cardiac progenitor cells, showing that ISL1 directly regulates hundreds of potential downstream target genes that are implicated in cardiac differentiation, through an epigenetic mechanism. Specifically, ISL1 promotes the demethylation of tri-methylation of histone H3K27 (H3K27me3) at the enhancers of key downstream target genes, including Myocd and Mef2c, which are core cardiac transcription factors. ISL1 physically interacts with JMJD3, a H3K27me3 demethylase, and conditional depletion of JMJD3 leads to impaired cardiac progenitor cell differentiation, phenocopying that of ISL1 depletion. Interestingly, ISL1 is not only responsible for the recruitment of JMJD3 to specific target loci during cardiac progenitor differentiation, but also modulates its demethylase activity. In conclusion, ISL1 and JMJD3 partner to alter the cardiac epigenome, instructing gene expression changes that drive cardiac differentiation.
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Wnt-promoted ISL1 expression through a novel TCF/LEF1 binding site and H3K9 acetylation in early stages of cardiomyocyte differentiation of P19CL6 cells.
Molecular and Cellular Biochemistry, 2014Co-Authors: Yang Wang, Weiping Wang, Ping Chen, Yinan Liu, Zhuqing Jia, Chunyan ZhouAbstract:Islet 1 (ISL1), a marker of second heart field progenitors, plays a crucial role in cardiomyocyte differentiation and proliferation. However, little is known about transcriptional regulating mechanisms on ISL1 gene expression. Recent studies have demonstrated that Wnt/β-catenin signaling regulates ISL1 expression during heart development. However, the detailed mechanisms still remain unclear. In the present study performed during differentiation of P19CL6 into cardiomyocytes, we explored the underlying regulating mechanisms on Wnt/β-catenin-mediated ISL1 expression after we first confirmed that Wnt/β-catenin signaling promoted cardiomyocyte differentiation partly through ISL1 activation. We found a novel TCF/LEF1 binding site that was located 2300 bp upstream of the ISL1 ATG. Furthermore, Wnt/β-catenin signaling upregulated histone H3K9 acetylation on TCF/LEF1 binding sites on the ISL1 promoter, resulting in upregulation of ISL1 expression. This Wnt-mediated H3K9 acetylation on the ISL1 promoter was modulated by the acetyltransferase CREB-binding protein (CBP), instead of p300, through interaction with β-catenin. Collectively, these results suggest that in early stages of cardiomyocyte differentiation Wnt/β-catenin signaling promotes ISL1 expression via two ways: a novel TCF/LEF1 binding site and H3K9 acetylation conducted by CBP on the ISL1 promoter. To our knowledge, this is the first study reporting Wnt/β-catenin-regulated H3K9 acetylation on promoters of its target genes. And this study gives new insights into transcriptional regulating mechanisms of Wnt-mediated ISL1 expression during cardiomyocyte differentiation.
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wnt promoted ISL1 expression through a novel tcf lef1 binding site and h3k9 acetylation in early stages of cardiomyocyte differentiation of p19cl6 cells
Molecular and Cellular Biochemistry, 2014Co-Authors: Yang Wang, Weiping Wang, Ping Chen, Yinan Liu, Zhuqing Jia, Chunyan ZhouAbstract:Islet 1 (ISL1), a marker of second heart field progenitors, plays a crucial role in cardiomyocyte differentiation and proliferation. However, little is known about transcriptional regulating mechanisms on ISL1 gene expression. Recent studies have demonstrated that Wnt/β-catenin signaling regulates ISL1 expression during heart development. However, the detailed mechanisms still remain unclear. In the present study performed during differentiation of P19CL6 into cardiomyocytes, we explored the underlying regulating mechanisms on Wnt/β-catenin-mediated ISL1 expression after we first confirmed that Wnt/β-catenin signaling promoted cardiomyocyte differentiation partly through ISL1 activation. We found a novel TCF/LEF1 binding site that was located 2300 bp upstream of the ISL1 ATG. Furthermore, Wnt/β-catenin signaling upregulated histone H3K9 acetylation on TCF/LEF1 binding sites on the ISL1 promoter, resulting in upregulation of ISL1 expression. This Wnt-mediated H3K9 acetylation on the ISL1 promoter was modulated by the acetyltransferase CREB-binding protein (CBP), instead of p300, through interaction with β-catenin. Collectively, these results suggest that in early stages of cardiomyocyte differentiation Wnt/β-catenin signaling promotes ISL1 expression via two ways: a novel TCF/LEF1 binding site and H3K9 acetylation conducted by CBP on the ISL1 promoter. To our knowledge, this is the first study reporting Wnt/β-catenin-regulated H3K9 acetylation on promoters of its target genes. And this study gives new insights into transcriptional regulating mechanisms of Wnt-mediated ISL1 expression during cardiomyocyte differentiation.
