Available online at www.sciencedirect.com
ScienceDirect Editorial overview: Developmental mechanisms, patterning and evolution Lori Sussel and Lee Niswander Current Opinion in Genetics & Development 2014, 27:v–vii For a complete overview see the Issue Available online 2nd July 2014 http://dx.doi.org/10.1016/j.gde.2014.06.007 0959-437X/# 2014 Elsevier Ltd. All right reserved.
Lori Sussel Department of Genetics and Development, Columbia University, 1150 St. Nicholas Avenue, New York, NY 10032, USA e-mail: [email protected] Dr. Lori Sussel is an Associate professor of Genetics and Development and the Naomi Berrie Diabetes Center at Columbia University Medical Center. Her research focuses on the molecular mechanisms underlying cell fate specification, with a particular emphasis on the induction, differentiation and maintenance of pancreatic islet cell types, including the insulinproducing beta cells.
Lee Niswander HHMI, Developmental Biology Program, University of Colorado Anschutz Medical Campus, 12801 East 17th Avenue, Aurora, CO 80045-0511, USA e-mail: [email protected] Dr. Lee Niswander is a Professor and Head of the Developmental Biology Section at University of Colorado Anschutz Medical Campus and Children’s Hospital Colorado. Her research focuses on early central and peripheral nervous system development in the mouse embryo. She studies the intersection between genes and environmental factors and epigenetic mechanisms and how defects in these processes lead to birth defects and disease such as neural tube defects and myopathies.
www.sciencedirect.com
Innovations ‘sense’ order in developmental mechanisms and evolution The recent surge in technological advances, including novel imaging tools, higher resolution microscopy and high-throughput sequencing has greatly improved our understanding of developmental biology, genetics and evolutionary processes. These new tools have facilitated many paradigm-shifting discoveries and enhanced our knowledge of basic biological systems. The reviews comprised in this issue of Current Opinion in Genetics and Development illustrate exciting innovations in many aspects of transcriptional regulation and cell biology that impact developmental mechanisms, patterning and evolution. Each review demonstrates how these new approaches are allowing us to confirm or revise existing models and raise exciting new biological questions.
Cellular compartmentalization brings order to developmental signaling Strategies to gain efficiency within the intracellular milieu (signaling) and the nucleus (transcription) are highlighted in this issue, as well as how changes in these systems may be selected for evolutionary adaptation. One of the fundamental concepts in developmental biology is that of a morphogen: a signal that is produced in one cell and which acts on neighboring cells to relay positional information in a concentration-dependent manner. Historically this has been conceptualized as secretion of the morphogen from the producing cell and free diffusion to neighboring responding cells. Now it is realized through studies by the Kornberg lab in Drosophila wing disc and by the Barna lab in the vertebrate limb that there can be direct contact between signaling and receiving cells through long thin cellular projections. Using dynamic imaging, the Barna lab has visualized the movement of signaling molecules and receptor/signal transduction proteins and the direct contact between specialized filopodia within the intricate multi-cellular and multi-dimensional landscape of an actively growing vertebrate tissue. Two other insights stand out from these studies as reviewed by Fairchild and Barna: one, the intricate shape and numerous cell projections from mesenchymal cells in vivo in their 3D context, and two, the surprising restriction of Hedgehog particles to some filopodia but not others extending from the same cell. Many signaling molecules are posttranslationally modified, making them lipophilic and hydrophobic and placing constraints on extracellular trafficking. At least some morphogens can be processed through the endocytic pathway and released from the producing cell as membranous microvesicles during development in invertebrates and vertebrates, and in cancer cells. The review by Zhang and Wrana Current Opinion in Genetics & Development 2014, 27:v–vii
vi Development mechanisms, patterning and evolution
