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The LIM protein complex establishes a retinal circuitry of visual adaptation by regulating Pax6 α-enhancer activity.
Kim Y, Lim S, Ha T, Song YH, Sohn YI, Park DJ, Paik SS, Kim-Kaneyama JR, Song MR, Leung A, Levine EM, Kim IB, Goo YS, Lee SH, Kang KH, Kim JW
(2017) Elife 6:
MeSH Terms: Adaptation, Ocular, Animals, Cytoskeletal Proteins, DNA-Binding Proteins, Enhancer Elements, Genetic, Gene Expression Regulation, LIM Domain Proteins, LIM-Homeodomain Proteins, Mice, Mice, Knockout, PAX6 Transcription Factor, Retina, Transcription Factors
Show Abstract · Added February 14, 2018
The visual responses of vertebrates are sensitive to the overall composition of retinal interneurons including amacrine cells, which tune the activity of the retinal circuitry. The expression of is regulated by multiple cis-DNA elements including the intronic α-enhancer, which is active in GABAergic amacrine cell subsets. Here, we report that the transforming growth factor ß1-induced transcript 1 protein (Tgfb1i1) interacts with the LIM domain transcription factors Lhx3 and Isl1 to inhibit the α-enhancer in the post-natal mouse retina. mice show elevated α-enhancer activity leading to overproduction of Pax6ΔPD isoform that supports the GABAergic amacrine cell fate maintenance. Consequently, the mouse retinas show a sustained light response, which becomes more transient in mice with the auto-stimulation-defective mutation. Together, we show the antagonistic regulation of the α-enhancer activity by Pax6 and the LIM protein complex is necessary for the establishment of an inner retinal circuitry, which controls visual adaptation.
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13 MeSH Terms
Inactivating the permanent neonatal diabetes gene Mnx1 switches insulin-producing β-cells to a δ-like fate and reveals a facultative proliferative capacity in aged β-cells.
Pan FC, Brissova M, Powers AC, Pfaff S, Wright CV
(2015) Development 142: 3637-48
MeSH Terms: Animals, Cell Transdifferentiation, Cellular Senescence, Diabetes Mellitus, Eye Proteins, Homeodomain Proteins, Humans, Hyperplasia, Insulin-Secreting Cells, Mice, PAX6 Transcription Factor, Paired Box Transcription Factors, Repressor Proteins, Somatostatin-Secreting Cells, Transcription Factors
Show Abstract · Added December 28, 2015
Homozygous Mnx1 mutation causes permanent neonatal diabetes in humans, but via unknown mechanisms. Our systematic and longitudinal analysis of Mnx1 function during murine pancreas organogenesis and into the adult uncovered novel stage-specific roles for Mnx1 in endocrine lineage allocation and β-cell fate maintenance. Inactivation in the endocrine-progenitor stage shows that Mnx1 promotes β-cell while suppressing δ-cell differentiation programs, and is crucial for postnatal β-cell fate maintenance. Inactivating Mnx1 in embryonic β-cells (Mnx1(Δbeta)) caused β-to-δ-like cell transdifferentiation, which was delayed until postnatal stages. In the latter context, β-cells escaping Mnx1 inactivation unexpectedly upregulated Mnx1 expression and underwent an age-independent persistent proliferation. Escaper β-cells restored, but then eventually surpassed, the normal pancreatic β-cell mass, leading to islet hyperplasia in aged mice. In vitro analysis of islets isolated from Mnx1(Δbeta) mice showed higher insulin secretory activity and greater insulin mRNA content than in wild-type islets. Mnx1(Δbeta) mice also showed a much faster return to euglycemia after β-cell ablation, suggesting that the new β-cells derived from the escaper population are functional. Our findings identify Mnx1 as an important factor in β-cell differentiation and proliferation, with the potential for targeting to increase the number of endogenous β-cells for diabetes therapy.
© 2015. Published by The Company of Biologists Ltd.