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ISL1 Promotes Pancreatic Islet Cell Proliferation
PLoS ONE, 2011Co-Authors: Ting Guo, Hui Zhang, Weiping Wang, Ping Chen, Yinan Liu, Chunyan ZhouAbstract:Background Islet 1 (ISL1), a LIM-homeodomain transcription factor is essential for promoting pancreatic islets proliferation and maintaining endocrine cells survival in embryonic and postnatal pancreatic islets. However, how ISL1 exerts the role in adult islets is, to date, not clear. Methodology/Principal Findings Our results show that ISL1 expression was up-regulated at the mRNA level both in cultured pancreatic cells undergoing glucose oxidase stimulation as well in type 1 and type 2 diabetes mouse models. The knockdown of ISL1 expression increased the apoptosis level of HIT-T15 pancreatic islet cells. Using HIT-T15 and primary adult islet cells as cell models, we show that ISL1 promoted adult pancreatic islet cell proliferation with increased c-Myc and CyclinD1 transcription, while knockdown of ISL1 increased the proportion of cells in G1 phase and decreased the proportion of cells in G2/M and S phases. Further investigation shows that ISL1 activated both c-Myc and CyclinD1 transcription through direct binding on their promoters. Conclusions/Significance ISL1 promoted adult pancreatic islet cell proliferation and probably by activating c-Myc and CyclinD1 transcription through direct binding on their promoters. Our findings extend the knowledge about the crucial role of ISL1 in maintaining mature islet cells homeostasis. Our results also provide insights into the new regulation relationships between ISL1 and other growth factors.
Samuel L. Pfaff - One of the best experts on this subject based on the ideXlab platform.
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ISL1 is required for multiple aspects of motor neuron development.
Molecular and Cellular Neuroscience, 2011Co-Authors: Xingqun Liang, Sylvia M Evans, Samuel L. Pfaff, Yihan Chen, Mi-ryoung Song, Guillermo M. Lanuza, Yali Liu, Tao Zhuang, Yunfu SunAbstract:The LIM homeodomain transcription factor Islet1 (ISL1) is expressed in multiple organs and plays essential roles during embryogenesis. ISL1 is required for the survival and specification of spinal cord motor neurons. Due to early embryonic lethality and loss of motor neurons, the role of ISL1 in other aspects of motor neuron development remains unclear. In this study, we generated ISL1 mutant mouse lines expressing graded doses of ISL1. Our study has revealed essential roles of ISL1 in multiple aspects of motor neuron development, including motor neuron cell body localization, motor column formation and axon growth. In addition, ISL1 is required for survival of cranial ganglia neurons.
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a postmitotic role for isl class lim homeodomain proteins in the assignment of visceral spinal motor neuron identity
Neuron, 2004Co-Authors: Joshua P Thaler, Thomas M Jessell, Sonya J Koo, Artur Kania, Karen Lettieri, Shane E Andrews, Christopher L Cox, Samuel L. PfaffAbstract:LIM homeobox genes have a prominent role in the regulation of neuronal subtype identity and distinguish motor neuron subclasses in the embryonic spinal cord. We have investigated the role of Isl-class LIM homeodomain proteins in motor neuron diversification using mouse genetic methods. All spinal motor neuron subtypes initially express both ISL1 and Isl2, but Isl2 is rapidly downregulated by visceral motor neurons. Mouse embryos lacking Isl2 function exhibit defects in the migration and axonal projections of thoracic level motor neurons that appear to reflect a cell-autonomous switch from visceral to somatic motor neuron character. Additional genetic mutations that reduce or eliminate both ISL1 and Isl2 activity result in more pronounced defects in visceral motor neuron generation and erode somatic motor neuron character. Thus, an early phase of high Isl expression and activity in newly generated motor neurons permits the diversification of visceral and somatic motor neuron subtypes in the developing spinal cord.
