- Email: [email protected]
Pattern formation and developmental mechanisms
323
Pattern formation and developmental mechanisms From cell patterning to organogenesis Editorial overview Anne Ephrussi and Olivier Pourquie´ Current Opinion in Genetics & Development 2003, 13:323–325 0959-437X/$ – see front matter ß 2003 Elsevier Ltd. All rights reserved. DOI 10.1016/S0959-437X(03)00092-3
Anne Ephrussi European Molecular Biology Laboratory, Heidelberg, Germany e-mail: [email protected]
Anne Ephrussi is Senior Scientist at the European Molecular Biology Laboratory in Heidelberg, Germany. Research in her group focuses on mechanisms of cytoplasmic mRNA localization and localized translational control in the Drosophila oocyte, as well as on the establishment of the cell polarity underlying mRNA localization. Olivier Pourquie´ Stowers Institute for Medical Research, Kansas City, USA e-mail: [email protected]
Oliver Pourquie´ is Associate Investigator at the Stowers Institute for Medical Research in Kansas City (USA). Work in his group is focused on the study of the vertebrate segmentation process with a particular emphasis on the role of the segmentation clock oscillator and on the coupling of the segmentation and axis elongation processes.
Introduction During development, patterning events at the cellular and tissue level play a key role in the movements and interactions that ultimately lead to the formation of the embryo. This special issue of Current Opinion in Genetics & Development dedicated to pattern formation and developmental mechanisms comprises a discussion of the evolution of patterning mechanisms and of the use of mathematical modeling as applied to the study of pattern formation. Several reviews describe the fundamental mechanisms involved in cell and tissue patterning, including cell polarization and membrane growth, adhesion and migration, as well as novel modes of gene regulation by miRNAs. Two reviews focus on the basic patterning mechanisms of the vertebrate embryo, segmentation, and the generation of left-right asymmetry. The final series of reviews discusses how these patterning mechanisms are at play in the development of different embryonic tissues or organs including the endoderm and pancreas, the circulatory system, the skeletal muscles and the central nervous system.
Evolution and modeling In recent years, molecular phylogenetic analyses have allowed the classification of bilaterians among Deuterostomia, Ecdysosoa and Lophotrochozoa. In spite of their prominent representation in the animal kingdom, Lophotrochozoans have been relatively ignored. In their review, Tessmar-Raible and Arendt make a strong case for the adoption of members of Lophotrochozoa as model systems. Indeed, some genes concluded to be vertebrate specializations as a result of comparisons between the classical vertebrate, fruitfly, and nematode worm models have subsequently been identified in Lophotrochozoa, forcing a redefinition of phylogenetic relationships. The ideal model would of course be the Urbilateria. This ancestor of all bilaterians is long gone, but fossil characteristics suggest that some extant species of Lophotrochozoans might come relatively close — and studying these should help in the determination of what constitutes novel recruitment versus evolutionary conservation of gene function. One of these species, the freshwater planarian Schmidtea mediterranea, has for some time been a model for the study of regeneration. In his Commentary, Sa´nchez Alvarado reveals to us its particular suitability for comparative developmental studies, including studies of inductive interactions, as well as its ideal position as a model for studies comparing regeneration and development. Increasingly detailed qualitative and quantitative data on gene regulatory interactions, feed-back loops, and inductive interactions during early development have been generated by laboratories over the past decades. Although Alan Turing became fascinated with and tackled the problem of morphogenesis as early as 1952, what is still seriously lacking is an
www.current-opinion.com
Current Opinion in Genetics & Development 2003, 13:323–325
324 Pattern formation and developmental mechanisms
integrated view and predictive models of how, individually and collectively, these circuits pattern the embryo. In their review, Thieffry and Sanchez present in simple terms the ‘why and how’ of mathematical modeling, describing the different parameters and methods employed to derive computational models of pattern formation and cell behavior during embryonic development. Specific predictions coming from these models can then be tested in vivo, allowing their refinement and the emergence, from great complexity, of basic principles underlying embryonic patterning.
