Pattern formation and developmental mechanisms Editorial overview Michael Akam and John Gerhart Wellcome/CRC Institute, Cambridge, UK and University of California, Berkeley, California, USA Current Opinion in Genetics and Development 1992, 2:541-542 This year, the reviews provide updates on cytoplasmic localization, axis specification, induction, morphogenesis and organogenesis, with somewhat more emphasis on vertebrates than in the past issue, and on the cell biological aspects of these developmental processes. Genetics has revolutionized developmental biology, but cell biology has also had a major and growing impact. With respect to cell--cell interactions, cell biology has focussed on assays of cell behavior in culture, on the purifications of factors from culture media, and finally on the cloning of DNA sequences. The sequences for receptors, growth factors, adhesion molecules and extracellular matrix components have served developmental biologists well in their searches for homologous genes and functions in embryos of many phyla, as have the sequences from the Drosophila developmental mutants. Furthermore, the analysis of Drosophila developmental mutants has frequently led to cell biological problems. EB Wilson would surely appreciate the current synergism of genetics and cell biology in tile study of development.
Drosophila maternal-effect mutants have made possible the identification of a small set or proteins and mRNAs that are located at the poles of the ooc3,te and egg and are necessary for anteroposterior axis specification and for the germ-cell lineage. Localization of these materials in the oocyte depends on directional transport along microtubules, on specific attachment sequences in the RNAs, and on pole-specifying interactions of follicle cells with the oocyte (Lehmann, pp 543-549). The frog egg still leads the way for studies of axis specification in vertebrates. The egg's vegetal hemisphere conrains localized materials which, when later secreted, induce adjacent cells of the animal hemisphere to foml mesoderm. Fibroblast growth factor (FGF) and transtbrming growth factor (TGF)-IB (activin) family members probably serve this secretory function, as shown by the developmental defects caused by inactivating the receptors of these growth factors (Niehrs and De Robertis, Pp 550-555; Stern pp 556-561). Furthermore, a materhal member of the Wnt-family, secreted only on the egg's dorsal side, may sensitize local animal cells to the vegetal growth factors, allowing them to form dorsal meso-
derm, namely the Spemann organizer. Wnt's action as a co-inducer or a competence-modifying agent is a new twist in the induction story (Dickinson and McMahon, pp 562-566). The renowned Spemann organizer of the amphibian embryo, or its counterpart (Hensen's node) in embryo's of reptiles, birds and mammals, is the crucial cell population for morphogenesis and inductive patterning during gastrulation. Through its activities, mediated by zygotic gene expression, the true embryonic axes are established within the framework of the maternally derived egg axes. In the absence of mutants, we are now in the age of markers in vertebrate development. Organizer cells can now be recognized by their expression of the genes goosecoid, LIM-1 and forkhead, which encode specific transcription factors. At the same time, Xwnt-8 is a good marker for ventral mesoderm, X'orafor chordamesodema, MyoD for somites and twistfor lateral plate. The final expression domains of these markers depend on inductive signals from the organizer, some markers turned on and others off by the signals. Changing patterns of gene expression can now be seen during morphogenesis and induction. An initial low level of expression of some of these transcription factors may be part of a cell's competence to respond to inducing signals (Niehrs and De Robertis; Stern; Dickinson and McMahon). In plants, the phenotypic analysis of mutants affected in the earliest stages of embryogenesis has led to new insights about the independence of apical development and radial tissue specification, and to the identification of nine new genes that promise to be for Arabidopsis what the coordinate, gap, pair role and segment polarity genes have been for Drosophila (J/.irgens, pp 567-570). Cell interactions mediate the continuous patterning of the root and shoot meristem, and prove to be much more prevalent and important than first suggested (Becraft and Freeling, pp 571-575). Once the vertebrate body plan is laid out in gastrulation, and the Hox genes are regionally expressed, a second wave of cell migrations takes place. Neural crest, sclerotome, myotome and angioblast cells move to new sites where new inductive interactions and organogenesis o o
Abbreviations
FGF~fibroblast growth factor; TGF~transforminggrowth factor. Current Biology Ltd ISSN.0959-437X
541
542
Pattern formation and developmental mechanisms