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ISL1 Identifies a Cardiac Progenitor Population that Proliferates Prior to Differentiation and Contributes a Majority of Cells to the Heart
Developmental Cell, 2003Co-Authors: Chen-leng Cai, Samuel L. Pfaff, Xingqun Liang, Yunqing Shi, Po-hsien Chu, Ju Chen, Sylvia M EvansAbstract:Hearts of mice lacking ISL1, a LIM homeodomain transcription factor, are completely missing the outflow tract, right ventricle, and much of the atria. ISL1 expression and lineage tracing of ISL1-expressing progenitors demonstrate that ISL1 is a marker for a distinct population of undifferentiated cardiac progenitors that give rise to the cardiac segments missing in ISL1 mutants. ISL1 function is required for these progenitors to contribute to the heart. In ISL1 mutants, ISL1-expressing progenitors are progressively reduced in number, and FGF and BMP growth factors are downregulated. Our studies define two sets of cardiogenic precursors, one of which expresses and requires ISL1 and the other of which does not. Our results have implications for the development of specific cardiac lineages, left-right asymmetry, cardiac evolution, and isolation of cardiac progenitor cells.
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the nuclear lim domain interactor nli mediates homo and heterodimerization of lim domain transcription factors
Journal of Biological Chemistry, 1998Co-Authors: Linda W Jurata, Samuel L. Pfaff, Gordon N GillAbstract:Abstract LIM domain-containing transcription factors are required for embryonic survival and for the determination of many cell types. The combinatorial expression of the LIM homeodomain proteins ISL1, Isl2, Lhx1, and Lhx3 in subsets of developing motor neurons correlates with the future organization of these neurons into motor columns with distinct innervation targets, implying a functional role for LIM homeodomain protein combinations in the specification of neuronal identity. NLI is a widely expressed, dimeric protein that has been shown to specifically interact with the LIM domains of LIM domain-containing transcription factors. The present studies demonstrate that NLI mediates homo- and heteromeric complex formation between LIM domain transcription factors, requiring both the N-terminal dimerization and C-terminal LIM interaction domains of NLI. Although the interaction between most LIM homeodomain proteins is dependent on NLI, a direct interaction between the LIM domains of Lhx3 and the homeodomains of ISL1 and Isl2 was also observed. This interaction was disrupted by NLI, demonstrating that the conformational state of Lhx3-ISL1/Isl2 complexes is modified by NLI. Evidence indicating that NLI facilitates long range enhancer-promoter interactions suggests that NLI-dependent LIM domain transcription factor complexes are involved in communication between transcriptional control elements.
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independent requirement for ISL1 in formation of pancreatic mesenchyme and islet cells
Nature, 1997Co-Authors: Ulf Ahlgren, Thomas M Jessell, Samuel L. Pfaff, Thomas Edlund, Helena EdlundAbstract:The mammalian pancreas is a specialized derivative of the primitive gut endoderm and controls many homeostatic functions through the activity of its component exocrine acinar and endocrine islet cells. The LIM homeodomain protein ISL1 is expressed in all classes of islet cells in the adult1,2 and its expression in the embryo is initiated soon after the islet cells have left the cell cycle. ISL1 is also expressed in mesenchymal cells that surround the dorsal but not ventral evagination of the gut endoderm, which together comprise the pancreatic anlagen. To define the role of ISL1 in the development of the pancreas, we have now analysed acinar and islet cell differentiation in mice deficient in ISL1 function3. Dorsal pancreatic mesenchyme does not form in ISL1-mutant embryos and there is an associated failure of exocrine cell differentiation in the dorsal but not the ventral pancreas. There is also a complete loss of differentiated islet cells. Exocrine, but not endocrine, cell differentiation in the dorsal pancreas can be rescued in vitro by provision of mesenchyme derived from wild-type embryos. These results indicate that ISL1, by virtue of its requirement for the formation of dorsal mesenchyme, is necessary for the development of the dorsal exocrine pancreas, and also that ISL1 function in pancreatic endodermal cells is required for the generation of all endocrine islet cells.
Lin Gan - One of the best experts on this subject based on the ideXlab platform.