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15 MeSH Terms
DMH1, a highly selective small molecule BMP inhibitor promotes neurogenesis of hiPSCs: comparison of PAX6 and SOX1 expression during neural induction.
Neely MD, Litt MJ, Tidball AM, Li GG, Aboud AA, Hopkins CR, Chamberlin R, Hong CC, Ess KC, Bowman AB
(2012) ACS Chem Neurosci 3: 482-91
MeSH Terms: Adult, Animals, Bone Morphogenetic Proteins, Carrier Proteins, Child, Eye Proteins, Female, Gene Expression Regulation, Homeodomain Proteins, Humans, Induced Pluripotent Stem Cells, Male, Mice, Middle Aged, Neural Inhibition, Neural Stem Cells, Neurogenesis, Neurons, PAX6 Transcription Factor, Paired Box Transcription Factors, Pyrazoles, Quinolines, Repressor Proteins, SOXB1 Transcription Factors, Stem Cells
Show Abstract · Added August 25, 2013
Recent successes in deriving human-induced pluripotent stem cells (hiPSCs) allow for the possibility of studying human neurons derived from patients with neurological diseases. Concomitant inhibition of the BMP and TGF-β1 branches of the TGF-β signaling pathways by the endogenous antagonist, Noggin, and the small molecule SB431542, respectively, induces efficient neuralization of hiPSCs, a method known as dual-SMAD inhibition. The use of small molecule inhibitors instead of their endogenous counterparts has several advantages including lower cost, consistent activity, and the maintenance of xeno-free culture conditions. We tested the efficacy of DMH1, a highly selective small molecule BMP-inhibitor for its potential to replace Noggin in the neuralization of hiPSCs. We compare Noggin and DMH1-induced neuralization of hiPSCs by measuring protein and mRNA levels of pluripotency and neural precursor markers over a period of seven days. The regulation of five of the six markers assessed was indistinguishable in the presence of concentrations of Noggin or DMH1 that have been shown to effectively inhibit BMP signaling in other systems. We observed that by varying the DMH1 or Noggin concentration, we could selectively modulate the number of SOX1 expressing cells, whereas PAX6, another neural precursor marker, remained the same. The level and timing of SOX1 expression have been shown to affect neural induction as well as neural lineage. Our observations, therefore, suggest that BMP-inhibitor concentrations need to be carefully monitored to ensure appropriate expression levels of all transcription factors necessary for the induction of a particular neuronal lineage. We further demonstrate that DMH1-induced neural progenitors can be differentiated into β3-tubulin expressing neurons, a subset of which also express tyrosine hydroxylase. Thus, the combined use of DMH1, a highly specific BMP-pathway inhibitor, and SB431542, a TGF-β1-pathway specific inhibitor, provides us with the tools to independently regulate these two pathways through the exclusive use of small molecule inhibitors.
3 Communities
4 Members
0 Resources
25 MeSH Terms
Islet beta-cell-specific MafA transcription requires the 5'-flanking conserved region 3 control domain.