Mechanisms of cellular and tissue patterning Polarization underlies many cell fate decisions and specialized cell functions. Genetic and biochemical investigations have led to the identification of conserved pathways and complexes crucially involved in polarization of many cell types. The apical Par-6/aPKC complex is central among these, regulating the distribution and activity of protein complexes along the apical–basal cell axis. The comprehensive review by Henrique and Schweisguth discusses the role of the apical complex in regulating cell polarity in different systems and the events underlying the localization and activity of the complex itself, its downstream effectors and the other molecular complexes with which it interacts to effect and maintain cell polarization. In his review, Lecuit highlights the importance of cell surface remodeling and polarized membrane growth in the cellular response to extracellular signals during in morphogenesis. He describes how the apical targeting of membranes is a central aspect of epithelial cell polarization, underlying morphogenetic events such as tubulogenesis, tissue spreading and the cellular movements of convergence extension. Continuing on the question of cell shape change and movement, in their review Dormann and Weijer describe the diverse ligands (e.g. c-AMP), growth factors and growth-factor receptors that direct cells in their migration during development, in organisms ranging from Dictyostelium to vertebrates. Classical signaling pathways, such as the frizzled and JAK/STAT pathways, are emerging as key regulators of cell shape change and movement. Mechanisms such as the differential activation of receptors along the length of a cell triggering actin polymerization at the leading edge and directed movement are discussed. Adhesion is clearly an important factor in cell movement, as well as in many other morphogenetic processes ranging from cell sorting and the formation of tissue boundaries to organogenesis. Undaunted by the large number of molecules involved in regulating and mediating cell adhesion — estimated at up to 5% of the human genome — Thiery describes in his review the multitude of cell types and events in which adhesion is involved. He shows how the combination of specific adhesion molecules and their integration in different Current Opinion in Genetics & Development 2003, 13:323–325
signaling pathways plays a central role in patterning and morphogenesis. Finally, at a time when miRNAs are emerging as key regulators of growth and pattern in many organisms, Hunter and Poethig review the evidence that such molecules regulate plant development. Although no phenotypes have been ascribed to individual plant miRNAs to date, genes encoding conserved proteins involved in their generation are essential for the maintenance of undifferentiated cells in the shoot apical meristem, the establishment of organ polarity and timing of the vegetal-toreproductive transition. This comprehensive review also compares and contrasts what is known of miRNAs in plants and animals, their mechanisms of action and their relation to siRNAs.
Patterning the vertebrate embryo The next two reviews focus on major patterning mechanisms operating in the vertebrate embryo. The vertebrate body axis can be subdivided into a series of repeated structures called segments. This segmental pattern is first established in the paraxial mesoderm during somitogenesis. This process involves a molecular oscillator termed the segmentation clock. Bessho and Kageyama’s review describes recent findings that shed light on the molecular mechanisms involved in the control of the oscillations and that open up the exciting perspective that the oscillator might be at work in tissues other than the presomitic mesoderm. Although vertebrate embryos are initially symmetrical along their left–right axis, this symmetry is rapidly broken during the organogenesis process. This ultimately results in the asymmetrical disposition of the internal organs in the body cavity. McGrath and Brueckner focus essentially on the initial trigger controlling the symmetry breakdown. They describe recent findings evidencing the role of cilia located in the node during gastrulation. These cilia control fluid dynamics and create a left-right oriented flow in the node, which represents the first asymmetry of the embryo and triggers a subsequent signaling cascade that leads to the differential development of the two embryonic halves.