cur, to add a second level of complexity to vertebrate organization. The vertebrate head is a monument to these migrations and interactions (Noden, pp 576-581) and 'cephalization' is a major theme in vertebrate evolution. Most craniofacial development occurs anterior to the Hox-controlled regions of the body, and so the search is on for region-specific transcription factors of the head. Pax- and MSH-fanlily members have proven useful in distinguishing the initial variety of cells and the changes that they undergo during head development. The vertebrate eye is a classic example of secondary and tertiary inductions that allow the image-receMng and image-forming parts of the eye (the retina, lens, and cornea) to develop in alignment with each other (Salla, Servemick and Grainger, pp 582-588). Kidney development is a classic example of epithelial-mesenchymal interactions, involving multiple inductions and complex morphogenesis (Bard, pp 589-595). In both these cases of organogenesis, new markers including many transcription factors are revealing unsuspected regional differences and cell interactions. The vertebrate gonad develops from an initial 'indifferent' state, along mutually exclusive paths toward ovary or testis. The recent finding of the testis-determining S~3, gene on the mouse Y-chromosome has caused this subject to be reopened. Sr3J is expressed briefly in certain somatic cells, the Sertoli precursors, which then interact with other gonad somatic cells to establish the testis and block ovary development. Germ cells then develop as egg or speml depending on the signals from somatic neighbors (Lovell-Badge, pp 596-601). The technique of selective cell ablation, by the expression of toxin genes under the control of cell-type- or region-specific promoter-enhancers, m W allow fl.,rther analysis of cell interactions in these cases of organogenesis (O'Kane and Moffat, pp 602-607). Finally, the use of mutants in Drosophila has led to the identification of some of the molecules involved in neurogenesis. Homeobox and other transcription factors define specific classes of neurons (Jan and Jan, pp 608-613). The pattern of these neurons is established by successive cell interactions including lateral inhibitions. Ligands and receptors that mediate these interactions have been identified. Some of these same gene products prove to be used elsewhere in the animal, by other interacting cells. These genes and gene products may constitute a common functional cassette that can be used at different times and places in development. The adhesion, movement, shape and division of cells vary in different regions of the embryo, and many developmental biologists consider it likely that transcription factors from master-control genes, such as the HOM/Ho:~:
family members, act on target genes for these aspects of cell behavior. At the same time, these behaviors alter in response to the cell's enviro~m~ent. The cell cycle, about which so much has been learned during the past five years, differs regionally in its length ,and arrest phase, tile signals releasing it from arrest, and the positions of cleavage planes (Saint and Wigley, pp 614-620). Cadherins, a large family of homophilic adhesion proteins, some of which associate with adherens junctions and desmosomes (Hynes, pp 621-624) may well participate in the control of cell proliferation, as indicated by the Drosophila fat mutant. Integrins and the immunoglobulin-related family of receptors allow interactions with the extracellular matrix, an important aspect of directed neurite outgrowth and of neural crest migration (Letourneau, Condic and Snow, pp 625-634). As might be expected, patterned cell death is a carefully controlled behavior, involving in the nematode the signaled suppression of a gene whose expression otherwise prevents death (Ellis, pp 635--641). kald finally, the egg, as a cell, turns general mechanisms of calcium-mediated signaling to its own ends of activation, blocking polyspermy, and resumption of the cell cycle (Shen, pp 642-646). Regarding the large number of different inductive interactions involved in the patterning of embryonic cells, what generalizations can be made? As Cox (pp 647-650) points out, modeling has led to the recognition of the power of lateral-inhibition mechanisms, with their properties of self-organization, symmetry breaking, and regulative restoration of pattern within groups of equivalent cells. These mechanisms make no assumption about the ligands and receptors used in signaling, or the transcription factors and genes used in the cell's response. While lateral inhibitions seem applicable to some spacing patterns, such as those of neuroblasts and bristles, the organism seems to employ completely unanticipated patterning mechanisms in other cases, for exan~ple in Drosophila, where very complex promoterenhancer regions are used to place seven evenly spaced pair rule stripes on the aperiodic background of gap gene products. Transcriptional control is only one box in the systems matrix of molecular interactions that may constitiute development, and cell-cell signaling is another. We are still a long way from plugging the genome's sequence together with a set of initial transcriptional conditions into a computer and watching them build an organism.
