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  • 1
    Publication Date: 2010-03-26
    Description: After fertilization the embryonic genome is inactive until transcription is initiated during the maternal-zygotic transition. This transition coincides with the formation of pluripotent cells, which in mammals can be used to generate embryonic stem cells. To study the changes in chromatin structure that accompany pluripotency and genome activation, we mapped the genomic locations of histone H3 molecules bearing lysine trimethylation modifications before and after the maternal-zygotic transition in zebrafish. Histone H3 lysine 27 trimethylation (H3K27me3), which is repressive, and H3K4me3, which is activating, were not detected before the transition. After genome activation, more than 80% of genes were marked by H3K4me3, including many inactive developmental regulatory genes that were also marked by H3K27me3. Sequential chromatin immunoprecipitation demonstrated that the same promoter regions had both trimethylation marks. Such bivalent chromatin domains also exist in embryonic stem cells and are thought to poise genes for activation while keeping them repressed. Furthermore, we found many inactive genes that were uniquely marked by H3K4me3. Despite this activating modification, these monovalent genes were neither expressed nor stably bound by RNA polymerase II. Inspection of published data sets revealed similar monovalent domains in embryonic stem cells. Moreover, H3K4me3 marks could form in the absence of both sequence-specific transcriptional activators and stable association of RNA polymerase II, as indicated by the analysis of an inducible transgene. These results indicate that bivalent and monovalent domains might poise embryonic genes for activation and that the chromatin profile associated with pluripotency is established during the maternal-zygotic transition.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2874748/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2874748/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Vastenhouw, Nadine L -- Zhang, Yong -- Woods, Ian G -- Imam, Farhad -- Regev, Aviv -- Liu, X Shirley -- Rinn, John -- Schier, Alexander F -- 1R01 HG004069/HG/NHGRI NIH HHS/ -- 5R01 GM56211/GM/NIGMS NIH HHS/ -- DP1 OD003958/OD/NIH HHS/ -- R01 GM056211/GM/NIGMS NIH HHS/ -- R01 GM056211-11/GM/NIGMS NIH HHS/ -- R01 GM056211-12/GM/NIGMS NIH HHS/ -- R01 GM056211-12S1/GM/NIGMS NIH HHS/ -- R01 GM056211-13/GM/NIGMS NIH HHS/ -- England -- Nature. 2010 Apr 8;464(7290):922-6. doi: 10.1038/nature08866. Epub 2010 Mar 24.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular and Cellular Biology, Harvard University, 16 Divinity Avenue, Cambridge, Massachusetts 02138, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20336069" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Chromatin/*genetics/*metabolism ; Chromatin Immunoprecipitation ; *Gene Expression Regulation, Developmental/genetics ; Gene Silencing ; Genome/*genetics ; Histones/chemistry/metabolism ; Lysine/metabolism ; Methylation ; Oligonucleotide Array Sequence Analysis ; Pluripotent Stem Cells/*metabolism ; Promoter Regions, Genetic/genetics ; RNA Polymerase II/metabolism ; Transcriptional Activation ; Transgenes ; Zebrafish/*embryology/*genetics/metabolism ; Zebrafish Proteins/genetics ; Zygote/cytology/metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 2
    Publication Date: 2009-09-26
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Schier, Alexander F -- Needleman, Daniel -- England -- Nature. 2009 Sep 24;461(7263):480-1. doi: 10.1038/461480a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19779439" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Diffusion ; Drosophila Proteins/metabolism ; Drosophila melanogaster/embryology/metabolism ; Embryo, Nonmammalian/cytology/embryology/metabolism ; *Endocytosis ; Extracellular Space/metabolism ; Fibroblast Growth Factors/analysis/genetics/*metabolism ; *Models, Biological ; Morphogenesis/*physiology ; Zebrafish/*embryology/*metabolism ; Zebrafish Proteins/analysis/genetics/*metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 3
    Publication Date: 2007-09-01
    Description: MicroRNAs (miRNAs) repress hundreds of target messenger RNAs (mRNAs), but the physiological roles of specific miRNA-mRNA interactions remain largely elusive. We report that zebrafish microRNA-430 (miR-430) dampens and balances the expression of the transforming growth factor-beta (TGF-beta) Nodal agonist squint and the TGF-beta Nodal antagonist lefty. To disrupt the interaction of specific miRNA-mRNA pairs, we developed target protector morpholinos complementary to miRNA binding sites in target mRNAs. Protection of squint or lefty mRNAs from miR-430 resulted in enhanced or reduced Nodal signaling, respectively. Simultaneous protection of squint and lefty or absence of miR-430 caused an imbalance and reduction in Nodal signaling. These findings establish an approach to analyze the in vivo roles of specific miRNA-mRNA pairs and reveal a requirement for miRNAs in dampening and balancing agonist/antagonist pairs.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Choi, Wen-Yee -- Giraldez, Antonio J -- Schier, Alexander F -- New York, N.Y. -- Science. 2007 Oct 12;318(5848):271-4. Epub 2007 Aug 30.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular and Cellular Biology, Harvard University, 16 Divinity Avenue, Cambridge, MA 02138, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/17761850" target="_blank"〉PubMed〈/a〉