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Transcription factor ISL1 is dispensable for the development of the mouse prosensory region
Cytotechnology, 2020Co-Authors: Rui Guo, Dongwang Zheng, Luming Guo, Lin GanAbstract:In order to identify genes involved in the development of inner ear hair cells, we investigated the role of the transcription factor Islet-class LIM-homeodomain (LIM-HD) 1 (ISL1) in the development of the mouse prosensory region. ISL1 was deleted using the Pax2-Cre system, and deletion of both alleles was verified using cochlea sections. Changes in the number of prosensory region cells were measured to determine the effect of ISL1 on the development of the mouse prosensory region. In order to test whether ISL1 formed a protein complex with Ldb1 and Gata3, co-immunoprecipitation experiments were performed in HEK293 cells using the Flag-tagged LIM-domain of ISL1, HA-tagged LID of Ldb1 and Myc-tagged C-terminal domain of Gata3. The expression of Gata3, Sox2, Jag1 and P27 proteins in the prosensory region were not affected in ISL1-/- prosensory cells. Thus, ISL1 did not form a protein complex with Gata3 through Ldb1 in the ISL1-/- cells. Our results suggest that ISL1 may be dispensable for the development of the mouse prosensory region.
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ISL1 regulation of nkx2 1 in the early foregut epithelium is required for trachea esophageal separation and lung lobation
Developmental Cell, 2019Co-Authors: Eugene Kim, Lin Gan, Ming Jiang, Huachao Huang, Yongchun Zhang, Natalie Tjota, Xia Gao, Jacques Robert, Nikesha Gilmore, Jianwen QueAbstract:The esophagus and trachea arise from the dorsal and ventral aspects of the anterior foregut, respectively. Abnormal trachea-esophageal separation leads to the common birth defect esophageal atresia with or without trachea-esophageal fistula (EA/TEF). Yet the underlying cellular mechanisms remain unknown. Here, we combine Xenopus and mouse genetic models to identify that the transcription factor ISL1 orchestrates trachea-esophageal separation through modulating a specific epithelial progenitor cell population (midline epithelial cells [MECs], ISL1+ Nkx2.1+ Sox2+) located at the dorsal-ventral boundary of the foregut. Lineage tracing experiments show that MECs contribute to both tracheal and esophageal epithelium, and ISL1 is required for Nkx2.1 transcription in MECs. Deletion of the chromosomal region spanning the ISL1 gene has been found in patients with abnormal trachea-esophageal separation. Our studies thus provide definitive evidence that ISL1 is a critical player in the process of foregut morphogenesis, acting in a small progenitor population of boundary cells.
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ISL1 Regulation of Nkx2.1 in the Early Foregut Epithelium Is Required for Trachea-Esophageal Separation and Lung Lobation
SSRN Electronic Journal, 2019Co-Authors: Eugene Kim, Lin Gan, Ming Jiang, Huachao Huang, Yongchun Zhang, Jacques Robert, Nikesha Gilmore, Jianwen QueAbstract:The esophagus and trachea arise from the dorsal and ventral aspects of the anterior foregut, respectively. Abnormal separation of the esophagus and trachea leads to the formation of the common birth defect esophageal atresia with/without tracheoesophageal fistula (EA/TEF). Although loss of multiple signaling molecules and transcription factors has been implicated in EA/TEF formation, the underlying cellular mechanisms remain unknown. Here, we combine Xenopus and mouse genetic models to identify the transcription factor ISL1 as a new player regulating trachea-esophageal separation. Significantly, we find that ISL1 orchestrates the separation process through modulating a specific epithelial progenitor cell population (ISL1+ Nkx2.1+ Sox2+) located at the dorsal-ventral boundary of the foregut. Our lineage tracing experiments show that this population contributes to both tracheal and esophageal epithelium. Moreover, ISL1 is required for the transcription of Nkx2.1 in this unique population. Finally, deletion of the chromosomal region spanning the ISL1 gene has been found in patients with abnormal trachea-esophageal separation. Our studies thus provide definitive evidence that ISL1 is a new player in the process of foregut morphogenesis, acting in a small progenitor population of boundary cells.
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ISL1 Is Necessary for Maximal Thyrotrope Response to Hypothyroidism.