NI Akam, Wellcome/CRC Institute, Tennis Court Road, Cambridge CM2 1QR, UK. J Gerhart, Department of Molecular Biology, University of California, Berkele% California 94720, USA.
Drosophila maternal-effect mutants have made possible the identification of a small set or proteins and mRNAs that are located at the poles of the ooc3,te and egg and are necessary for anteroposterior axis specification and for the germ-cell lineage. Localization of these materials in the oocyte depends on directional transport along microtubules, on specific attachment sequences in the RNAs, and on pole-specifying interactions of follicle cells with the oocyte (Lehmann, pp 543-549). The frog egg still leads the way for studies of axis specification in vertebrates. The egg's vegetal hemisphere conrains localized materials which, when later secreted, induce adjacent cells of the animal hemisphere to foml mesoderm. Fibroblast growth factor (FGF) and transtbrming growth factor (TGF)-IB (activin) family members probably serve this secretory function, as shown by the developmental defects caused by inactivating the receptors of these growth factors (Niehrs and De Robertis, Pp 550-555; Stern pp 556-561). Furthermore, a materhal member of the Wnt-family, secreted only on the egg's dorsal side, may sensitize local animal cells to the vegetal growth factors, allowing them to form dorsal meso-
derm, namely the Spemann organizer. Wnt's action as a co-inducer or a competence-modifying agent is a new twist in the induction story (Dickinson and McMahon, pp 562-566). The renowned Spemann organizer of the amphibian embryo, or its counterpart (Hensen's node) in embryo's of reptiles, birds and mammals, is the crucial cell population for morphogenesis and inductive patterning during gastrulation. Through its activities, mediated by zygotic gene expression, the true embryonic axes are established within the framework of the maternally derived egg axes. In the absence of mutants, we are now in the age of markers in vertebrate development. Organizer cells can now be recognized by their expression of the genes goosecoid, LIM-1 and forkhead, which encode specific transcription factors. At the same time, Xwnt-8 is a good marker for ventral mesoderm, X'orafor chordamesodema, MyoD for somites and twistfor lateral plate. The final expression domains of these markers depend on inductive signals from the organizer, some markers turned on and others off by the signals. Changing patterns of gene expression can now be seen during morphogenesis and induction. An initial low level of expression of some of these transcription factors may be part of a cell's competence to respond to inducing signals (Niehrs and De Robertis; Stern; Dickinson and McMahon). In plants, the phenotypic analysis of mutants affected in the earliest stages of embryogenesis has led to new insights about the independence of apical development and radial tissue specification, and to the identification of nine new genes that promise to be for Arabidopsis what the coordinate, gap, pair role and segment polarity genes have been for Drosophila (J/.irgens, pp 567-570). Cell interactions mediate the continuous patterning of the root and shoot meristem, and prove to be much more prevalent and important than first suggested (Becraft and Freeling, pp 571-575). Once the vertebrate body plan is laid out in gastrulation, and the Hox genes are regionally expressed, a second wave of cell migrations takes place. Neural crest, sclerotome, myotome and angioblast cells move to new sites where new inductive interactions and organogenesis o o
Abbreviations
FGF~fibroblast growth factor; TGF~transforminggrowth factor. Current Biology Ltd ISSN.0959-437X
541
542
Pattern formation and developmental mechanisms
cur, to add a second level of complexity to vertebrate organization. The vertebrate head is a monument to these migrations and interactions (Noden, pp 576-581) and 'cephalization' is a major theme in vertebrate evolution. Most craniofacial development occurs anterior to the Hox-controlled regions of the body, and so the search is on for region-specific transcription factors of the head. Pax- and MSH-fanlily members have proven useful in distinguishing the initial variety of cells and the changes that they undergo during head development. The vertebrate eye is a classic example of secondary and tertiary inductions that allow the image-receMng and image-forming parts of the eye (the retina, lens, and cornea) to develop in alignment with each other (Salla, Servemick and Grainger, pp 582-588). Kidney development is a classic example of epithelial-mesenchymal