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Cell differentiation Cell asymmetry in development
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Cell differentiation Cell asymmetry in development Editorial overview Stephen Cohen* and Kai Simonst Addresses European Molecular Biology Laboratory, Meyerhofstrasse 1, D-6900 Heidelberg, Germany *e-mail: [email protected] te-mail: [email protected] Current Opinion in Cell Biology 1997, 9:831-832
http:llbiomednet.comlelecref10955067400900831 © Current Biology Ltd ISSN 0955-0674
In recent years there has been a growing awareness among developmental biologists that many fundamental aspects of pattern formation take place at the level of the polarization and asymmetry of single cells. T h e study of cell polarity has traditionally been the domain of cell biology, reflecting the interest in the molecular mechanisms by which yeast cells, epithelial cells, and neurons are polarized. However, the distinctions between these disciplines are becoming less clear cut. It is our hope that the compilation of reviews in this section of Current Opinion in Cell Biology will help to reduce the barriers between these areas of cell biology and developmental biology and to stimulate research in the field. In some developmental mechanisms the importance of cell asymmetry has long been evident. Familiar examples include the asymmetric localization of fate determinants in the eggs of invertebrates (Drosophila and Caenorhabditis elegans) and vertebrates (Xenopus and ascidians), and the asymmetric cell divisions that take place in budding yeast, caulobacter, the early C. elegans embryo and in the segregation of neuronal precursor cells in Drosophila. Asymmetries of this sort are generated through cell-intrinsic mechanisms that differentially localize the determinants during cell division so as to produce unequal daughter cells. This section of Current Opinion in Cell Biology begins by considering exciting recent advances in understanding the cellular mechanisms by which such asymmetries are generated in animal and plant cells and how these asymmetries impact on development. Asymmetries generated at the level of cell populations are also of central importance in development of tissues and organs. Extrinsic cues can instruct cells to adopt particular fates or to alter their differentiated state. Such changes may lead to altered local cell-cell interactions or to the production of new signals that act at long range to influence the behavior of cell populations in coordinated ways. Examples of cell-extrinsic mechanisms for generating and
using asymmetry are also considered in several reviews in this section. In addition to these familiar questions, it is becoming apparent that subtle aspects of cell asymmetry will prove to be of profound developmental significance. Among the examples considered here are the generation of cell asymmetry within the plane of an epithelium and how subcellular localization of the cell signaling and signal transduction machinery can be used to modulate polarized cell interactions in vivo. Knoblich (pp 833-841) reviews an evolutionarily conserved system for generating asymmetric cell division in animal cells. One way to generate different cell types involves differential distribution of molecules during cell division. To localize a determinant, it is first necessary to have a polarized cell and a means to direct asymmetric localization of the determinant within the cell. Localized determinants may be RNAs or proteins. Next, the plane of cell division must be oriented in a manner that is coordinated with the mechanisms for localization of the determinant. Recent work suggests that the Inscuteable protein may be intimately involved in this coordination process. What do localized determinants do? If they are RNAs they may allow for the localized translation of a protein that influences cell fate or differentiation; examples of such proteins include transcription factors such as Prospero and ASH-1. An intriguing alternative is suggested by the finding that the localized determinant N u m b modulates signaling by Notch family receptors. Thus, an asymmetric cell division can modulate how daughter cells are able to respond to cell-extrinsic signals and can therefore have far-reaching consequences in pattern formation. Gallagher and Smith (pp 842-848) and JiJrgens, Grebe and Steinmann (pp 849-852) consider mechanisms of asymmetric cell division in plants and the consequences of early asymmetry in embryonic patterning. Control of cell polarity, the plane of cell division and growth are all particularly important in plant development because cells are constrained by their cell walls to remain in the position and near-neighbor relationships with which they are born. T h e authors of these two reviews discuss the use of localized determinants for generating asymmetric division and how aspects of cell polarity, such as polarized secretion and growth, contribute to the generation of asymmetric daughter cells. T h e use of diffusible signaling molecules as a source of positional information is well documented in animal cells, and it is particularly interesting to see that cell-extrinsic cues (other than hormones) and cell-cell
832
Cell differentiation
signaling mechanisms may also be used in plants to provide positional information.
ago. Today, a plethora of protein factors involved is being cataloged.