Molecular Endocrinology, 2015Co-Authors: Frederic Castinetti, Lin Gan, Michelle L. Brinkmeier, Amanda H. Mortensen, Kristen R. Vella, Peter Gergics, Thierry Brue, Anthony N. Hollenberg, Sally A. CamperAbstract:ISLET1 is a homeodomain transcription factor necessary for development of the pituitary, retina, motor neurons, heart, and pancreas. ISL1-deficient mice (ISL1(-/-)) die early during embryogenesis at embryonic day 10.5 due to heart defects, and at that time, they have an undersized pituitary primordium. ISL1 is expressed in differentiating pituitary cells in early embryogenesis. Here, we report the cell-specific expression of ISL1 and assessment of its role in gonadotropes and thyrotropes. ISL1 expression is elevated in pituitaries of Cga(-/-) mice, a model of hypothyroidism with thyrotrope hypertrophy and hyperplasia. Thyrotrope-specific disruption of ISL1 with Tshb-cre is permissive for normal serum TSH, but T4 levels are decreased, suggesting decreased thyrotrope function. Inducing hypothyroidism in normal mice causes a reduction in T4 levels and dramatically elevated TSH response, but mice with thyrotrope-specific disruption of ISL1 have a blunted TSH response. In contrast, deletion of ISL1 in gonadotropes with an Lhb-cre transgene has no obvious effect on gonadotrope function or fertility. These results show that ISL1 is necessary for maximal thyrotrope response to hypothyroidism, in addition to its role in development of Rathke's pouch.
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Comparative expression analysis of POU4F1, POU4F2 and ISL1 in developing mouse cochleovestibular ganglion neurons
Gene Expression Patterns, 2014Co-Authors: Min Deng, Hua Yang, Xiaoling Xie, Guoqing Liang, Lin GanAbstract:POU-homeodomain and LIM-homeodomain transcription factors are expressed in developing projection neurons within retina, inner ear, dorsal root ganglion, and trigeminal ganglion, and play synergistic roles in their differentiation and survival. Here, using immunohistochemistry, we present a comparative analysis of the spatiotemporal expression pattern of POU4F1, POU4F2, and ISL1 during the development of cochleovestibular ganglion (CVG) neurons in mouse inner ear. At early stages, when otic neurons are first detected in the otic epithelium (OE) and migrate into periotic mesenchyme to form the CVG, POU4F1 and ISL1 are co-expressed in a majority of the delaminated CVG neurons, which are marked by NEUROD1 expression, but POU4F1 is absent in the otic epithelium. The onset of POU4F2 expression starts after that of POU4F1 and ISL1, and is observed in the NEUROD1-negative, post-mitotic CVG neurons. When the CVG neurons innervate the vestibular and cochlear sensory organs, the expression of POU4F1, POU4F2, and ISL1 continues in both vestibular and spiral ganglion cells. Later in development, POU4F1 expression becomes down-regulated in a majority of spiral ganglion (SG) neurons and more neurons express POU4F2 expression while ISL1 expression is maintained. The differential as well as overlapping expression of POU4F1, POU4F2, and ISL1 combined with previous studies suggests possible functional interaction and regulatory relationship of these transcription factors in the development of inner ear neurons.
Sylvia M Evans - One of the best experts on this subject based on the ideXlab platform.
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LIM Homeodomain Transcription Factor ISL1 Affects Urethral Epithelium Differentiation and Apoptosis via Shh
Cell Death & Disease, 2019Co-Authors: Hui Liu, Sylvia M Evans, Di Zhang, Jiali Liu, Jirong Pan, Sheng CuiAbstract:Urethral hypoplasia, including failure of urethral tube closure, is one of the common phenotypes observed in hereditary human disorders, the mechanism of which remains unclear. The present study was thus designed to study the expression, functions, and related mechanisms of the LIM homeobox transcription factor ISL1 throughout mouse urethral development. Results showed that ISL1 was highly expressed in urethral epithelial cells and mesenchymal cells of the genital tubercle (GT). Functional studies were carried out by utilizing the tamoxifen-inducible ISL1-knockout mouse model. Histological and morphological results indicated that ISL1 deletion caused urethral hypoplasia and inhibited maturation of the complex urethral epithelium. In addition, we show that ISL1-deleted mice failed to maintain the progenitor cell population required for renewal of urethral epithelium during tubular morphogenesis and exhibited significantly increased cell death within the urethra. Dual-Luciferase reporter assays and yeast one-hybrid assays showed that ISL1 was essential for normal urethral development by directly targeting the Shh gene. Collectively, results presented here demonstrated that ISL1 plays a crucial role in mouse urethral development, thus increasing our potential for understanding the mechanistic basis of hereditary urethral hypoplasia.
