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Differentiation and gene regulation: Strategies of metazoan evolution: endless forms most beautiful and most wonderful
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Differentiation and gene regulation Strategies of metazoan evolution: endless forms most beautiful and most wonderful Editorial overview Michael Levine*and Peter Rigby Addresses *Division of Genetics, Department of Molecular and Cell Biology, 21 Koshland Hall, University of California, Berkeley, California 94720, USA; e-mail: [email protected] †Division of Eukaryotic Molecular Genetics, MRC National Institute for Medical Research, The Ridgeway, Mill Hill, London, NW7 1AA, UK; e-mail: [email protected] Current Opinion in Genetics & Development 1999, 9:497–498 0959-437X/99/$ — see front matter © 1999 Elsevier Science Ltd. All rights reserved. Abbreviations APC adenomatous polyposis coli BMP bone morphogenetic protein FGF fibroblast growth factor Pol II RNA polymerase II UTR untranslated region
enhancer–promoter interactions. The section ends with a review of mechanisms of translational control. Maternal mRNAs are inhibited in a variety of early embryos, and translational control appears to be an important regulatory strategy in development. Preiss and Hentze (pp 515–521) discuss evidence that mRNAs can form 5′–3′ loops; translation depends on the interaction of activator elements in the 5′ UTR with repressor elements in the 3′ UTR.
Part II: embryonic systems Frasch (pp 522–529) reviews the various signaling pathways and regulatory networks that control muscle specification in the Drosophila embryo. He proposes a stepwise model for the establishment of muscle founder cells, and notes parallels between this process and the patterning of the nervous system.
Introduction This issue of Current Opinion in Genetics & Development focuses on strategies of gene regulation in a variety of metazoan developmental and physiological processes, including embryonic patterning, tissue differentiation, circadian rhythms, cell growth and homeostasis. The reviews are divided into three sections. Part I is devoted to an overview of basic regulatory mechanisms such as transcription activation, the regulation of enhancer–promoter interactions, and the control of mRNA translation. Part II provides a comparison of most of the embryonic systems that are used to study gene regulation: Drosophila, sea urchins, ascidians, zebrafish, Xenopus, and mice. Part III summarizes some of the regulatory factors, gene networks, and signaling pathways that are used in both developmental and physiological processes.
Davidson (pp 530–541) describes the unique advantages of sea urchins in understanding how localized patterns of gene expression are established during embryogenesis. A variety of techniques are discussed, including protein purification methods, arrayed libraries, transgenesis, and novel gene disruption strategies. Dynamic patterns of transcription in the gut and ectoderm are shown to involve complex but highly structured cis-regulatory regions. Satou and Satoh (pp 542–547) review the strengths of ascidian embryos for unraveling the gene networks responsible for specifying basic chordate features, such as the notochord, neural tube, and tail muscles. Transgenic assays have been coupled with subtractive hybridization screens to identify gene batteries that function downstream of Brachyury and coordinate notochord differentiation.
Part I: basic regulatory mechanisms One of the most surprising and important discoveries in the field of metazoan transcription is the demonstration that large protein complexes are required for linking sequence-specific upstream regulatory factors to the Pol II transcription machinery. At least some of these newly identified complexes share similarities with the previously identified yeast mediator complex. Lemon and Freedman (pp 499–504) propose a two-step model of gene activation: chromatin decondensation followed by the recruitment of the Pol II complex via mediators. Dorsett (pp 505–514) describes the next tier of gene regulation, namely, the targeting of remote enhancers to specific promoters in complex genetic loci. He reviews recent studies on insulator DNAs and discusses evidence for facilitator proteins, which permit long-range
Amacher (pp 548–552) summarizes the emerging methods that are now available for the study of gene networks and transcription cascades in the zebrafish embryo. Transgenic methods include gal4-mediated misexpression assays, gene tagging with transposons, and the use of bacterial artificial chromosome expression vectors for analyzing extended cis-regulatory regions. The use of these methods, along with the high cellular resolution available in this system, should provide new insights into mechanisms of tissue differentiation and organogenesis. Kimelman (pp 553–558) discusses recent studies that have begun to link signaling pathways to known transcription factors in the embryonic development of Xenopus. Particular progress has been made in identifying mediators of the Wnt-signaling pathway, including coregulators that
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interact with the transcription factor XTcf. Improved transgenic methods should facilitate these studies and permit rapid progress in the characterization of gene networks. When considering gene-regulation studies in zebrafish and frogs it should be noted that there is currently much discussion of the potential role of Xenopus tropicalis as a model organism for work of this sort. It could combine the biochemical and embryological advantages of Xenopus laevis with the genetic tractability that is a major attraction of the zebrafish. If the potential is lived up to, this organism could have a major impact on our understanding of the transcriptional strategies used during development. Dasen and Rosenfeld (pp 566–574) end the section with a review of pituitary development in the mouse embryo. The specification of diverse cell types in the anterior pituitary is emerging as a key paradigm of mammalian organogenesis. Recent studies suggest that opposing gradients of FGF-8 and BMP-2 establish localized patterns of regulatory gene expression in the pituitary rudiment. The encoded transcription factors, such as Pit-1 and Gata-2, function in a combinatorial fashion to establish diverse cell types.