Organogenesis The remaining series of reviews deals with various aspects of the organogenesis of the derivatives of the three germ layers of vertebrates. These reviews nicely illustrate the conservation and the diversity of the molecular mechanisms involved in organ development. The review by Tam, Kanai-Azuma and Kanai describes our current understanding of the early steps of endoderm induction in vertebrates, illustrating nicely how, in different species, a variety of mechanisms involved in the initiation of the process subsequently converge towards the activation of the Nodal signaling pathway, which www.current-opinion.com
Editorial overview Ephrussi and Pourquie´ 325
controls endoderm induction. The conservation among vertebrates of transcription factor networks involving genes such as Mixer or Sox17 and their role in specification of the endodermal fate is discussed. The authors also highlight the recently reported role of endoderm in the control of morphogenesis of the facial structures. Development of an important endodermal derivative, the pancreas, has been recently very actively investigated with the hope of developing cellular replacement therapies aimed at curing diabetes. Recent results in this area are presented in the review by Kumar and Melton. They describe how the endoderm must first become competent to form pancreas before responding to a series of local signals provided by the surrounding structures, including the notochord, the aorta or the lateral plate, that control the specification of the pancreatic rudiment. They also discuss the recent identification of key transcription factors, such as PDX1 or PTP1a, that play a major role in the control of pancreatic development. Two reviews deal with aspects of vertebrate mesoderm development. Rossant and Hirashima summarize our knowledge in the field of angiogenesis. It is now well established that endothelial development begins with the formation of a capillary plexus formed de novo by precursor cells. This plexus subsequently becomes remodeled to form the blood vessels which can then become artery, vein or lymphatic. The review summarizes how the initial precursors acquire their endothelial fate in response to vascular endothelial growth factor signals, and how their subsequent fate is controlled by the Notch and Ephrin signaling pathways. Recent advances in the development of long forgotten lymphatic vessels are also included. The other review, by Tajbakhsh, is focused on the development of skeletal muscles in the embryo and adult. All skeletal
www.current-opinion.com
muscles arise from the paraxial mesoderm and in the trunk and tail they derive from the somitic myotome. An account of the current controversy on the early stages of myotome formation is provided in the review. Subsequent muscle formation via repeated waves of myoblasts and aspects of muscle regeneration by satellite cells are discussed. An interesting aspect of the review is the emphasis placed on the role of stem cells in muscle generation and repair. The therapeutic potential of such stem cells to cure myopathies has led to numerous and sometimes controversial studies in the field, which are discussed in the article. Finally, aspects of the patterning of the vertebrate telencephalon, which generates our cortex, are presented in the review by Zaki, Quinn and Price. They provide a current view of the patterning mechanisms implicated in setting up the early forebrain territories and report the roles of local signaling by BMP, Wnt and Hedgehog family members and of the downstream networks of transcription factors they control. The part played by these systems in controlling local proliferation, cell fate decisions and migrations and how they participate in shaping the brain is discussed.
Conclusions Taken together, the reviews in this issue of Current Opinions in Genetics & Development highlight the remarkable degree of conservation of basic patterning mechanisms at levels ranging from the cell to the organism as a whole. Cell polarization, signaling, adhesion and motility all come into play in the establishment of pattern and organogenesis. A new level of regulation, at the RNA level, is now glimpsed and the future will undoubtedly reveal unsuspected players and new ways of achieving organismic complexity from the unpatterned one-cell zygote.
Current Opinion in Genetics & Development 2003, 13:323–325
Pattern formation and developmental mechanisms From cell patterning to organogenesis Editorial overview Anne Ephrussi and Olivier Pourquie´ Current Opinion in Genetics & Development 2003, 13:323–325 0959-437X/$ – see front matter ß 2003 Elsevier Ltd. All rights reserved. DOI 10.1016/S0959-437X(03)00092-3
Anne Ephrussi European Molecular Biology Laboratory, Heidelberg, Germany e-mail: [email protected]
Anne Ephrussi is Senior Scientist at the European Molecular Biology Laboratory in Heidelberg, Germany. Research in her group focuses on mechanisms of cytoplasmic mRNA localization and localized translational control in the Drosophila oocyte, as well as on the establishment of the cell polarity underlying mRNA localization. Olivier Pourquie´ Stowers Institute for Medical Research, Kansas City, USA e-mail: [email protected]
Oliver Pourquie´ is Associate Investigator at the Stowers Institute for Medical Research in Kansas City (USA). Work in his group is focused on the study of the vertebrate segmentation process with a particular emphasis on the role of the segmentation clock oscillator and on the coupling of the segmentation and axis elongation processes.
Introduction During development, patterning events at the cellular and tissue level play a key role in the movements and interactions that ultimately lead to the formation of the embryo. This special issue of Current Opinion in Genetics & Development dedicated to pattern formation and developmental mechanisms comprises a discussion of the evolution of patterning mechanisms and of the use of mathematical modeling as applied to the study of pattern formation. Several reviews describe the fundamental mechanisms involved in cell and tissue patterning, including cell polarization and membrane growth, adhesion and migration, as well as novel modes of gene regulation by miRNAs. Two reviews focus on the basic patterning mechanisms of the vertebrate embryo, segmentation, and the generation of left-right asymmetry. The final series of reviews discusses how these patterning mechanisms are at play in the development of different embryonic tissues or organs including the endoderm and pancreas, the circulatory system, the skeletal muscles and the central nervous system.