    Keywords: 3' Untranslated Regions ; Animals ; Embryo, Nonmammalian/physiology ; Embryonic Development ; Gene Expression Regulation ; Left-Right Determination Factors ; MicroRNAs/*metabolism ; Mutation ; Nodal Protein ; Nodal Signaling Ligands ; RNA, Messenger/genetics/*metabolism ; Transforming Growth Factor beta/agonists/antagonists & ; inhibitors/*genetics/*metabolism ; Zebrafish/embryology/*genetics/metabolism ; Zebrafish Proteins/*genetics
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 4
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    American Association for the Advancement of Science (AAAS)
    Publication Date: 2007-04-21
    Description: Maternal gene products drive early development when the newly formed embryo is transcriptionally inactive. During the maternal-zygotic transition, embryonic transcription is initiated and many maternal RNAs are degraded. Multiple mechanisms regulate the birth of zygotic RNAs and the death of maternal RNAs. Genome activation appears to rely in part on the sequestration of transcriptional repressors by the exponentially increasing amount of DNA during cleavage divisions. Maternal RNA degradation is induced by the binding of proteins and microRNAs to the 3' untranslated region of target RNAs.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Schier, Alexander F -- New York, N.Y. -- Science. 2007 Apr 20;316(5823):406-7.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular and Cellular Biology, Harvard Stem Cell Institute, Center for Brain Science, Broad Institute, Harvard University, 16 Divinity Avenue, Room 1027, Cambridge, MA 02138, USA. schier@fas.harvard.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/17446392" target="_blank"〉PubMed〈/a〉
    Keywords: 3' Untranslated Regions ; Animals ; Cell Cycle ; Embryonic Development ; Female ; *Gene Expression Regulation, Developmental ; Gene Silencing ; MicroRNAs ; *RNA Stability ; RNA, Messenger/*metabolism ; RNA, Messenger, Stored/*metabolism ; RNA-Binding Proteins/metabolism ; Transcription, Genetic ; Zygote/cytology/*metabolism
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 5
    Publication Date: 2005-03-19
    Description: MicroRNAs (miRNAs) are small RNAs that regulate gene expression posttranscriptionally. To block all miRNA formation in zebrafish, we generated maternal-zygotic dicer (MZdicer) mutants that disrupt the Dicer ribonuclease III and double-stranded RNA-binding domains. Mutant embryos do not process precursor miRNAs into mature miRNAs, but injection of preprocessed miRNAs restores gene silencing, indicating that the disrupted domains are dispensable for later steps in silencing. MZdicer mutants undergo axis formation and differentiate multiple cell types but display abnormal morphogenesis during gastrulation, brain formation, somitogenesis, and heart development. Injection of miR-430 miRNAs rescues the brain defects in MZdicer mutants, revealing essential roles for miRNAs during morphogenesis.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Giraldez, Antonio J -- Cinalli, Ryan M -- Glasner, Margaret E -- Enright, Anton J -- Thomson, J Michael -- Baskerville, Scott -- Hammond, Scott M -- Bartel, David P -- Schier, Alexander F -- New York, N.Y. -- Science. 2005 May 6;308(5723):833-8. Epub 2005 Mar 17.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Developmental Genetics Program, Skirball Institute of Biomolecular Medicine and Department of Cell Biology, New York University School of Medicine, New York, NY 10016, USA. giraldez@saturn.med.nyu.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/15774722" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Body Patterning ; Brain/*embryology ; Cell Differentiation ; Central Nervous System/embryology ; Gastrula/physiology ; Gene Silencing ; Heart/embryology ; MicroRNAs/genetics/metabolism/*physiology ; *Morphogenesis ; Mutation ; Neurons/cytology ; Phenotype ; RNA Processing, Post-Transcriptional ; RNA, Double-Stranded/metabolism ; Ribonuclease III/genetics/metabolism ; Signal Transduction ; Somites/cytology/physiology ; Spinal Cord/embryology ; Zebrafish/*embryology/*genetics
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 6
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    Nature Publishing Group (NPG)
    Publication Date: 2013-04-19