T h e inherent polarity of cells can influence interactions between them in vivo. T h e importance of subcellular localization of the signaling machinery is obvious in neurons. Kim (pp 853-859) reviews recent studies of C. elegans that show that the subcellular localization of both ligand and receptor is also important for signaling in less extremely polarized cells. A number of P D Z domain containing proteins have been implicated in the subcellular localization of receptors and in the co-localization of downstream signal transduction components with each other, suggesting that the subcellular organization of signaling cascades may be a broadly conserved means by which the inherent apical-basal polarity of epithelial cells is used to fine-tune cell interactions. In addition to apical-basal polarity, many epithelial cells also exhibit signs of polarity within the plane of the epithelium. Eaton (pp 860-866) discusses two examples where epithelial planar polarity occurs; one is the vertebrate inner ear and the other is the Drosophila wing and eye. Analysis of mutants affecting planar polarity raises the intriguing possibility that subcellular localization of signaling interactions might also be involved here.
Lastly, Bronner-Fraser and Fraser (pp 885-891) review the molecular basis for the cell interactions that pattern the vertebrate neural tube. There is evidence for both planar and cross-tissue interactions in early stages of neural induction. It will be interesting to see to what extent the polarity of the neural epithelium influences the cell interactions that pattern it at both early and later stages where intercellular signals mediated by bone morphogenetic proteins and Sonic Hedgehog are involved.
T h e last three reviews in this section consider developmental systems in which cellular asymmetries are an important prerequisite for pattern formation. In the past few years, substantial progress has been made in understanding the cell interactions that control limb development in vertebrates and insects. Long-range signaling mediated by secreted proteins of the Wnt, transforming growth factor-l~, Hedgehog and fibroblast growth factor families has been implicated in cell fate specification and growth control. Short-range interactions mediated by transmembrane ligands of the Notch receptor also play central roles in forming tissue boundaries. Irvine and Vogt (pp 867-876) review exciting recent advances which suggest that the fringe genes play important roles in generating the asymmetries in cell signaling that are required for boundary formation. Several of the examples considered thus far involve interactions between cells within a single tissue layer. However, organogenesis in vertebrate embryos depends on polarized cell interactions across tissue layers. For example, reciprocal interactions between epithelial and mesenchymal cells are critical for the development of the kidney and lung. Sariola and Sainio (pp 877-884) review recent advances in understanding the nature of the signals that direct tubule branching and bud growth in the developing kidney. This is an area of research in which almost no identified molecules were known a few years
What is obvious from the reviews in this section is that we are rapidly gaining access to a growing catalog of possible players in the processes that lead to cell asymmetries, be they RNAs or proteins. However, how these components work together is still difficult to discern. T h e possible scenarios have not yet been disclosed. An obvious locality where the action will take place is the cell surface itself which, by its organization, will contain and generate local differences that can be utilized for further generation of intracellular asymmetries. Biosynthetic and endocytic membrane transport will influence how different domains arise within the plasma membrane. Another locality is the underlying cell cortex; this is currently seen as a 'black box' with little meaning, but it is the site of connection of cell surface proteins to the actin and microtubular networks which will play a key role in cellular fate determination. Transport not only of vesicular carriers but also of RNA and protein packets, using motors to translocate them along cytoskeletal tracks, will lead to asymmetric distributions within the cell. Interactions of cell surface molecules with neighboring cells and extracellular matrices as well as with circulating signaling molecules generate local surface foci for the dissipation of signals into the cell. In multicellular organisms, the cellular context will be defined by information from the outside acting on cell surface molecules which then respond to change their cellular insides. T h e positional information can only be really understood by unraveling the mechanisms that cells use to convert the signals into changes in intracellular organization. How asymmetries are generated within cells is a problem that is only recently beginning to get the attention it deserves. Obviously different cells will respond in different ways to extracellular signals depending on their genetic readout status. T h e exciting message to all researchers working in these areas of biology is that the tools are becoming available to tackle problems of such complexity. Needless to say, the prospects are exciting.