Evolution and modeling In recent years, molecular phylogenetic analyses have allowed the classification of bilaterians among Deuterostomia, Ecdysosoa and Lophotrochozoa. In spite of their prominent representation in the animal kingdom, Lophotrochozoans have been relatively ignored. In their review, Tessmar-Raible and Arendt make a strong case for the adoption of members of Lophotrochozoa as model systems. Indeed, some genes concluded to be vertebrate specializations as a result of comparisons between the classical vertebrate, fruitfly, and nematode worm models have subsequently been identified in Lophotrochozoa, forcing a redefinition of phylogenetic relationships. The ideal model would of course be the Urbilateria. This ancestor of all bilaterians is long gone, but fossil characteristics suggest that some extant species of Lophotrochozoans might come relatively close — and studying these should help in the determination of what constitutes novel recruitment versus evolutionary conservation of gene function. One of these species, the freshwater planarian Schmidtea mediterranea, has for some time been a model for the study of regeneration. In his Commentary, Sa´nchez Alvarado reveals to us its particular suitability for comparative developmental studies, including studies of inductive interactions, as well as its ideal position as a model for studies comparing regeneration and development. Increasingly detailed qualitative and quantitative data on gene regulatory interactions, feed-back loops, and inductive interactions during early development have been generated by laboratories over the past decades. Although Alan Turing became fascinated with and tackled the problem of morphogenesis as early as 1952, what is still seriously lacking is an
www.current-opinion.com
Current Opinion in Genetics & Development 2003, 13:323–325
324 Pattern formation and developmental mechanisms
integrated view and predictive models of how, individually and collectively, these circuits pattern the embryo. In their review, Thieffry and Sanchez present in simple terms the ‘why and how’ of mathematical modeling, describing the different parameters and methods employed to derive computational models of pattern formation and cell behavior during embryonic development. Specific predictions coming from these models can then be tested in vivo, allowing their refinement and the emergence, from great complexity, of basic principles underlying embryonic patterning.
Mechanisms of cellular and tissue patterning Polarization underlies many cell fate decisions and specialized cell functions. Genetic and biochemical investigations have led to the identification of conserved pathways and complexes crucially involved in polarization of many cell types. The apical Par-6/aPKC complex is central among these, regulating the distribution and activity of protein complexes along the apical–basal cell axis. The comprehensive review by Henrique and Schweisguth discusses the role of the apical complex in regulating cell polarity in different systems and the events underlying the localization and activity of the complex itself, its downstream effectors and the other molecular complexes with which it interacts to effect and maintain cell polarization. In his review, Lecuit highlights the importance of cell surface remodeling and polarized membrane growth in the cellular response to extracellular signals during in morphogenesis. He describes how the apical targeting of membranes is a central aspect of epithelial cell polarization, underlying morphogenetic events such as tubulogenesis, tissue spreading and the cellular movements of convergence extension. Continuing on the question of cell shape change and movement, in their review Dormann and Weijer describe the diverse ligands (e.g. c-AMP), growth factors and growth-factor receptors that direct cells in their migration during development, in organisms ranging from Dictyostelium to vertebrates. Classical signaling pathways, such as the frizzled and JAK/STAT pathways, are emerging as key regulators of cell shape change and movement. Mechanisms such as the differential activation of receptors along the length of a cell triggering actin polymerization at the leading edge and directed movement are discussed. Adhesion is clearly an important factor in cell movement, as well as in many other morphogenetic processes ranging from cell sorting and the formation of tissue boundaries to organogenesis. Undaunted by the large number of molecules involved in regulating and mediating cell adhesion — estimated at up to 5% of the human genome — Thiery describes in his review the multitude of cell types and events in which adhesion is involved. He shows how the combination of specific adhesion molecules and their integration in different Current Opinion in Genetics & Development 2003, 13:323–325
signaling pathways plays a central role in patterning and morphogenesis. Finally, at a time when miRNAs are emerging as key regulators of growth and pattern in many organisms, Hunter and Poethig review the evidence that such molecules regulate plant development. Although no phenotypes have been ascribed to individual plant miRNAs to date, genes encoding conserved proteins involved in their generation are essential for the maintenance of undifferentiated cells in the shoot apical meristem, the establishment of organ polarity and timing of the vegetal-toreproductive transition. This comprehensive review also compares and contrasts what is known of miRNAs in plants and animals, their mechanisms of action and their relation to siRNAs.