provides the current view of these vesicles, called exosomes, and the molecular processes that regulate their secretion and transport. Compartmentalization of signal transduction components can significantly boost signaling efficiency. McCormick and Baillie review the compartmentalization scheme used by the second messengers cAMP, cGMP, calcium and nitric oxide. The spatial segregation of these secondary messengers along with localized effector proteins provides an effective strategy to turn a broad multi-functional signal into an exquisitely controlled set of outputs within the milieu of the cell. Wada et al. focus on recent studies of the role of autophagy in embryonic development. Autophagy is a mechanism by which the cell can degrade and recycle organelles and proteins to allow conservation of resources and rapid regulation of intracellular and extracellular activities. The authors highlight the consequences of deficiencies in autophagic components including the inability to terminate developmental signaling, leading to failure in the spatial restriction of signaling and profound defects in embryonic patterning and morphogenesis. With the advent of unbiased genome-wide methods to evaluate transcription, it is now clear that a large proportion of the genome of animals and plants is transcribed as RNA products. Beyond the traditional protein coding regions lie a great assortment of short and long non-coding sequences. Experimental and genetic studies indicate that a predominant role of these non-coding RNAs is to modulate the abundance of gene products either at a transcriptional or post-transcriptional level. The review by Benkovics and Timmermans highlights the roles that small RNAs play in intercellular communication and target-specific establishment of positional identify in plants, and hints at whether miRNAs may serve as mobile instructive signals in animal development. The review by Posadas and Carthew focuses on miRNAs within the context of providing robustness to the biological system and suppressing phenotypic variation due to environmental or genetic perturbations. Long non-coding RNAs (lncRNA), as reviewed by Marques and Ponting, undergo rapid changes in sequence and expression over evolutionary time, leading to the speculation that lncRNAs may underlie phenotypic variation and can be a mechanism that drives evolutionary change. Together these reviews highlight research over the past few years that has redefined how we conceptualize signal production and reception, and pattern generation in multicellular animals.
Interface of genomic and epigenetic mechanisms with development and evolution Our understanding of how genomic architecture influences cell specific gene regulation has also been transformed by the advent of high throughput genomic Current Opinion in Genetics & Development 2014, 27:v–vii
technologies. Techniques such as chromosome conformation capture (3C, 4C, 5C) and ChIP-Seq have revealed how the three dimensional architecture of the genome facilitates long range genomic interactions. The review by Bonara, Plath and Denholtz describes how complex protein-DNA interactions allow genomes to be organized into topologically associated domains (TADs) that function to establish and maintain cell identities. Schwarzer and Spitz expand on this topic to demonstrate how multiple enhancers add a higher level of complexity by cooperating with TADs to establish and modulate the regulatory programs that guide embryonic development. In their discussion, the authors raise the interesting idea that enhancer crosstalk may offer a mechanism by which gene expression patterns can evolve and gene expression levels can be modulated. The review by Anderson and Hill then provides an excellent example of how a collection of enhancers can generate the spatial and temporal expression of a specific gene — Sonic hedgehog (Shh). This review summarizes the studies of many labs that have identified multiple long-range enhancer elements that confer tissue-specific regulation of Shh during development. Genome-wide epigenetic studies have also been instrumental in our understanding of how physiological changes can result in both temporary and permanent fluctuations in gene expression. The review by Beckwith and Yanovsky discusses how gene expression programs directly respond to environmental influences, such as circadian rhythms. Interestingly, it appears that multiple transcriptional and post-transcriptional processes are responsive to circadian oscillations, demonstrating how a cell can rapidly adjust to changing environmental conditions. Changes in physiological conditions can also have long-term impact on gene expression. Notably, the rapid rise in human metabolic disorders provides a striking example of how geneenvironment interactions can cooperate to not only influence metabolic function, but to also have longterm multi-generational consequences on gene expression. The review by Somer and Thummel discuss the human, mouse and Drosophila studies that implicate the transgenerational effects of DNA methylation and histone modifications on gene expression and metabolic dysfunction. In particular, the authors discuss how studies in the genetically tractable and simpler model system of Drosophila are able to uniquely facilitate our understanding of the multigenerational inheritance of metabolic state. On the basis of large scale genomic analyses across species, it is now well documented that changes in both the function and regulation of gene products are responsible for phenotypic variation and can contribute to evolutionary diversity. In the review by Achim and Arendt, comparative www.sciencedirect.com