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the ISL1 ldb1 complex orchestrates genome wide chromatin organization to instruct differentiation of multipotent cardiac progenitors
Cell Stem Cell, 2015Co-Authors: Luca Caputo, Sirisha Cheedipudi, Hagen R. Witzel, Petros Kolovos, Mario Looso, Athina Mylona, Wilfred F. J. Van Ijcken, Karl-ludwig Laugwitz, Sylvia M EvansAbstract:Cardiac stem/progenitor cells hold great potential for regenerative therapies however the mechanisms regulating their expansion and differentiation remain insufficiently defined. Here we show that the multi-adaptor protein Ldb1 is a central regulator of cardiac progenitor cell differentiation and second heart field (SHF) development. Mechanistically, we demonstrate that Ldb1 binds to the key regulator of SHF progenitors ISL1 and protects it from proteasomal degradation. Furthermore, the ISL1/Ldb1 complex promotes long-range promoter-enhancer interactions at the loci of the core cardiac transcription factors Mef2c and Hand2. Chromosome conformation capture followed by sequencing identified surprisingly specific, Ldb1-mediated interactions of the ISL1/Ldb1 responsive Mef2c anterior heart field enhancer with genes which play key roles in cardiac progenitor cell function and cardiovascular development. Importantly, the expression of these genes was downregulated upon Ldb1 depletion and ISL1/Ldb1 haplodeficiency. In conclusion, the ISL1/Ldb1 complex orchestrates a network for heart-specific transcriptional regulation and coordination in three-dimensional space during cardiogenesis.
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The ISL1/Ldb1 Complex Orchestrates Genome-wide Chromatin Organization to Instruct Differentiation of Multipotent Cardiac Progenitors
Cell Stem Cell, 2015Co-Authors: Luca Caputo, Sylvia M Evans, Sirisha Cheedipudi, Hagen R. Witzel, Petros Kolovos, Mario Looso, Athina Mylona, Wilfred F. J. Van Ijcken, Karl-ludwig Laugwitz, Thomas BraunAbstract:Cardiac stem/progenitor cells hold great potential for regenerative therapies however the mechanisms regulating their expansion and differentiation remain insufficiently defined. Here we show that the multi-adaptor protein Ldb1 is a central regulator of cardiac progenitor cell differentiation and second heart field (SHF) development. Mechanistically, we demonstrate that Ldb1 binds to the key regulator of SHF progenitors ISL1 and protects it from proteasomal degradation. Furthermore, the ISL1/Ldb1 complex promotes long-range promoter-enhancer interactions at the loci of the core cardiac transcription factors Mef2c and Hand2. Chromosome conformation capture followed by sequencing identified surprisingly specific, Ldb1-mediated interactions of the ISL1/Ldb1 responsive Mef2c anterior heart field enhancer with genes which play key roles in cardiac progenitor cell function and cardiovascular development. Importantly, the expression of these genes was downregulated upon Ldb1 depletion and ISL1/Ldb1 haplodeficiency. In conclusion, the ISL1/Ldb1 complex orchestrates a network for heart-specific transcriptional regulation and coordination in three-dimensional space during cardiogenesis.
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Distinct populations within ISL1 lineages contribute to appendicular and facial skeletogenesis through the β-catenin pathway
Developmental Biology, 2014Co-Authors: Ryutaro Akiyama, Sylvia M Evans, Hiroko Kawakami, Makoto Mark Taketo, Naoyuki Wada, Anna Petryk, Yasuhiko KawakamiAbstract:ISL1 expression marks progenitor populations in developing embryos. In this study, we investigated the contribution of ISL1-expressing cells that utilize the β-catenin pathway to skeletal development. Inactivation of β-catenin in ISL1-expressing cells caused agenesis of the hindlimb skeleton and absence of the lower jaw (agnathia). In the hindlimb, ISL1-lineages broadly contributed to the mesenchyme; however, deletion of β-catenin in the ISL1-lineage caused cell death only in a discrete posterior domain of nascent hindlimb bud mesenchyme. We found that the loss of posterior mesenchyme, which gives rise to Shh-expressing posterior organizer tissue, caused loss of posterior gene expression and failure to expand chondrogenic precursor cells, leading to severe truncation of the hindlimb. In facial tissues, ISL1-expressing cells broadly contributed to facial epithelium. We found reduced nuclear β-catenin accumulation and loss of Fgf8 expression in mandibular epithelium of ISL1(-/-) embryos. Inactivating β-catenin in ISL1-expressing epithelium caused both loss of epithelial Fgf8 expression and death of mesenchymal cells in the mandibular arch without affecting epithelial proliferation and survival. These results suggest a ISL1→β-catenin→Fgf8 pathway that regulates mesenchymal survival and development of the lower jaw in the mandibular epithelium. By contrast, activating β-catenin signaling in ISL1-lineages caused activation of Fgf8 broadly in facial epithelium. Our results provide evidence that, despite its broad contribution to hindlimb mesenchyme and facial epithelium, the ISL1-β-catenin pathway regulates skeletal development of the hindlimb and lower jaw through discrete populations of cells that give rise to Shh-expressing posterior hindlimb mesenchyme and Fgf8-expressing mandibular epithelium.