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Schier, Alexander F -- England -- Nature. 2013 Apr 25;496(7446):443-4. doi: 10.1038/nature12094. Epub 2013 Apr 17.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23594741" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Conserved Sequence/*genetics ; Female ; Genome/*genetics ; Humans ; Male ; Zebrafish/*genetics ; Zebrafish Proteins/*genetics
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 7
    Publication Date: 2012-05-25
    Description: A fundamental question in neuroscience is how entire neural circuits generate behaviour and adapt it to changes in sensory feedback. Here we use two-photon calcium imaging to record the activity of large populations of neurons at the cellular level, throughout the brain of larval zebrafish expressing a genetically encoded calcium sensor, while the paralysed animals interact fictively with a virtual environment and rapidly adapt their motor output to changes in visual feedback. We decompose the network dynamics involved in adaptive locomotion into four types of neuronal response properties, and provide anatomical maps of the corresponding sites. A subset of these signals occurred during behavioural adjustments and are candidates for the functional elements that drive motor learning. Lesions to the inferior olive indicate a specific functional role for olivocerebellar circuitry in adaptive locomotion. This study enables the analysis of brain-wide dynamics at single-cell resolution during behaviour.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3618960/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3618960/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ahrens, Misha B -- Li, Jennifer M -- Orger, Michael B -- Robson, Drew N -- Schier, Alexander F -- Engert, Florian -- Portugues, Ruben -- 085474/Wellcome Trust/United Kingdom -- 5K99NS62780-2/NS/NINDS NIH HHS/ -- 5R01EY014429/EY/NEI NIH HHS/ -- DP1 NS082121/NS/NINDS NIH HHS/ -- R01 DA030304/DA/NIDA NIH HHS/ -- R01 GM085357/GM/NIGMS NIH HHS/ -- R01 HL109525/HL/NHLBI NIH HHS/ -- RC2NS069407/NS/NINDS NIH HHS/ -- Wellcome Trust/United Kingdom -- England -- Nature. 2012 May 9;485(7399):471-7. doi: 10.1038/nature11057.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular and Cellular Biology, Harvard University, 16 Divinity Avenue, Cambridge, Massachusetts 02138, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22622571" target="_blank"〉PubMed〈/a〉
    Keywords: Adaptation, Physiological/*physiology ; Animals ; Animals, Genetically Modified ; Brain/*cytology/*physiology ; Larva/physiology ; Learning/physiology ; Locomotion/physiology ; Models, Neurological ; Nerve Net ; Neurons/*physiology ; Neuropil/physiology ; Photic Stimulation ; Psychomotor Performance/*physiology ; Single-Cell Analysis ; Zebrafish/anatomy & histology/growth & development/*physiology
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 8
    Publication Date: 2006-02-18
    Description: MicroRNAs (miRNAs) comprise 1 to 3% of all vertebrate genes, but their in vivo functions and mechanisms of action remain largely unknown. Zebrafish miR-430 is expressed at the onset of zygotic transcription and regulates morphogenesis during early development. By using a microarray approach and in vivo target validation, we find that miR-430 directly regulates several hundred target messenger RNA molecules (mRNAs). Most targets are maternally expressed mRNAs that accumulate in the absence of miR-430. We also show that miR-430 accelerates the deadenylation of target mRNAs. These results suggest that miR-430 facilitates the deadenylation and clearance of maternal mRNAs during early embryogenesis.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Giraldez, Antonio J -- Mishima, Yuichiro -- Rihel, Jason -- Grocock, Russell J -- Van Dongen, Stijn -- Inoue, Kunio -- Enright, Anton J -- Schier, Alexander F -- New York, N.Y. -- Science. 2006 Apr 7;312(5770):75-9. Epub 2006 Feb 16.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Developmental Genetics Program, Skirball Institute of Biomolecular Medicine, and Department of Cell Biology, New York University School of Medicine, New York, NY 10016, USA. giraldez@mcb.harvard.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/16484454" target="_blank"〉PubMed〈/a〉
    Keywords: 3' Untranslated Regions ; Adenosine/*metabolism ; Animals ; Embryo, Nonmammalian/*physiology ; *Embryonic Development ; Female ; Gene Expression Profiling ; *Gene Expression Regulation, Developmental ; Genes, Reporter ; Green Fluorescent Proteins/genetics/metabolism ; MicroRNAs/*physiology ; Mutation ; Oligonucleotide Array Sequence Analysis ; Polymers/*metabolism ; Protein Biosynthesis ; RNA Stability ; RNA, Messenger/genetics/*metabolism ; Ribonuclease III/genetics/metabolism ; Transcription, Genetic ; Up-Regulation ; Zebrafish/embryology ; Zygote/physiology
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 9
    Publication Date: 2010-01-16