Editorial overview: Developmental mechanisms, patterning and evolution Sussel and Niswander vii
genomic studies are used to understand the evolution of specialized cell types, such as neurons and muscle cells. These studies suggest that as new cell types evolve, they exploit and adapt pre-existing protein modules for use in novel specialized functions. The authors show how the identification and functional adaptation of conserved protein modules has provided a novel view of phenotypic evolution. The review by Wang and Davis also uses comparative genomic analysis to reveal mechanisms by which permanent changes in genomic DNA can contribute to the evolution of organisms. Interestingly, a broad range of organisms utilize a process of programmed DNA elimination as a mechanism to generate phenotypic diversity, eliminate repetitive elements, and permanently silence genes. The existence of programmed DNA elimination may not influence genomic evolution in a natural context, but pathological conditions such as cancer may utilize such a mechanism of genome alteration.
www.sciencedirect.com
Function meets form The ultimate outcome of the vast and complicated interplay between intracellular and extracellular activities and genetic and epigenetic mechanisms is the creation of embryonic form. Mechanical mechanisms, which are dictated by molecular and genetic processes as well as differential growth, provide the biophysical forces to twist, bend and remodel tissues into functioning organs. Taber reviews the mechanics of heart looping and shaping of the early embryonic brain, highlighting the gaps in our understanding, with the goal of stimulating renewed interest in the biophysical properties that create embryonic form and structure. Future studies to define how mechanical properties feedback to regulate gene expression and developmental signaling will allow us to come full-circle in integrating the key components that drive embryonic tissue structure and function.
Current Opinion in Genetics & Development 2014, 27:v–vii
ScienceDirect Editorial overview: Developmental mechanisms, patterning and evolution Lori Sussel and Lee Niswander Current Opinion in Genetics & Development 2014, 27:v–vii For a complete overview see the Issue Available online 2nd July 2014 http://dx.doi.org/10.1016/j.gde.2014.06.007 0959-437X/# 2014 Elsevier Ltd. All right reserved.
Lori Sussel Department of Genetics and Development, Columbia University, 1150 St. Nicholas Avenue, New York, NY 10032, USA e-mail: [email protected] Dr. Lori Sussel is an Associate professor of Genetics and Development and the Naomi Berrie Diabetes Center at Columbia University Medical Center. Her research focuses on the molecular mechanisms underlying cell fate specification, with a particular emphasis on the induction, differentiation and maintenance of pancreatic islet cell types, including the insulinproducing beta cells.
Lee Niswander HHMI, Developmental Biology Program, University of Colorado Anschutz Medical Campus, 12801 East 17th Avenue, Aurora, CO 80045-0511, USA e-mail: [email protected] Dr. Lee Niswander is a Professor and Head of the Developmental Biology Section at University of Colorado Anschutz Medical Campus and Children’s Hospital Colorado. Her research focuses on early central and peripheral nervous system development in the mouse embryo. She studies the intersection between genes and environmental factors and epigenetic mechanisms and how defects in these processes lead to birth defects and disease such as neural tube defects and myopathies.
www.sciencedirect.com
Innovations ‘sense’ order in developmental mechanisms and evolution The recent surge in technological advances, including novel imaging tools, higher resolution microscopy and high-throughput sequencing has greatly improved our understanding of developmental biology, genetics and evolutionary processes. These new tools have facilitated many paradigm-shifting discoveries and enhanced our knowledge of basic biological systems. The reviews comprised in this issue of Current Opinion in Genetics and Development illustrate exciting innovations in many aspects of transcriptional regulation and cell biology that impact developmental mechanisms, patterning and evolution. Each review demonstrates how these new approaches are allowing us to confirm or revise existing models and raise exciting new biological questions.
