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Copyright 0 1997 by the Genetics Society of America Plants and the Logic of Development m o t M. Meyerowitz Division of Biology, California Institute of Technology, Pasadena, California 91 125 . . . plantsconstituteover 90% of theworld’s present (and past) biomass. Thus, simply in terms of their bulk, whatever we learn about plants has the potential to tip thebalanceinany debate concerning therelativefrequency of occurrence of abiological phenomenon. NIKLA~1992 I T seems likely that plants and animals have independently evolved multicellular development. Members of each kingdom are composed of different types of eukaryotic cells,implying thatthe two kingdoms diverged when theircommon eukaryotic ancestor was unicellular and that each lineage had a considerable unicellular history after they separated. This indicates that each kingdom separately evolved its mechanisms of cellular differentiation and cell-cell communication. This in turn raises a series of questions: do land plants and metazoans use the same fundamental mechanisms of development and perhaps even the same genes for similar processes, or has independent evolution of development meant theinvention of completely different ways of doing things? Is there only one way to evolve a developmental system, or more than one?Is more than one type of multicellular development even possible? The answers would reveal something of the logic of development as a general phenomenonand would indicate the types of constraints that exist on the evolution of development. A priori, the strongest constraints would seem to be the starting toolkit and the fact that any existing developmental system must be of a type that can continue to evolve-otherwise, it would have been competed to obscurity or extinction. The toolkits (i.e., the startingsets offunctional genes) used by plants and animals in their separate inventions ofdevelopment should have been similar, since both plants and animals arose, ultimately, from the same eukaryotic lineage. That this is true is also experimentally demonstrated, as many plant and animal genes of similar function are homologous. The question then is whether the genes used to regulate development are also homologous. If not, it is stillpossible thatnonhomologous genes can be used for similar functions, so that the general logicof the developmental mechanisms of plants and animals is the same, even though theindividual gene families used for each particular function are different. If this is the case, comparative study should reveal the principles of development. Alternatively, plants and animals could use completely different developmental mechanisms, in which case studying plant development would be like finding living organisms on Genetics 145 5-9 (January, 1997) another planet-an opportunity tosee something completely novel. In any case, understanding the independently evolved mechanisms of development in two very distantly related types of complex, multicellular organisms should allow a much better understanding of the logic of development and of the interplay of chance and necessity in the evolution of developmental mechanisms. So, do plants and animals use the same genes for the same developmental processes, or is everything different? Part of the answer is known, but only part. So far, it seems that the general cellular functions of plants and animals are homologous, but that only some of the regulatory genes that specify organ types or cellular domains are homologous, while others have a similar functional logic, but use members of different families of proteins to carry out similar functions. In one area it seems (so far) thatplants and animals are quitedifferent-while internal cellular mechanisms are homologous, the mechanisms by which plant and animal cells recognize their neighbors and theirenvironments seem (at least in our currentstate of partial knowledge) strikingly different. Thus, we are beginning tofind a gradient of difference between plants and animals. At the level of the nucleus, things look very much the same: in plants and animals chromosomes exist and contain highly similar histones, the chromosomes dance similarly through mitosis and meiosis, and the generaltranscriptional machinery seems very similar. When we observe the regulators of spatial patterns of gene expression, it appears that the logic by which homeotic selector genes and their regulators act are similar, but the proteins that carry out comparable developmental functions seem to be from different families. This indicates convergence on a similar type of developmental mechanism in both kingdoms. In the cytoplasm the gene products that carry out processes such as secretion, cellular trafficking, and biosynthesis are generally comparable, but there arespecial processes that differentiate plants and animals-protein import in chloroplasts, for example, or muscle contraction. By the time we are at the cell surface and consider interactions with the outside world, the receptors for external stimuli seem quite different, and theextracellular matrix ( k . , the plant cell walls, the protein matrix secreted by animal cells) is also noncomparable. Cellular functions: The past decade and more of m e lecular cloning of genes, and the various plant and animal genome projects, have provided a means for direct 6 E. M. Meyerowitz comparison between the cellular functions of plants and animals. The extensive