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islet1 deletion causes kidney agenesis and hydroureter resembling cakut
Journal of The American Society of Nephrology, 2013Co-Authors: Yusuke Kaku, Tomoko Ohmori, Kuniko Kudo, Sayoko Fujimura, Yasuhiko Kawakami, Sylvia M Evans, Kentaro Suzuki, Ryuichi NishinakamuraAbstract:Islet1 (ISL1) is a transcription factor transiently expressed in a subset of heart and limb progenitors. During studies of limb development, conditional ISL1 deletion produced unexpected kidney abnormalities. Here, we studied the renal expression of ISL1 and whether it has a role in kidney development. In situ hybridization revealed ISL1 expression in the mesenchymal cells surrounding the base of the ureteric bud in mice. Conditional deletion of ISL1 caused kidney agenesis or hypoplasia and hydroureter, a phenotype resembling human congenital anomalies of the kidney and urinary tract (CAKUT). The absence of ISL1 led to ectopic branching of the ureteric bud out from the nephric duct or to the formation of accessory buds, both of which could lead to obstruction of the ureter-bladder junction and consequent hydroureter. The abnormal elongation and poor branching of the ureteric buds were the likely causes of the kidney agenesis or hypoplasia. Furthermore, the lack of ISL1 reduced the expression of Bmp4, a gene implicated in the CAKUT-like phenotype, in the metanephric region before ureteric budding. In conclusion, ISL1 is essential for proper development of the kidney and ureter by repressing the aberrant formation of the ureteric bud. These observations call for further studies to investigate whether ISL1 may be a causative gene for human CAKUT.
Alessandra Moretti - One of the best experts on this subject based on the ideXlab platform.
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the renewal and differentiation of ISL1 cardiovascular progenitors are controlled by a wnt β catenin pathway
Cell Stem Cell, 2007Co-Authors: Yibing Qyang, Silvia Martinpuig, Murali Chiravuri, Shuibing Chen, Huansheng Xu, Lei Bu, Xin Jiang, Anne Granger, Alessandra MorettiAbstract:Summary ISL1 + cardiovascular progenitors and their downstream progeny play a pivotal role in cardiogenesis and lineage diversification of the heart. The mechanisms that control their renewal and differentiation are largely unknown. Herein, we show that the Wnt/β-catenin pathway is a major component by which cardiac mesenchymal cells modulate the prespecification, renewal, and differentiation of ISL1 + cardiovascular progenitors. This microenvironment can be reconstituted by a Wnt3a-secreting feeder layer with ES cell-derived, embryonic, and postnatal ISL1 + cardiovascular progenitors. In vivo activation of β-catenin signaling in ISL1 + progenitors of the secondary heart field leads to their massive accumulation, inhibition of differentiation, and outflow tract (OFT) morphogenic defects. In addition, the mitosis rate in OFT myocytes is significantly reduced following β-catenin deletion in ISL1 + precursors. Agents that manipulate Wnt signals can markedly expand ISL1 + progenitors from human neonatal hearts, a key advance toward the cloning of human ISL1 + heart progenitors.
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biology of ISL1 cardiac progenitor cells in development and disease
Cellular and Molecular Life Sciences, 2007Co-Authors: Alessandra Moretti, Sylvia M Evans, J. Lam, Karl-ludwig LaugwitzAbstract:The LIM-homeodomain transcription factor Islet-1 (ISL1) marks a cell population which makes a substantial contribution to the embryonic heart. ISL1 expression is downregulated as soon as the cells adopt a differentiated phenotype, suggesting that this transcription factor delineates a cardiogenic progenitor cell population. Taking advantage of this developmental lineage marker, we have identified in the postnatal heart a novel cardiac cell type, which is capable of self-renewal and readily differentiates into mature cardiomyocytes. Utilization of embryonic stem (ES) cells that harbour knock-ins of reporter genes into the endogenous ISL1 locus will enable us to isolate ISL1+ cardiac progenitors from mouse and human ES cell systems during in vitro cardiogenesis. These genetic cell-based systems should allow the direct identification of signalling pathways which guide formation, renewal and diversification of ISL1+ cardiogenic progenitors into distinct heart cell lineages, and would complement in vitro studies in the mouse embryo during cardiac development.