Cell differentiation Cell asymmetry in development Editorial overview Stephen Cohen* and Kai Simonst Addresses European Molecular Biology Laboratory, Meyerhofstrasse 1, D-6900 Heidelberg, Germany *e-mail: [email protected] te-mail: [email protected] Current Opinion in Cell Biology 1997, 9:831-832
http:llbiomednet.comlelecref10955067400900831 © Current Biology Ltd ISSN 0955-0674
In recent years there has been a growing awareness among developmental biologists that many fundamental aspects of pattern formation take place at the level of the polarization and asymmetry of single cells. T h e study of cell polarity has traditionally been the domain of cell biology, reflecting the interest in the molecular mechanisms by which yeast cells, epithelial cells, and neurons are polarized. However, the distinctions between these disciplines are becoming less clear cut. It is our hope that the compilation of reviews in this section of Current Opinion in Cell Biology will help to reduce the barriers between these areas of cell biology and developmental biology and to stimulate research in the field. In some developmental mechanisms the importance of cell asymmetry has long been evident. Familiar examples include the asymmetric localization of fate determinants in the eggs of invertebrates (Drosophila and Caenorhabditis elegans) and vertebrates (Xenopus and ascidians), and the asymmetric cell divisions that take place in budding yeast, caulobacter, the early C. elegans embryo and in the segregation of neuronal precursor cells in Drosophila. Asymmetries of this sort are generated through cell-intrinsic mechanisms that differentially localize the determinants during cell division so as to produce unequal daughter cells. This section of Current Opinion in Cell Biology begins by considering exciting recent advances in understanding the cellular mechanisms by which such asymmetries are generated in animal and plant cells and how these asymmetries impact on development. Asymmetries generated at the level of cell populations are also of central importance in development of tissues and organs. Extrinsic cues can instruct cells to adopt particular fates or to alter their differentiated state. Such changes may lead to altered local cell-cell interactions or to the production of new signals that act at long range to influence the behavior of cell populations in coordinated ways. Examples of cell-extrinsic mechanisms for generating and
using asymmetry are also considered in several reviews in this section. In addition to these familiar questions, it is becoming apparent that subtle aspects of cell asymmetry will prove to be of profound developmental significance. Among the examples considered here are the generation of cell asymmetry within the plane of an epithelium and how subcellular localization of the cell signaling and signal transduction machinery can be used to modulate polarized cell interactions in vivo. Knoblich (pp 833-841) reviews an evolutionarily conserved system for generating asymmetric cell division in animal cells. One way to generate different cell types involves differential distribution of molecules during cell division. To localize a determinant, it is first necessary to have a polarized cell and a means to direct asymmetric localization of the determinant within the cell. Localized determinants may be RNAs or proteins. Next, the plane of cell division must be oriented in a manner that is coordinated with the mechanisms for localization of the determinant. Recent work suggests that the Inscuteable protein may be intimately involved in this coordination process. What do localized determinants do? If they are RNAs they may allow for the localized translation of a protein that influences cell fate or differentiation; examples of such proteins include transcription factors such as Prospero and ASH-1. An intriguing alternative is suggested by the finding that the localized determinant N u m b modulates signaling by Notch family receptors. Thus, an asymmetric cell division can modulate how daughter cells are able to respond to cell-extrinsic signals and can therefore have far-reaching consequences in pattern formation. Gallagher and Smith (pp 842-848) and JiJrgens, Grebe and Steinmann (pp 849-852) consider mechanisms of asymmetric cell division in plants and the consequences of early asymmetry in embryonic patterning. Control of cell polarity, the plane of cell division and growth are all particularly important in plant development because cells are constrained by their cell walls to remain in the position and near-neighbor relationships with which they are born. T h e authors of these two reviews discuss the use of localized determinants for generating asymmetric division and how aspects of cell polarity, such as polarized secretion and growth, contribute to the generation of asymmetric daughter cells. T h e use of diffusible signaling molecules as a source of positional information is well documented in animal cells, and it is particularly interesting to see that cell-extrinsic cues (other than hormones) and cell-cell
832
Cell differentiation
signaling mechanisms may also be used in plants to provide positional information.
ago. Today, a plethora of protein factors involved is being cataloged.