catalogues of Arabidopsis thaliana expressed sequence tags, e.g., reveal that this flowering plant has homologues of animal genes involved in most housekeeping functions (NEWMAN et al. 1994; COOKEet al. 1996). Ribosomal proteins and translation factors are similar; chaperonins arehomologous; and ATP synthesis is mediated by homologous genes. Glycolytic enzymes, amino acid biosynthetic enzymes, actin, tubulin, kinesins, keratin, vacuolar sorting proteins, ubiquitin and the enzymes that act upon it, calmodulin and calmodulin-dependent kinases, and on and on, are held in common by plants and animals. There are of course specialized proteins that are kingdom-specific, at least so far, such as the enzymes involved in biosynthesis ofplant hormones such as gibberellins or ethylene, or counterparts thatmake specialized products, such as thyroid hormone, found only in animals. Some hormones are in common, though-both plants and animals use steroid hormones, though the exact structures of the active hormones are different, and we have no idea if the mechanism of reception is similar in thetwo kingdoms, as the plant receptorshave not been characterized (CLOUSE 1996; HOOLEY1996; LI et al. 1996; SZEKERES et al. 1996). There are most certainly also specialized celltypes that distinguish plants and animals. Plants do nothave neurons or muscles; animals do not have photosynthetic leaf mesophyll cells, stomatal guard cells or xylem. In terms of cell types, plants and animals are completely distinct. Even so, the structural proteins and enzymes that make up these very different celltypes are comparable: guard cells andneuronsboth use homologous potassium channels to fulfill their functions (WARMKEand GANETZKY 1994). Developmental regulatory proteins:The sequencing projects and many experiments involving the cloning of specific individual genes also show that the families of transcription factors involved in transcriptional regulation are held in commonby plants and animals. Both kingdoms have MADS box proteins, basic leucine zipper proteins, homeobox proteins, myb family factors, zinc finger proteins, and so on. Functional information on the products of individual genes allows us to begin to see the independent evolution of plant and animal development. Take for exampletwo families of transcription factors foundinboth kingdoms: homeoboxproteins and MADS domain proteins. Inanimals many of the homeobox proteins act as homeotic selector genes, serving the general function of differentiating different body regions from each other, presumably by activating and repressing different sets of downstream genes in different regions (MANAK and SCOTT1994). Plants also have many homeobox genes, but so far none has been shown to play a role in the specification of cell typein specific spatial domains. Instead, the best-studied set of plant homeobox genes (The K N O ~ class, ~ l KERSTEITER et al. 1994; LINCOLN et al. 1994) serve as activators of cell division in different spatial domains. When animal homeobox genes are ectopically expressed, homeotic conversions can result (e.g., GIBSON and GEHIUNC 1988; HALDER et ul. 1995). Overexpression of members of the KNOTTEDI classof plant homeobox genes activates generalized cell division, leading to formation of new meristems (e.g., SINHAet aZ. 1993; CHUCKet al. 1996). In this respect, at least so far, all of the members of this class ofhomeobox genes seem to have the same activity: their gain of function phenotypes all seem identical. This is not atall the case withthe fly genes, for example, ectopic expression of the Drosophila Antennupedia gene has utterly different effects than ectopic expression of e y e b s . Furthermore,the animal genes arefound in chromosomal complexes, with the order of genes related to the spatial pattern of their expression. The plant genes are not found in complexes. The converse situation occurs with the MADS box genes. In this case, mutations in many of theplant genes, or their ectopic expression, causes homeotic conversions (e.g., MIZUKAMIand M4 1992; KRIZEK and MEYEROWITZ 1996). This is best-studied in flowers, where each of the four organ types (sepals, petals, stamens, and carpels) is specified by a different combination of MADS box organ identity genes, expressed in overlapping spatial domains (WEIGEL and MEYEROWITZ 1994). The function of theplant MADS box genes seems to parallel the function of the animal homeobox genes-both classes serve as homeotic selector genes whose spatial pattern of activation determines the identity of segments, in animals, or floral whorls, in plants. In keeping with this parallel, each of the MADS box genes shows a different homeotic phenotype when ectopically expressed-each has functional specificity, just as do the animal homeobox genes. So far as we know, the animal MADS box proteins serve another typeof function. The best-studied is serum response factor, which is a general transcription factor that is activated by phosphorylation of an accessory protein to whichit binds and that serves in growth control by regulation of @os-eventually acting in the control of cellular proliferation, like some of the plant homeobox genes (PRICEet al. 1996). There are other animal MADS box proteins also, such as MEF-2, involved in activation of muscle cell differentiation (OLSONet al. 1995). So we can see a strong logical parallel between the patterns of activation, loss-of-function phenotypes, gainof-function phenotypes, and