Part III: factors, networks and pathways The specification of diverse hematopoietic lineages, particularly lymphocytes, requires every conceivable strategy of gene regulation. Engel and Murre (pp 575–579) discuss the convergence of the large number of signaling pathways and regulatory networks that control this process. General survival and cell proliferation pathways are discussed. The authors also emphasize the importance of new technologies for determining how local cell signals (the microenvironment) control differentiation. Crews and Fan (pp 580–587) review the many roles of bHLH–PAS regulatory proteins in development and physiology, including hypoxia, sensory cell development, gene regulation in the mammalian hypothalamus, and the metabolism of toxins. The authors review evidence that these proteins might function as direct sensors of small molecules such as oxygen and hydrocarbons.
Brown and Schibler (pp 588–594) review evidence that evolutionarily conserved gene regulatory networks control circadian rhythms in Drosophila, mammals, and possibly all living cells. In Drosophila, competition between two activators, Clock and Cycle, and two repressors, period and timeless, generate rhythmic patterns of transcription. The authors discuss how this simple gene network is modulated by light and other external stimuli. Pourquié (pp 559–565) reviews evidence that a molecular clock controls the formation of somites in vertebrate embryos. A vertebrate homolog of the Drosophila hairy segmentation gene exhibits pulses of expression in developing somites. These pulses lead to the expression of a Notch signaling component, Lunatic Fringe, thereby providing an explanation for how cell-autonomous oscillations can propagate a wave of gene expression. Bienz (pp 595–603) reinforces the connection between development and cancer. Wingless was first identified as a patterning gene in Drosophila, while the related Int-1 gene was identified as a mammalian oncogene. The author reviews evidence that this link extends to an intracellular signaling component in the Wnt pathway, APC, which is a key suppressor of human colon cancer. New models are presented for how APC might regulate β-catenin degradation and Wnt signaling. The issue ends with a Commentary by Lee and McPherron (pp 604–607), who discuss evidence for the classical chalone hypothesis of secreted growth inhibitors. A novel member of the TGF-β family of signaling molecules, myostatin, controls muscle mass. It is conceivable that similar inhibitors control tissue mass in other growth phenomena such as liver regeneration.
Acknowledgements We thank the authors for describing their respective fields in the context of simple models. We are confident that the reader will find these reviews up to date, accessible, and illuminating.
11/10/1999 12:22 PM
Page 497
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Differentiation and gene regulation Strategies of metazoan evolution: endless forms most beautiful and most wonderful Editorial overview Michael Levine*and Peter Rigby Addresses *Division of Genetics, Department of Molecular and Cell Biology, 21 Koshland Hall, University of California, Berkeley, California 94720, USA; e-mail: [email protected] †Division of Eukaryotic Molecular Genetics, MRC National Institute for Medical Research, The Ridgeway, Mill Hill, London, NW7 1AA, UK; e-mail: [email protected] Current Opinion in Genetics & Development 1999, 9:497–498 0959-437X/99/$ — see front matter © 1999 Elsevier Science Ltd. All rights reserved. Abbreviations APC adenomatous polyposis coli BMP bone morphogenetic protein FGF fibroblast growth factor Pol II RNA polymerase II UTR untranslated region
enhancer–promoter interactions. The section ends with a review of mechanisms of translational control. Maternal mRNAs are inhibited in a variety of early embryos, and translational control appears to be an important regulatory strategy in development. Preiss and Hentze (pp 515–521) discuss evidence that mRNAs can form 5′–3′ loops; translation depends on the interaction of activator elements in the 5′ UTR with repressor elements in the 3′ UTR.
Part II: embryonic systems Frasch (pp 522–529) reviews the various signaling pathways and regulatory networks that control muscle specification in the Drosophila embryo. He proposes a stepwise model for the establishment of muscle founder cells, and notes parallels between this process and the patterning of the nervous system.
Introduction This issue of Current Opinion in Genetics & Development focuses on strategies of gene regulation in a variety of metazoan developmental and physiological processes, including embryonic patterning, tissue differentiation, circadian rhythms, cell growth and homeostasis. The reviews are divided into three sections. Part I is devoted to an overview of basic regulatory mechanisms such as transcription activation, the regulation of enhancer–promoter interactions, and the control of mRNA translation. Part II provides a comparison of most of the embryonic systems that are used to study gene regulation: Drosophila, sea urchins, ascidians, zebrafish, Xenopus, and mice. Part III summarizes some of the regulatory factors, gene networks, and signaling pathways that are used in both developmental and physiological processes.