Raum JC, Hunter CS, Artner I, Henderson E, Guo M, Elghazi L, Sosa-Pineda B, Ogihara T, Mirmira RG, Sussel L, Stein R
(2010) Mol Cell Biol 30: 4234-44
MeSH Terms: 5' Flanking Region, Animals, Base Sequence, Basic Helix-Loop-Helix Transcription Factors, Cells, Cultured, Eye Proteins, Glucose, Homeodomain Proteins, Humans, Insulin-Secreting Cells, Maf Transcription Factors, Large, Mice, Mice, Transgenic, Molecular Sequence Data, Mutation, Nerve Tissue Proteins, PAX6 Transcription Factor, Paired Box Transcription Factors, Protein Binding, Regulatory Sequences, Nucleic Acid, Repressor Proteins, Transcription, Genetic
Show Abstract · Added December 5, 2013
MafA is a key transcriptional activator of islet beta cells, and its exclusive expression within beta cells of the developing and adult pancreas is distinct among pancreatic regulators. Region 3 (base pairs -8118 to -7750 relative to the transcription start site), one of six conserved 5' cis domains of the MafA promoter, is capable of directing beta-cell-line-selective expression. Transgenic reporters of region 3 alone (R3), sequences spanning regions 1 to 6 (R1-6; base pairs -10428 to +230), and R1-6 lacking R3 (R1-6(DeltaR3)) were generated. Only the R1-6 transgene was active in MafA(+) insulin(+) cells during development and in adult cells. R1-6 also mediated glucose-induced MafA expression. Conversely, pancreatic expression was not observed with the R3 or R1-6(DeltaR3) line, although much of the nonpancreatic expression pattern was shared between the R1-6 and R1-6(DeltaR3) lines. Further support for the importance of R3 was also shown, as the islet regulators Nkx6.1 and Pax6, but not NeuroD1, activated MafA in gel shift, chromatin immunoprecipitation (ChIP), and transfection assays and in vivo mouse knockout models. Lastly, ChIP demonstrated that Pax6 and Pdx-1 also bound to R1 and R6, potentially functioning in pancreatic and nonpancreatic expression. These data highlight the nature of the cis- and trans-acting factors controlling the beta-cell-specific expression of MafA.
2 Communities
1 Members
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22 MeSH Terms
Genetic determinants of pancreatic epsilon-cell development.
Heller RS, Jenny M, Collombat P, Mansouri A, Tomasetto C, Madsen OD, Mellitzer G, Gradwohl G, Serup P
(2005) Dev Biol 286: 217-24
MeSH Terms: Animals, Basic Helix-Loop-Helix Transcription Factors, Eye Proteins, Gene Expression Regulation, Developmental, Ghrelin, Glucagon, Green Fluorescent Proteins, Homeodomain Proteins, Islets of Langerhans, Mice, Mice, Mutant Strains, Mice, Transgenic, Nerve Tissue Proteins, PAX6 Transcription Factor, Paired Box Transcription Factors, Peptide Hormones, Recombinant Proteins, Repressor Proteins, Transcription Factors
Show Abstract · Added October 30, 2012
Recently, the expression of the peptide hormone ghrelin was detected in alpha-cells of the islets of Langerhans as well as in epsilon-cells, a newly discovered endocrine cell type, but it remains unclear how the latter is related in lineage to the four classical islet cell types, alpha-, beta-, delta-, and PP-cells. Here, we provide further evidence that ghrelin is predominantly produced in the alpha-cells of mouse islets but also in single hormone ghrelin-secreting epsilon-cells. We additionally demonstrate that pancreatic epsilon-cells derive from Neurogenin3-expressing precursor cells and their genesis depends on Neurogenin3 activity. Furthermore, our data indicate that the number of ghrelin-producing cells is differentially regulated during pancreas morphogenesis by the homeodomain-containing transcription factors Arx, Pax4, and Pax6. Arx mutants lack ghrelin+ glucagon+ alpha-cells whereas Pax4 mutants develop an excess of these cells. Importantly, the ghrelin+ glucagon- epsilon-cell population is not affected following Arx or Pax4 disruption. In contrast, the loss of Pax6 provokes an unexpected increase of the ghrelin+ glucagon- epsilon-cell number which is not due to increased proliferation. Thus, we demonstrate that the development of ghrelin-producing cells is differentially dependent on Neurogenin3 in different domains of the gastrointestinal tract and that, in the endocrine pancreas, epsilon-cell genesis does not require Arx or Pax4 activities but is antagonized by Pax6.
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19 MeSH Terms
Molecular profiling indicates avian branchiomotor nuclei invade the hindbrain alar plate.