Cellular compartmentalization brings order to developmental signaling Strategies to gain efficiency within the intracellular milieu (signaling) and the nucleus (transcription) are highlighted in this issue, as well as how changes in these systems may be selected for evolutionary adaptation. One of the fundamental concepts in developmental biology is that of a morphogen: a signal that is produced in one cell and which acts on neighboring cells to relay positional information in a concentration-dependent manner. Historically this has been conceptualized as secretion of the morphogen from the producing cell and free diffusion to neighboring responding cells. Now it is realized through studies by the Kornberg lab in Drosophila wing disc and by the Barna lab in the vertebrate limb that there can be direct contact between signaling and receiving cells through long thin cellular projections. Using dynamic imaging, the Barna lab has visualized the movement of signaling molecules and receptor/signal transduction proteins and the direct contact between specialized filopodia within the intricate multi-cellular and multi-dimensional landscape of an actively growing vertebrate tissue. Two other insights stand out from these studies as reviewed by Fairchild and Barna: one, the intricate shape and numerous cell projections from mesenchymal cells in vivo in their 3D context, and two, the surprising restriction of Hedgehog particles to some filopodia but not others extending from the same cell. Many signaling molecules are posttranslationally modified, making them lipophilic and hydrophobic and placing constraints on extracellular trafficking. At least some morphogens can be processed through the endocytic pathway and released from the producing cell as membranous microvesicles during development in invertebrates and vertebrates, and in cancer cells. The review by Zhang and Wrana Current Opinion in Genetics & Development 2014, 27:v–vii
vi Development mechanisms, patterning and evolution
provides the current view of these vesicles, called exosomes, and the molecular processes that regulate their secretion and transport. Compartmentalization of signal transduction components can significantly boost signaling efficiency. McCormick and Baillie review the compartmentalization scheme used by the second messengers cAMP, cGMP, calcium and nitric oxide. The spatial segregation of these secondary messengers along with localized effector proteins provides an effective strategy to turn a broad multi-functional signal into an exquisitely controlled set of outputs within the milieu of the cell. Wada et al. focus on recent studies of the role of autophagy in embryonic development. Autophagy is a mechanism by which the cell can degrade and recycle organelles and proteins to allow conservation of resources and rapid regulation of intracellular and extracellular activities. The authors highlight the consequences of deficiencies in autophagic components including the inability to terminate developmental signaling, leading to failure in the spatial restriction of signaling and profound defects in embryonic patterning and morphogenesis. With the advent of unbiased genome-wide methods to evaluate transcription, it is now clear that a large proportion of the genome of animals and plants is transcribed as RNA products. Beyond the traditional protein coding regions lie a great assortment of short and long non-coding sequences. Experimental and genetic studies indicate that a predominant role of these non-coding RNAs is to modulate the abundance of gene products either at a transcriptional or post-transcriptional level. The review by Benkovics and Timmermans highlights the roles that small RNAs play in intercellular communication and target-specific establishment of positional identify in plants, and hints at whether miRNAs may serve as mobile instructive signals in animal development. The review by Posadas and Carthew focuses on miRNAs within the context of providing robustness to the biological system and suppressing phenotypic variation due to environmental or genetic perturbations. Long non-coding RNAs (lncRNA), as reviewed by Marques and Ponting, undergo rapid changes in sequence and expression over evolutionary time, leading to the speculation that lncRNAs may underlie phenotypic variation and can be a mechanism that drives evolutionary change. Together these reviews highlight research over the past few years that has redefined how we conceptualize signal production and reception, and pattern generation in multicellular animals.