general role of the plant MADS domain proteins and the animal homeodomain proteins; however, the two families ofproteins are unrelated, and the founding genes of each family were almost certainly inherited in each lineage from the commonancestor. From this we can at least begin to conclude that certain developmental functions (homeotic selector genefunctions) evolved independently 1996 GSA Medal Essay and also perhaps that there is a necessity for this function in evolving, developing systems. Otherwise, why would such a mechanism have arisen independently in the only two complex multicellular lineages that we know? There is another set of parallels, too-the plant MADS box genes and the animal homeobox genes are spatially regulated at thetranscriptional level, by earlieracting transcription factors. Each group of genes also codes for transcription factors that are thought to act by regulating downstream genes. In both plants and animals pattern formation results from a longconversation between transcription factors, prior toany regional differentiation. But the transcription factors used as homeotic selector genes are different. Cell-cell and cell-environmentinterface: Develop ment requires communication between cells and their external environments, including neighboring cells. It is here that differences between plants and animals seem greatest, at least in our present state of partial knowledge. Such differences may not be unexpected, as the independent evolution of multicellularity in the two kingdoms might imply that they need to have evolved different ways of communicating from one cell to another. However, the great differences in response to similar environmental stimuli such as light are not expected on this basis. Nonetheless, they exist. Little is known about cell-cell communication in plants. One mechanism of this communication isby planthormones. The only plant hormone for which we have biochemical information on the receptor is ethylene, a gas made in plants as a response to various sorts of stress and during ripening of some types of fruits, and perceived by plant cells, which, depending on the cell type, respond in a variety of ways (ECKER1995). The ethylene receptors are two-component receptors with clear homology to bacterial receptors of the same class, which are histidine kinase/phosphatases and which act through transfer of phosphates from histidines to aspartates on response regulator proteins (CHANGet al. 1993; CHANC and MEYEROWITZ 1994; SCHALLER and BLEECKER 1995). In bacteria these molecules act as environmental sensors, e.g., in chemotaxis and in oxygen and osmolarity responses (PAFWNSONand KOFOID 1992). No member of the two-component receptor class has yet been found in animals, though there have been examples discovered in fungi and slime molds (OTA and VARsHAVSK%' 1993; ALEX et al. 1996; SCHUSTER et al. 1996; WANGet al. 1996). Despite the dissimilarity ofthis plant receptor with any known animal receptor, the closer the pathway gets to the nucleus, the more it resembles animal pathways. It is thought that the ethylene recep tors communicate with a protein that resembles mammalian raf kinases, and in yeast, where more of the downstream part of the pathway from the yeast twocomponent osmolarity receptor is known, the nextsteps are aseries of phosphate transfers between components of a M A P kinase cascade (MAEDA et al. 1995). MAP 7 kinases arecommon in plants aswell, thoughtheir involvement in ethylene perception is unproven. Animals for their part use a variety of cell surface receptors that appear tohave no counterpart in plants. No member of the animal receptor tyrosine kinasegene family has been found in any plant (or in any fungus, for that matter, HUNTER 1994). Plants do have small GTP-binding proteins of various types, but no real ras homologue has been found (MA 1994). No serpentine (seven transmembranesegment)receptor has been found in plants, either. Plants do appear to have heterotrimeric G proteins; based on the molecular cloning of reasonable homologues of Galpha and Gbeta subunits (MA 1994). But their role in the plant is generally unknown (though see below), and they do not have the sort of diversityfound in animals: there is, for example, only one Galpha gene known in any species of plant, rather than the multitude of cross-hybridizing genes found in animals. The absence (so far, at least) of serpentine receptors, which are so often associated with heterotrimeric G proteins in animals, indicates again that the receptor may be different, but as the pathway closes in on the nucleus, things become more similar. Plants also havea large family ofapparent cell surface receptors that have extracellular leucine-rich repeats and that act in the cytoplasm as serine/threonine kinases ( C W G et al. 1992; WALKER1994). These LRR kinases havebeen found to act in perception of external pathogens and in a variety of developmental processes such ascelldivision that depend on signaling from neighboring cells ( . g . , SONG et al. 1995; TONI et al. 1996). While animals have leucine-rich repeat proteins and serine threonine kinases, there are no known animal homologues of the large plant receptorfamily. Perhaps the plant proteins fill the role filled in animals by receptor tyrosine kinases. To cite one additional example, despite the fact that plants and animals perceive and act upon light information in many ways, the receptors are completely different. Multicellular