Ju MJ, Aroca P, Luo J, Puelles L, Redies C
(2004) Neuroscience 128: 785-96
MeSH Terms: Animals, Body Patterning, Cadherins, Chick Embryo, Eye Proteins, Gene Expression Regulation, Developmental, Hedgehog Proteins, Homeodomain Proteins, Immunohistochemistry, In Situ Hybridization, Interferon Type I, Metalloproteins, Neurons, PAX6 Transcription Factor, PAX7 Transcription Factor, Paired Box Transcription Factors, Pregnancy Proteins, RNA, Messenger, Repressor Proteins, Reverse Transcriptase Polymerase Chain Reaction, Rhombencephalon, Spinal Cord, Trans-Activators, Transcription Factors
Show Abstract · Added November 5, 2010
It is generally believed that the spinal cord and hindbrain consist of a motor basal plate and a sensory alar plate. We now have molecular markers for these territories. The relationship of migrating branchiomotor neurons to molecularly defined alar and basal domains was examined in the chicken embryo by mapping the expression of cadherin-7 and cadherin-6B, in comparison to genetic markers for ventrodorsal patterning (Otp, Pax6, Pax7, Nkx2.2, and Shh) and motoneuron subpopulations (Phox2b and Isl1). We show cadherin-7 is expressed in a complete radial domain occupying a lateral region of the hindbrain basal plate. The cadherin-7 domain abuts the medial border of Pax7 expression; this common limit defines, or at least approximates, the basal/alar boundary. The hindbrain branchiomotor neurons originate in the medial part of the basal plate, close to the floor plate. Their cadherin-7-positive axons grow into the alar plate and exit the hindbrain close to the corresponding afferent nerve root. The cadherin-7-positive neuronal cell bodies later translocate laterally, following this axonal trajectory, thereby passing through the cadherin-7-positive basal plate domain. Finally, the cell bodies traverse the molecularly defined basal/alar boundary and move into positions within the alar plate. After the migration has ended, the branchiomotor neurons switch expression from cadherin-7 to cadherin-6B. These findings demonstrate that a specific subset of primary motor neurons, the branchiomotor neurons, migrate into the alar plate of the chicken embryo. Consequently, the century-old concept that all primary motor neurons come to reside in the basal plate should be revised.
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24 MeSH Terms
Differential regulation of islet-specific glucose-6-phosphatase catalytic subunit-related protein gene transcription by Pax-6 and Pdx-1.
Martin CC, Oeser JK, O'Brien RM
(2004) J Biol Chem 279: 34277-89
MeSH Terms: Amino Acid Motifs, Animals, Base Sequence, Binding Sites, Catalytic Domain, Cell Nucleus, Cells, Cultured, Chloramphenicol O-Acetyltransferase, Chromatin, DNA, Diabetes Mellitus, Experimental, Disease Models, Animal, Dose-Response Relationship, Drug, Electrophoresis, Polyacrylamide Gel, Eye Proteins, Gene Expression Regulation, Enzymologic, Glucose-6-Phosphatase, Homeodomain Proteins, Islets of Langerhans, Luciferases, Methylation, Mice, Molecular Sequence Data, Mutagenesis, Site-Directed, Mutation, Oligonucleotides, PAX6 Transcription Factor, Paired Box Transcription Factors, Plasmids, Polymerase Chain Reaction, Precipitin Tests, Promoter Regions, Genetic, Protein Binding, Protein Structure, Tertiary, Rats, Repressor Proteins, Salts, Subcellular Fractions, Trans-Activators, Transcription, Genetic
Show Abstract · Added July 30, 2015
Islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP) is selectively expressed in islet beta cells and is a major autoantigen in a mouse model of type I diabetes. The analysis of IGRP-chloramphenicol acetyltransferase (CAT) fusion gene expression through transient transfection of islet-derived betaTC-3 cells revealed that a promoter region, located between -273 and -254, is essential for high IGRP-CAT fusion gene expression. The sequence of this promoter region does not match that for any known islet-enriched transcription factor. However, data derived from gel retardation assays, a modified ligation-mediated polymerase chain reaction in situ footprinting technique and a SDS-polyacrylamide separation/renaturation procedure led to the hypothesis that this protein might be Pax-6, a conclusion that was confirmed by gel supershift assays. Additional experiments revealed a second non-consensus Pax-6 binding site in the -306/-274 IGRP promoter region. Pax-6 binding to these elements is unusual in that it appears to require both its homeo and paired domains. Interestingly, loss of Pax-6 binding to the -273/ -246 element is compensated by Pax-6 binding to the -306/-274 element and vice versa. Gel retardation assays revealed that another islet-enriched transcription factor, namely Pdx-1, binds four non-consensus elements in the IGRP promoter. However, mutation of these elements has little effect on IGRP fusion gene expression. Although chromatin immunoprecipitation assays show that both Pax-6 and Pdx-1 bind to the IGRP promoter within intact cells, in contrast to the critical role of these factors in beta cell-specific insulin gene expression, IGRP gene transcription appears to require Pax-6 but not Pdx-1.