Patterning the vertebrate embryo The next two reviews focus on major patterning mechanisms operating in the vertebrate embryo. The vertebrate body axis can be subdivided into a series of repeated structures called segments. This segmental pattern is first established in the paraxial mesoderm during somitogenesis. This process involves a molecular oscillator termed the segmentation clock. Bessho and Kageyama’s review describes recent findings that shed light on the molecular mechanisms involved in the control of the oscillations and that open up the exciting perspective that the oscillator might be at work in tissues other than the presomitic mesoderm. Although vertebrate embryos are initially symmetrical along their left–right axis, this symmetry is rapidly broken during the organogenesis process. This ultimately results in the asymmetrical disposition of the internal organs in the body cavity. McGrath and Brueckner focus essentially on the initial trigger controlling the symmetry breakdown. They describe recent findings evidencing the role of cilia located in the node during gastrulation. These cilia control fluid dynamics and create a left-right oriented flow in the node, which represents the first asymmetry of the embryo and triggers a subsequent signaling cascade that leads to the differential development of the two embryonic halves.
Organogenesis The remaining series of reviews deals with various aspects of the organogenesis of the derivatives of the three germ layers of vertebrates. These reviews nicely illustrate the conservation and the diversity of the molecular mechanisms involved in organ development. The review by Tam, Kanai-Azuma and Kanai describes our current understanding of the early steps of endoderm induction in vertebrates, illustrating nicely how, in different species, a variety of mechanisms involved in the initiation of the process subsequently converge towards the activation of the Nodal signaling pathway, which www.current-opinion.com
Editorial overview Ephrussi and Pourquie´ 325
controls endoderm induction. The conservation among vertebrates of transcription factor networks involving genes such as Mixer or Sox17 and their role in specification of the endodermal fate is discussed. The authors also highlight the recently reported role of endoderm in the control of morphogenesis of the facial structures. Development of an important endodermal derivative, the pancreas, has been recently very actively investigated with the hope of developing cellular replacement therapies aimed at curing diabetes. Recent results in this area are presented in the review by Kumar and Melton. They describe how the endoderm must first become competent to form pancreas before responding to a series of local signals provided by the surrounding structures, including the notochord, the aorta or the lateral plate, that control the specification of the pancreatic rudiment. They also discuss the recent identification of key transcription factors, such as PDX1 or PTP1a, that play a major role in the control of pancreatic development. Two reviews deal with aspects of vertebrate mesoderm development. Rossant and Hirashima summarize our knowledge in the field of angiogenesis. It is now well established that endothelial development begins with the formation of a capillary plexus formed de novo by precursor cells. This plexus subsequently becomes remodeled to form the blood vessels which can then become artery, vein or lymphatic. The review summarizes how the initial precursors acquire their endothelial fate in response to vascular endothelial growth factor signals, and how their subsequent fate is controlled by the Notch and Ephrin signaling pathways. Recent advances in the development of long forgotten lymphatic vessels are also included. The other review, by Tajbakhsh, is focused on the development of skeletal muscles in the embryo and adult. All skeletal
www.current-opinion.com
muscles arise from the paraxial mesoderm and in the trunk and tail they derive from the somitic myotome. An account of the current controversy on the early stages of myotome formation is provided in the review. Subsequent muscle formation via repeated waves of myoblasts and aspects of muscle regeneration by satellite cells are discussed. An interesting aspect of the review is the emphasis placed on the role of stem cells in muscle generation and repair. The therapeutic potential of such stem cells to cure myopathies has led to numerous and sometimes controversial studies in the field, which are discussed in the article. Finally, aspects of the patterning of the vertebrate telencephalon, which generates our cortex, are presented in the review by Zaki, Quinn and Price. They provide a current view of the patterning mechanisms implicated in setting up the early forebrain territories and report the roles of local signaling by BMP, Wnt and Hedgehog family members and of the downstream networks of transcription factors they control. The part played by these systems in controlling local proliferation, cell fate decisions and migrations and how they participate in shaping the brain is discussed.
Conclusions Taken together, the reviews in this issue of Current Opinions in Genetics & Development highlight the remarkable degree of conservation of basic patterning mechanisms at levels ranging from the cell to the organism as a whole. Cell polarization, signaling, adhesion and motility all come into play in the establishment of pattern and organogenesis. A new level of regulation, at the RNA level, is now glimpsed and the future will undoubtedly reveal unsuspected players and new ways of achieving organismic complexity from the unpatterned one-cell zygote.
Current Opinion in Genetics & Development 2003, 13:323–325