interactions, involving multiple inductions and complex morphogenesis (Bard, pp 589-595). In both these cases of organogenesis, new markers including many transcription factors are revealing unsuspected regional differences and cell interactions. The vertebrate gonad develops from an initial 'indifferent' state, along mutually exclusive paths toward ovary or testis. The recent finding of the testis-determining S~3, gene on the mouse Y-chromosome has caused this subject to be reopened. Sr3J is expressed briefly in certain somatic cells, the Sertoli precursors, which then interact with other gonad somatic cells to establish the testis and block ovary development. Germ cells then develop as egg or speml depending on the signals from somatic neighbors (Lovell-Badge, pp 596-601). The technique of selective cell ablation, by the expression of toxin genes under the control of cell-type- or region-specific promoter-enhancers, m W allow fl.,rther analysis of cell interactions in these cases of organogenesis (O'Kane and Moffat, pp 602-607). Finally, the use of mutants in Drosophila has led to the identification of some of the molecules involved in neurogenesis. Homeobox and other transcription factors define specific classes of neurons (Jan and Jan, pp 608-613). The pattern of these neurons is established by successive cell interactions including lateral inhibitions. Ligands and receptors that mediate these interactions have been identified. Some of these same gene products prove to be used elsewhere in the animal, by other interacting cells. These genes and gene products may constitute a common functional cassette that can be used at different times and places in development. The adhesion, movement, shape and division of cells vary in different regions of the embryo, and many developmental biologists consider it likely that transcription factors from master-control genes, such as the HOM/Ho:~:
family members, act on target genes for these aspects of cell behavior. At the same time, these behaviors alter in response to the cell's enviro~m~ent. The cell cycle, about which so much has been learned during the past five years, differs regionally in its length ,and arrest phase, tile signals releasing it from arrest, and the positions of cleavage planes (Saint and Wigley, pp 614-620). Cadherins, a large family of homophilic adhesion proteins, some of which associate with adherens junctions and desmosomes (Hynes, pp 621-624) may well participate in the control of cell proliferation, as indicated by the Drosophila fat mutant. Integrins and the immunoglobulin-related family of receptors allow interactions with the extracellular matrix, an important aspect of directed neurite outgrowth and of neural crest migration (Letourneau, Condic and Snow, pp 625-634). As might be expected, patterned cell death is a carefully controlled behavior, involving in the nematode the signaled suppression of a gene whose expression otherwise prevents death (Ellis, pp 635--641). kald finally, the egg, as a cell, turns general mechanisms of calcium-mediated signaling to its own ends of activation, blocking polyspermy, and resumption of the cell cycle (Shen, pp 642-646). Regarding the large number of different inductive interactions involved in the patterning of embryonic cells, what generalizations can be made? As Cox (pp 647-650) points out, modeling has led to the recognition of the power of lateral-inhibition mechanisms, with their properties of self-organization, symmetry breaking, and regulative restoration of pattern within groups of equivalent cells. These mechanisms make no assumption about the ligands and receptors used in signaling, or the transcription factors and genes used in the cell's response. While lateral inhibitions seem applicable to some spacing patterns, such as those of neuroblasts and bristles, the organism seems to employ completely unanticipated patterning mechanisms in other cases, for exan~ple in Drosophila, where very complex promoterenhancer regions are used to place seven evenly spaced pair rule stripes on the aperiodic background of gap gene products. Transcriptional control is only one box in the systems matrix of molecular interactions that may constitiute development, and cell-cell signaling is another. We are still a long way from plugging the genome's sequence together with a set of initial transcriptional conditions into a computer and watching them build an organism.
NI Akam, Wellcome/CRC Institute, Tennis Court Road, Cambridge CM2 1QR, UK. J Gerhart, Department of Molecular Biology, University of California, Berkele% California 94720, USA.