Interface of genomic and epigenetic mechanisms with development and evolution Our understanding of how genomic architecture influences cell specific gene regulation has also been transformed by the advent of high throughput genomic Current Opinion in Genetics & Development 2014, 27:v–vii
technologies. Techniques such as chromosome conformation capture (3C, 4C, 5C) and ChIP-Seq have revealed how the three dimensional architecture of the genome facilitates long range genomic interactions. The review by Bonara, Plath and Denholtz describes how complex protein-DNA interactions allow genomes to be organized into topologically associated domains (TADs) that function to establish and maintain cell identities. Schwarzer and Spitz expand on this topic to demonstrate how multiple enhancers add a higher level of complexity by cooperating with TADs to establish and modulate the regulatory programs that guide embryonic development. In their discussion, the authors raise the interesting idea that enhancer crosstalk may offer a mechanism by which gene expression patterns can evolve and gene expression levels can be modulated. The review by Anderson and Hill then provides an excellent example of how a collection of enhancers can generate the spatial and temporal expression of a specific gene — Sonic hedgehog (Shh). This review summarizes the studies of many labs that have identified multiple long-range enhancer elements that confer tissue-specific regulation of Shh during development. Genome-wide epigenetic studies have also been instrumental in our understanding of how physiological changes can result in both temporary and permanent fluctuations in gene expression. The review by Beckwith and Yanovsky discusses how gene expression programs directly respond to environmental influences, such as circadian rhythms. Interestingly, it appears that multiple transcriptional and post-transcriptional processes are responsive to circadian oscillations, demonstrating how a cell can rapidly adjust to changing environmental conditions. Changes in physiological conditions can also have long-term impact on gene expression. Notably, the rapid rise in human metabolic disorders provides a striking example of how geneenvironment interactions can cooperate to not only influence metabolic function, but to also have longterm multi-generational consequences on gene expression. The review by Somer and Thummel discuss the human, mouse and Drosophila studies that implicate the transgenerational effects of DNA methylation and histone modifications on gene expression and metabolic dysfunction. In particular, the authors discuss how studies in the genetically tractable and simpler model system of Drosophila are able to uniquely facilitate our understanding of the multigenerational inheritance of metabolic state. On the basis of large scale genomic analyses across species, it is now well documented that changes in both the function and regulation of gene products are responsible for phenotypic variation and can contribute to evolutionary diversity. In the review by Achim and Arendt, comparative www.sciencedirect.com
Editorial overview: Developmental mechanisms, patterning and evolution Sussel and Niswander vii
genomic studies are used to understand the evolution of specialized cell types, such as neurons and muscle cells. These studies suggest that as new cell types evolve, they exploit and adapt pre-existing protein modules for use in novel specialized functions. The authors show how the identification and functional adaptation of conserved protein modules has provided a novel view of phenotypic evolution. The review by Wang and Davis also uses comparative genomic analysis to reveal mechanisms by which permanent changes in genomic DNA can contribute to the evolution of organisms. Interestingly, a broad range of organisms utilize a process of programmed DNA elimination as a mechanism to generate phenotypic diversity, eliminate repetitive elements, and permanently silence genes. The existence of programmed DNA elimination may not influence genomic evolution in a natural context, but pathological conditions such as cancer may utilize such a mechanism of genome alteration.
www.sciencedirect.com
Function meets form The ultimate outcome of the vast and complicated interplay between intracellular and extracellular activities and genetic and epigenetic mechanisms is the creation of embryonic form. Mechanical mechanisms, which are dictated by molecular and genetic processes as well as differential growth, provide the biophysical forces to twist, bend and remodel tissues into functioning organs. Taber reviews the mechanics of heart looping and shaping of the early embryonic brain, highlighting the gaps in our understanding, with the goal of stimulating renewed interest in the biophysical properties that create embryonic form and structure. Future studies to define how mechanical properties feedback to regulate gene expression and developmental signaling will allow us to come full-circle in integrating the key components that drive embryonic tissue structure and function.
Current Opinion in Genetics & Development 2014, 27:v–vii