T h e inherent polarity of cells can influence interactions between them in vivo. T h e importance of subcellular localization of the signaling machinery is obvious in neurons. Kim (pp 853-859) reviews recent studies of C. elegans that show that the subcellular localization of both ligand and receptor is also important for signaling in less extremely polarized cells. A number of P D Z domain containing proteins have been implicated in the subcellular localization of receptors and in the co-localization of downstream signal transduction components with each other, suggesting that the subcellular organization of signaling cascades may be a broadly conserved means by which the inherent apical-basal polarity of epithelial cells is used to fine-tune cell interactions. In addition to apical-basal polarity, many epithelial cells also exhibit signs of polarity within the plane of the epithelium. Eaton (pp 860-866) discusses two examples where epithelial planar polarity occurs; one is the vertebrate inner ear and the other is the Drosophila wing and eye. Analysis of mutants affecting planar polarity raises the intriguing possibility that subcellular localization of signaling interactions might also be involved here.
Lastly, Bronner-Fraser and Fraser (pp 885-891) review the molecular basis for the cell interactions that pattern the vertebrate neural tube. There is evidence for both planar and cross-tissue interactions in early stages of neural induction. It will be interesting to see to what extent the polarity of the neural epithelium influences the cell interactions that pattern it at both early and later stages where intercellular signals mediated by bone morphogenetic proteins and Sonic Hedgehog are involved.
T h e last three reviews in this section consider developmental systems in which cellular asymmetries are an important prerequisite for pattern formation. In the past few years, substantial progress has been made in understanding the cell interactions that control limb development in vertebrates and insects. Long-range signaling mediated by secreted proteins of the Wnt, transforming growth factor-l~, Hedgehog and fibroblast growth factor families has been implicated in cell fate specification and growth control. Short-range interactions mediated by transmembrane ligands of the Notch receptor also play central roles in forming tissue boundaries. Irvine and Vogt (pp 867-876) review exciting recent advances which suggest that the fringe genes play important roles in generating the asymmetries in cell signaling that are required for boundary formation. Several of the examples considered thus far involve interactions between cells within a single tissue layer. However, organogenesis in vertebrate embryos depends on polarized cell interactions across tissue layers. For example, reciprocal interactions between epithelial and mesenchymal cells are critical for the development of the kidney and lung. Sariola and Sainio (pp 877-884) review recent advances in understanding the nature of the signals that direct tubule branching and bud growth in the developing kidney. This is an area of research in which almost no identified molecules were known a few years
What is obvious from the reviews in this section is that we are rapidly gaining access to a growing catalog of possible players in the processes that lead to cell asymmetries, be they RNAs or proteins. However, how these components work together is still difficult to discern. T h e possible scenarios have not yet been disclosed. An obvious locality where the action will take place is the cell surface itself which, by its organization, will contain and generate local differences that can be utilized for further generation of intracellular asymmetries. Biosynthetic and endocytic membrane transport will influence how different domains arise within the plasma membrane. Another locality is the underlying cell cortex; this is currently seen as a 'black box' with little meaning, but it is the site of connection of cell surface proteins to the actin and microtubular networks which will play a key role in cellular fate determination. Transport not only of vesicular carriers but also of RNA and protein packets, using motors to translocate them along cytoskeletal tracks, will lead to asymmetric distributions within the cell. Interactions of cell surface molecules with neighboring cells and extracellular matrices as well as with circulating signaling molecules generate local surface foci for the dissipation of signals into the cell. In multicellular organisms, the cellular context will be defined by information from the outside acting on cell surface molecules which then respond to change their cellular insides. T h e positional information can only be really understood by unraveling the mechanisms that cells use to convert the signals into changes in intracellular organization. How asymmetries are generated within cells is a problem that is only recently beginning to get the attention it deserves. Obviously different cells will respond in different ways to extracellular signals depending on their genetic readout status. T h e exciting message to all researchers working in these areas of biology is that the tools are becoming available to tackle problems of such complexity. Needless to say, the prospects are exciting.