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40 MeSH Terms
The role of Brn4/Pou3f4 and Pax6 in forming the pancreatic glucagon cell identity.
Heller RS, Stoffers DA, Liu A, Schedl A, Crenshaw EB, Madsen OD, Serup P
(2004) Dev Biol 268: 123-34
MeSH Terms: Animals, DNA-Binding Proteins, Eye Proteins, Glucagon, Homeodomain Proteins, Immunohistochemistry, Mice, Mice, Knockout, Mice, Mutant Strains, Mice, Transgenic, Nerve Tissue Proteins, PAX6 Transcription Factor, POU Domain Factors, Paired Box Transcription Factors, Pancreas, Repressor Proteins, Transcription Factors
Show Abstract · Added June 21, 2005
Brain 4 (Brn4/Pou3f4) and Pax6 are POU-homeodomain and paired-homeodomain transcription factors, respectively, that are expressed in the brain and the glucagon-expressing cells in the pancreas. Brn4 expression begins at embryonic day 10 in the pancreas, just before pax6 and both appear in the glucagon immunoreactive cells. At a later time point, E19, no Brn4 co-localization is observed with insulin or somatostatin but a rare pancreatic polypeptide (PP)-producing cell can be found, while Pax6 is found in all endocrine cells. These data suggest that brn4 is the only alpha-cell specific transcription factor yet identified; therefore, we sought to analyze alpha-cell development and function in mice with a targeted disruption of the brn4 gene. In homozygous brn4(-/-) mice, pancreatic bud formation, glucagon cell numbers and physiological measurements all appear normal. Examination of other transcription factors found in the glucagon cells showed normal Pax6 and Nkx2.2 immunoreactivity, suggesting that Brn4 does not regulate these transcription factors. Pax6 mutant mice (pax6(Sey/Sey)), with a natural inactivating mutation in pax6, have few endocrine cells but normal numbers of Brn4 and Nkx2.2 cells. The pancreatic phenotype of the pax6 mutants can be rescued with a YAC clone containing the human Pax6 gene.
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2 Resources
17 MeSH Terms
Transcription factor occupancy of the insulin gene in vivo. Evidence for direct regulation by Nkx2.2.