    Description: A major obstacle for the discovery of psychoactive drugs is the inability to predict how small molecules will alter complex behaviors. We report the development and application of a high-throughput, quantitative screen for drugs that alter the behavior of larval zebrafish. We found that the multidimensional nature of observed phenotypes enabled the hierarchical clustering of molecules according to shared behaviors. Behavioral profiling revealed conserved functions of psychotropic molecules and predicted the mechanisms of action of poorly characterized compounds. In addition, behavioral profiling implicated new factors such as ether-a-go-go-related gene (ERG) potassium channels and immunomodulators in the control of rest and locomotor activity. These results demonstrate the power of high-throughput behavioral profiling in zebrafish to discover and characterize psychotropic drugs and to dissect the pharmacology of complex behaviors.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2830481/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2830481/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Rihel, Jason -- Prober, David A -- Arvanites, Anthony -- Lam, Kelvin -- Zimmerman, Steven -- Jang, Sumin -- Haggarty, Stephen J -- Kokel, David -- Rubin, Lee L -- Peterson, Randall T -- Schier, Alexander F -- K01 MH091449/MH/NIMH NIH HHS/ -- K99 NS060996/NS/NINDS NIH HHS/ -- MH085205/MH/NIMH NIH HHS/ -- MH086867/MH/NIMH NIH HHS/ -- R00 NS060996/NS/NINDS NIH HHS/ -- R01 GM085357/GM/NIGMS NIH HHS/ -- R01 GM085357-01A1/GM/NIGMS NIH HHS/ -- R01 GM085357-02/GM/NIGMS NIH HHS/ -- R01 MH086867/MH/NIMH NIH HHS/ -- New York, N.Y. -- Science. 2010 Jan 15;327(5963):348-51. doi: 10.1126/science.1183090.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA 02138, USA. rihel@fas.harvard.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20075256" target="_blank"〉PubMed〈/a〉
    Keywords: Algorithms ; Animals ; Anti-Inflammatory Agents/pharmacology ; Behavior, Animal/*drug effects ; Calcium Channel Blockers/pharmacology ; Calcium Channels, L-Type/metabolism ; Cluster Analysis ; Cytokines/metabolism ; Drug Discovery/*methods ; Ether-A-Go-Go Potassium Channels/antagonists & inhibitors/physiology ; *High-Throughput Screening Assays ; Larva/drug effects/physiology ; Motor Activity/*drug effects ; Potassium Channel Blockers/pharmacology ; Psychotropic Drugs/*pharmacology ; Rest ; Signal Transduction ; Sleep/drug effects ; Small Molecule Libraries ; Wakefulness/*drug effects ; Zebrafish/growth & development/*physiology ; Zebrafish Proteins/metabolism
    Print ISSN: 0036-8075
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  • 10
    Publication Date: 2012-04-14
    Description: Biological systems involving short-range activators and long-range inhibitors can generate complex patterns. Reaction-diffusion models postulate that differences in signaling range are caused by differential diffusivity of inhibitor and activator. Other models suggest that differential clearance underlies different signaling ranges. To test these models, we measured the biophysical properties of the Nodal/Lefty activator/inhibitor system during zebrafish embryogenesis. Analysis of Nodal and Lefty gradients revealed that Nodals have a shorter range than Lefty proteins. Pulse-labeling analysis indicated that Nodals and Leftys have similar clearance kinetics, whereas fluorescence recovery assays revealed that Leftys have a higher effective diffusion coefficient than Nodals. These results indicate that differential diffusivity is the major determinant of the differences in Nodal/Lefty range and provide biophysical support for reaction-diffusion models of activator/inhibitor-mediated patterning.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3525670/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3525670/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Muller, Patrick -- Rogers, Katherine W -- Jordan, Ben M -- Lee, Joon S -- Robson, Drew -- Ramanathan, Sharad -- Schier, Alexander F -- 5R01GM56211/GM/NIGMS NIH HHS/ -- R01 GM056211/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2012 May 11;336(6082):721-4. doi: 10.1126/science.1221920. Epub 2012 Apr 12.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA 02138, USA. pmueller@fas.harvard.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22499809" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Blastula/*metabolism ; *Body Patterning ; Diffusion ; Embryonic Development ; Fluorescence Recovery After Photobleaching ; Half-Life ; Intracellular Signaling Peptides and Proteins/genetics/*metabolism ; Kinetics ; Left-Right Determination Factors/genetics/*metabolism ; Models, Biological ; Nodal Signaling Ligands/genetics/*metabolism ; Recombinant Fusion Proteins/metabolism ; Zebrafish/*embryology/metabolism ; Zebrafish Proteins/genetics/*metabolism
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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