Davidson (pp 530–541) describes the unique advantages of sea urchins in understanding how localized patterns of gene expression are established during embryogenesis. A variety of techniques are discussed, including protein purification methods, arrayed libraries, transgenesis, and novel gene disruption strategies. Dynamic patterns of transcription in the gut and ectoderm are shown to involve complex but highly structured cis-regulatory regions. Satou and Satoh (pp 542–547) review the strengths of ascidian embryos for unraveling the gene networks responsible for specifying basic chordate features, such as the notochord, neural tube, and tail muscles. Transgenic assays have been coupled with subtractive hybridization screens to identify gene batteries that function downstream of Brachyury and coordinate notochord differentiation.
Part I: basic regulatory mechanisms One of the most surprising and important discoveries in the field of metazoan transcription is the demonstration that large protein complexes are required for linking sequence-specific upstream regulatory factors to the Pol II transcription machinery. At least some of these newly identified complexes share similarities with the previously identified yeast mediator complex. Lemon and Freedman (pp 499–504) propose a two-step model of gene activation: chromatin decondensation followed by the recruitment of the Pol II complex via mediators. Dorsett (pp 505–514) describes the next tier of gene regulation, namely, the targeting of remote enhancers to specific promoters in complex genetic loci. He reviews recent studies on insulator DNAs and discusses evidence for facilitator proteins, which permit long-range
Amacher (pp 548–552) summarizes the emerging methods that are now available for the study of gene networks and transcription cascades in the zebrafish embryo. Transgenic methods include gal4-mediated misexpression assays, gene tagging with transposons, and the use of bacterial artificial chromosome expression vectors for analyzing extended cis-regulatory regions. The use of these methods, along with the high cellular resolution available in this system, should provide new insights into mechanisms of tissue differentiation and organogenesis. Kimelman (pp 553–558) discusses recent studies that have begun to link signaling pathways to known transcription factors in the embryonic development of Xenopus. Particular progress has been made in identifying mediators of the Wnt-signaling pathway, including coregulators that
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interact with the transcription factor XTcf. Improved transgenic methods should facilitate these studies and permit rapid progress in the characterization of gene networks. When considering gene-regulation studies in zebrafish and frogs it should be noted that there is currently much discussion of the potential role of Xenopus tropicalis as a model organism for work of this sort. It could combine the biochemical and embryological advantages of Xenopus laevis with the genetic tractability that is a major attraction of the zebrafish. If the potential is lived up to, this organism could have a major impact on our understanding of the transcriptional strategies used during development. Dasen and Rosenfeld (pp 566–574) end the section with a review of pituitary development in the mouse embryo. The specification of diverse cell types in the anterior pituitary is emerging as a key paradigm of mammalian organogenesis. Recent studies suggest that opposing gradients of FGF-8 and BMP-2 establish localized patterns of regulatory gene expression in the pituitary rudiment. The encoded transcription factors, such as Pit-1 and Gata-2, function in a combinatorial fashion to establish diverse cell types.
Part III: factors, networks and pathways The specification of diverse hematopoietic lineages, particularly lymphocytes, requires every conceivable strategy of gene regulation. Engel and Murre (pp 575–579) discuss the convergence of the large number of signaling pathways and regulatory networks that control this process. General survival and cell proliferation pathways are discussed. The authors also emphasize the importance of new technologies for determining how local cell signals (the microenvironment) control differentiation. Crews and Fan (pp 580–587) review the many roles of bHLH–PAS regulatory proteins in development and physiology, including hypoxia, sensory cell development, gene regulation in the mammalian hypothalamus, and the metabolism of toxins. The authors review evidence that these proteins might function as direct sensors of small molecules such as oxygen and hydrocarbons.
Brown and Schibler (pp 588–594) review evidence that evolutionarily conserved gene regulatory networks control circadian rhythms in Drosophila, mammals, and possibly all living cells. In Drosophila, competition between two activators, Clock and Cycle, and two repressors, period and timeless, generate rhythmic patterns of transcription. The authors discuss how this simple gene network is modulated by light and other external stimuli. Pourquié (pp 559–565) reviews evidence that a molecular clock controls the formation of somites in vertebrate embryos. A vertebrate homolog of the Drosophila hairy segmentation gene exhibits pulses of expression in developing somites. These pulses lead to the expression of a Notch signaling component, Lunatic Fringe, thereby providing an explanation for how cell-autonomous oscillations can propagate a wave of gene expression. Bienz (pp 595–603) reinforces the connection between development and cancer. Wingless was first identified as a patterning gene in Drosophila, while the related Int-1 gene was identified as a mammalian oncogene. The author reviews evidence that this link extends to an intracellular signaling component in the Wnt pathway, APC, which is a key suppressor of human colon cancer. New models are presented for how APC might regulate β-catenin degradation and Wnt signaling. The issue ends with a Commentary by Lee and McPherron (pp 604–607), who discuss evidence for the classical chalone hypothesis of secreted growth inhibitors. A novel member of the TGF-β family of signaling molecules, myostatin, controls muscle mass. It is conceivable that similar inhibitors control tissue mass in other growth phenomena such as liver regeneration.
Acknowledgements We thank the authors for describing their respective fields in the context of simple models. We are confident that the reader will find these reviews up to date, accessible, and illuminating.