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Cardiovascular development: towards biomedical applicability: Biology of ISL1 + cardiac progenitor cells in development and disease
Cellular and Molecular Life Sciences, 2007Co-Authors: Alessandra Moretti, Sylvia M Evans, J. Lam, Karl-ludwig LaugwitzAbstract:The LIM-homeodomain transcription factor Islet-1 (ISL1) marks a cell population which makes a substantial contribution to the embryonic heart. ISL1 expression is downregulated as soon as the cells adopt a differentiated phenotype, suggesting that this transcription factor delineates a cardiogenic progenitor cell population. Taking advantage of this developmental lineage marker, we have identified in the postnatal heart a novel cardiac cell type, which is capable of self-renewal and readily differentiates into mature cardiomyocytes. Utilization of embryonic stem (ES) cells that harbour knock-ins of reporter genes into the endogenous ISL1 locus will enable us to isolate ISL1+ cardiac progenitors from mouse and human ES cell systems during in vitro cardiogenesis. These genetic cell-based systems should allow the direct identification of signalling pathways which guide formation, renewal and diversification of ISL1+ cardiogenic progenitors into distinct heart cell lineages, and would complement in vitro studies in the mouse embryo during cardiac development.
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The Renewal and Differentiation of ISL1+ Cardiovascular Progenitors Are Controlled by a Wnt/β-Catenin Pathway
Cell Stem Cell, 2007Co-Authors: Yibing Qyang, Lizhu Lin, Murali Chiravuri, Shuibing Chen, Xin Jiang, Anne Granger, Silvia Martin-puig, Alessandra MorettiAbstract:Summary ISL1 + cardiovascular progenitors and their downstream progeny play a pivotal role in cardiogenesis and lineage diversification of the heart. The mechanisms that control their renewal and differentiation are largely unknown. Herein, we show that the Wnt/β-catenin pathway is a major component by which cardiac mesenchymal cells modulate the prespecification, renewal, and differentiation of ISL1 + cardiovascular progenitors. This microenvironment can be reconstituted by a Wnt3a-secreting feeder layer with ES cell-derived, embryonic, and postnatal ISL1 + cardiovascular progenitors. In vivo activation of β-catenin signaling in ISL1 + progenitors of the secondary heart field leads to their massive accumulation, inhibition of differentiation, and outflow tract (OFT) morphogenic defects. In addition, the mitosis rate in OFT myocytes is significantly reduced following β-catenin deletion in ISL1 + precursors. Agents that manipulate Wnt signals can markedly expand ISL1 + progenitors from human neonatal hearts, a key advance toward the cloning of human ISL1 + heart progenitors.
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Cardiovascular development: towards biomedical applicability : Biology of ISL1+ cardiac progenitor cells in development and disease (Multi-author Review)
Cellular and Molecular Life Sciences, 2007Co-Authors: Alessandra Moretti, Sylvia M Evans, J. Lam, Karl-ludwig LaugwitzAbstract:The LIM-homeodomain transcription factor Islet-1 (ISL1) marks a cell population which makes a substantial contribution to the embryonic heart. ISL1 expression is downregulated as soon as the cells adopt a differentiated phenotype, suggesting that this transcription factor delineates a cardiogenic progenitor cell population. Taking advantage of this developmental lineage marker, we have identified in the postnatal heart a novel cardiac cell type, which is capable of self-renewal and readily differentiates into mature cardiomyocytes. Utilization of embryonic stem (ES) cells that harbour knock-ins of reporter genes into the endogenous ISL1 locus will enable us to isolate ISL1 + cardiac progenitors from mouse and human ES cell systems during in vitro cardiogenesis. These genetic cell-based systems should allow the direct identification of signalling pathways which guide formation, renewal and diversification of ISL1 + cardiogenic progenitors into distinct heart cell lineages, and would complement in vitro studies in the mouse embryo during cardiac development.