Cissell MA, Zhao L, Sussel L, Henderson E, Stein R
(2003) J Biol Chem 278: 751-6
MeSH Terms: Amyloid, Animals, Basic Helix-Loop-Helix Transcription Factors, Binding Sites, Cells, Cultured, DNA-Binding Proteins, Eye Proteins, Gene Expression Regulation, Glucose Transporter Type 2, Homeodomain Proteins, Insulin, Islet Amyloid Polypeptide, Islets of Langerhans, Mice, Monosaccharide Transport Proteins, PAX6 Transcription Factor, Paired Box Transcription Factors, Rats, Repressor Proteins, Trans-Activators, Transcription Factors
Show Abstract · Added December 10, 2013
Consensus-binding sites for many transcription factors are relatively non-selective and found at high frequency within the genome. This raises the possibility that factors that are capable of binding to a cis-acting element in vitro and regulating transcription from a transiently transfected plasmid, which would not have higher order chromatin structure, may not occupy this site within the endogenous gene. Closed chromatin structure and competition from another DNA-binding protein with similar nucleotide specificity are two possible mechanisms by which a transcription factor may be excluded from a potential binding site in vivo. Multiple transcription factors, including Pdx-1, BETA-2, and Pax6, have been implicated in expression of the insulin gene in pancreatic beta cells. In this study, the chromatin immunoprecipitation assay has been used to show that these factors do, in fact, bind to insulin control region sequences in intact beta cells. In addition, another key islet-enriched transcription factor, Nkx2.2, was found to occupy this region using the chromatin immunoprecipitation assay. In vitro DNA-binding and transient transfection assays defined how Nkx2.2 affected insulin gene expression. Pdx-1 was also shown to bind within a region of the endogenous islet amyloid polypeptide, pax-4, and glucokinase genes that were associated with control in vitro. Because Pdx-1 does not regulate gene transcription in isolation, these sequences were examined for occupancy by the other insulin transcriptional regulators. BETA-2, Pax6, and Nkx2.2 were also found to bind to amyloid polypeptide, glucokinase, and pax-4 control sequences in vivo. These studies reveal the broad application of the Pdx-1, BETA-2, Pax6, and Nkx2.2 transcription factors in regulating expression of genes selectively expressed in islet beta cells.
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21 MeSH Terms
Conserved sequences in a tissue-specific regulatory region of the pdx-1 gene mediate transcription in Pancreatic beta cells: role for hepatocyte nuclear factor 3 beta and Pax6.
Samaras SE, Cissell MA, Gerrish K, Wright CV, Gannon M, Stein R
(2002) Mol Cell Biol 22: 4702-13
MeSH Terms: Animals, Base Sequence, Cells, Cultured, Conserved Sequence, DNA-Binding Proteins, Eye Proteins, Female, Hepatocyte Nuclear Factor 3-beta, Homeodomain Proteins, Humans, Islets of Langerhans, Male, Mice, Mice, Transgenic, Molecular Sequence Data, Mutation, Nuclear Proteins, Organ Specificity, PAX6 Transcription Factor, Paired Box Transcription Factors, Regulatory Sequences, Nucleic Acid, Repressor Proteins, Trans-Activators, Transcription Factors, Transcription, Genetic
Show Abstract · Added January 6, 2014
Pancreas duodenum homeobox 1 (PDX-1) is absolutely required for pancreas development and the maintenance of islet beta-cell function. Temporal and cell-type-specific transcription of the pdx-1 gene is controlled by factors acting upon sequences found within its 5'-flanking region. Critical cis-acting transcriptional control elements are located within a nuclease hypersensitive site that contains three conserved subdomains, termed areas I, II, and III. We show that area II acts as a tissue-specific regulatory region of the pdx-1 gene, directing transgene expression to a subpopulation of islet cells. Mutation of the area II hepatocyte nuclear factor 3 (HNF3) binding element in the larger area I- and area II- containing PstBst fragment also decreases PB(hsplacZ) transgene penetrance. These two results indicate possible ontogenetic and/or functional heterogeneity of the beta-cell population. Several other potential positive- and negative-acting control elements were identified in area II after mutation of the highly conserved sequence blocks within this subdomain. Pax6, a factor essential for islet alpha-cell development and islet hormone gene expression, was shown to bind in area II in vitro. Pax6 and HNF3 beta were also found to bind to this region in vivo by using the chromatin immunoprecipitation assay. Collectively, these data suggest an important role for both HNF3 beta and Pax6 in regulating pdx-1 expression in beta cells.
3 Communities
3 Members
0 Resources
25 MeSH Terms