plants, like many animals, have color vision and receptors that act at different wavelengths. The red/far-red light receptors are phytochromes, proteins with no known homologues in animals, that use a tetrapyrrole chromophore (QUAIL et al. 1995). The plant blue light receptors (cryptochromes) are flavoproteins related to bacterial photolyases (AHMAD and CASHMORE 1996). Animal light receptors are rhodop sins, members of the serpentine receptor family, with a retinal chromophore; they act through heterotrimeric G proteins (ZLJKER 1996). It is not known whether the light pathwaysof plants and animals become similar after thereception event, because the pathways in plants are generally unknown. There is evidence, though, that at least some of the processes induced by phytochrome in plant cells require activation ofheterotrimeric G proteins (NEUHAUSet al. 1993), just as do processes activated by rhodopsins in animal cells. There 8 E. M.Meyerowitz are also early indications that proteins in one protein complex involved downstream of phytochrome have counterparts in mammals, but they are not proteins known to be involved in animal photoreception (CHAMOVITZ and DENG1995). The extracellular matrix of plant and animal cells is also completely different, plants having a cellulose/ hemicellulose cell wall that binds neighboring cells to each other; while animals rely on proteins for their extracellular matrix. Plant cell walls have proteins such as the various arabinogalactan proteins, and expansins (COSGROVE 1996; KREUGER and VAN HOLST1996). These are not related to animal extracellular matrix proteins. Thus, extracellular matrices and transmembrane receptors, even though they may serve similar functions in terms of development and cellular communication, appear tohave evolvedfrom different starting points and by use of different families of proteins. Conclusions: In our current state of partial knowledge, it appears that there is a gradient of difference between plants and animals, from quite similar in housekeeping processes in nucleus and cytoplasm, to logically similar but biochemically distinct regulatory aspects ofdevelopment and control of cellular differentiation, to utterly distinct means of communicating from each cell to its neighbors and to theoutside world. This view results in part from ignorance, though. The discovery of a set of animal homeotic selector genes that areMADS domain proteins,of an animal two-component receptor, or of a plant serpentine receptorand tyrosine kinase wouldchange it. Nonetheless, it is worth keeping a running score. If we accept thata comparison of the two independently evolved mechanisms of complex multicellular development allows us to differentiate those aspects of developmental biology that arenecessary for anyevolved developing system from those that are only accidental, we can pointto long conversations between transcription factors as being necessary for pattern formation and to cell-cell communication as being necessary for functional multicellularity. An additional take home lesson is that we need to learn more about both plant andanimal development to be certain that these lessons are true and to learn about additional logically parallel systems that use unrelated gene products. In particular we must understand the full array of mechanisms used in genetic regulation in both kingdoms and the nature of the molecules involved in cell-cell communication and environmental response. There areseveral paths to this understanding. One is to continue the successful application of developmental genetics to both plants and animals, starting with mutations that affect critical developmental functions and proceeding via genetics, molecular genetics, and biochemistry to an understanding of the actions of the proteinsand protein complexes that actto regulate differentiation, pattern formation,and cellular communication. Another is comparative genomics, to letus see if we have completed the job of understanding each species under study and to allow complete comparisons of gene numbers, gene homologies, and the genetic complements of as wide an array of organisms as possible (GABORMIKLOSand RUBIN1996). Comparisons of plants and animals will be an important part of this, but it should also be noted that a real comparison of plants and animals will also require knowledge of the starting toolkit of genes that was commonly inherited by both lineages. This means taking a careful look at prokaryotic genomes and also at those of a variety of unicellular eukaryotes. With this information we can also begin to come to an understanding of the evolutionary origin of the proteins used in developmental regulation and cellular communication and come to grips with the question of the origin of evolutionary novelties. To emphasize the importance of the broadest possible comparative approach to an understandingof development, consider an experiment to find out whether there is indeed a limited set of waysthat complex multicellular development can evolve from identical unicellular organisms. The experiment would be to take a series of identical cells and place them in conditions that favor multicellularity and then to wait for two billion years and observe the result. One would expect the result to be highly revealing, to lead to a new appreciation for the evolution of development, and to point the way to new ways of thinking about ontogeny. 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