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--> 3 Developmental Biology Introduction Traditionally, developmental biologists are concerned with the processes and mechanisms responsible for the development of the zygote into a primordial set of cell types, as well as the later developmental events that produce the mature organism, including organogenesis, histogenesis, and cellular differentiation. In effect, every process from conception to aging and death could be considered a component of development. In the Goldberg report published in 1987,1 two primary concerns were stressed regarding future investigations conducted in space on developmental processes: Can organisms undergo normal development in microgravity? and, Are there developmental phenomena that can be studied better in microgravity than on Earth? Since 1987 research has partly answered the first question, but some important issues must still be addressed. With regard to the second point, the distinct possibility remains that the space environment may be useful for understanding certain biological phenomena occurring in specific systems identified below. This chapter first reviews the major changes in perspective during the last few years in the general field of developmental biology and then discusses the importance of pursuing complete life cycles in space. The specific systems for which gravity is likely to play a critical role in development and/or maintenance include the vestibular system (that part of the ear and nervous system controlling posture and balance) and also the multiple sensory systems that interact with the vestibular system. In addition, gravity should influence the topographic neural space maps that exist throughout the brain. Space maps represent areas of the brain containing orderly structural and/or functional representations of either sensory or motor systems found within the brainstem, hippocampus, sensory and motor cortical areas, and corpus striatum. Neuroplasticity is discussed both generally and specifically as it pertains to gravity-sensitive systems. Neuroplasticity refers to long-term changes in neuron structure and function in response to changes in their activity. Finally, aspects of plant development that have special pertinence to microgravity are covered in Chapter 4.
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--> Progress In Developmental Biology Three major advances have transformed basic cellular and developmental studies during the past 10 to 15 years. These advances have, in turn, affected our ability to seek a molecular understanding of nearly every aspect of the response to microgravity by organisms in space. Developmental Genetics Saturation mutagenesis has been applied to identify key genetic components involved in specific developmental events using Drosophila melanogaster, Caenorhabditis elegans, and Arabidopsis thaliana. For the first time, these experiments are providing a molecular basis for understanding the mechanism underlying the step-by-step progression that occurs during development. Although these initial genetic screens revealed broad outlines of developmental mechanisms, new genetic screens are being tested that are sensitized to detect interacting genetic components. 2 Techniques to produce clones of cells in which the phenotype of mutations can be analyzed in a subset of cells3 4 5 have led to the identification of many constitutively important functions. These studies have shown that multiple genes are required to act collectively in a variety of developmental processes, so that mutations in any of these may be lethal. For example, the molecular cascade responding to growth factor signaling is used in many other receptor-mediated responses. In addition, by analyzing the effect of mutations in a clone of cells, researchers avoid the complexities that arise from the participation of these genes in essential functions in a wide variety of cells. Outstanding examples of the power of this genetic approach include recent advances in identifying the complex set of interacting systems involved in the development of the vulva in nematodes 6 and the eye in fruitflies,7 including the receptor tyrosine kinase-ras-raf-pathway. These studies have transformed the understanding of developmental progression and may provide a basis for similar analyses of vertebrate systems. Similar saturation genetic approaches have been applied with considerable success to zebrafish, Danio rerio.8 9 However, in this organism, identifying genes at the molecular level is still difficult. In mammals, the laboratory mouse, Mus musculus, has taken a central role in the genetic analysis of gene function. Two major advances have propelled this organism to the forefront of developmental studies. First, the development of embryonic stem (ES) cells, in which homologous recombination can be accomplished efficiently, has made targeted mutagenesis possible. 10 Mutated ES cells can be transplanted into genetically marked blastocysts, where they populate the germ line of the host embryo. By appropriate crosses, embryos can be produced that completely lack certain gene functions. Second, the introduction of ethyl-N-nitrosurea as a mutagen has allowed mutations to be produced in specific genes, either as alleles of known genes or as genes contained within deficiencies. 11 The availability of multiple alleles of known mutations complements the approach of targeted mutagenesis with ES cells. Although this is still in the future, it should soon be possible to use these technologies to investigate the genetic and molecular basis for inner ear function in mice, and then in humans. While the analysis of developmental events in vertebrates is more difficult to achieve and more expensive because of the animals' larger size and longer generation times, the potential for understanding specific developmental events in these systems is great, and may provide critical models for detailed analyses of human genetic defects. Molecular Conservation The second major advance has been the recognition that molecular mechanisms are conserved across phylogeny. The initial discovery of the homeobox sequence in Drosophila and its conservation
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--> in vertebrates in 1984 alerted the biological community that basic mechanisms for establishing polarity in the anteroposterior axis were conserved in multicellular organisms. This discovery was quickly followed by the recognition that control of the cell cycle in vertebrates used the same set of genes identified in yeast. New examples of the conservation of genetic function between simple model organisms, vertebrates, and humans have since been identified almost on a regular basis.12 For example, the organization of the arthropod embryo with a ventral nervous system and the vertebrate embryo with a dorsal neural tube have been shown to depend on the same molecular mechanisms for establishing polarity.13 The difference in organization is explained by differences in the formation of the mouth (stomodeum) rather than in differences in the dorsal-ventral patterning of the embryo. Similarly, the development of compound eyes in insects, squid, and certain vertebrates—animals that were once thought to depend on fundamentally different developmental processes and to have evolved independently of each other—have recently been shown to involve the same conserved gene, eyeless in Drosophila and small eye in the mouse.14 15 The genetic circuitry used for appendage formation in flies is used in a remarkably similar manner to control development of vertebrate limbs.16 Molecular experiments have even shown conservation of some developmentally associated mechanisms in organisms as distantly related as plants and animals. Even though plants and animals are thought to have evolved their developmental processes independently, it has recently been found, for example, that the proteins that maintain cellular memory of positional information are conserved, even though initially established by different types of genes in plants and animals.17 Although these examples seem diverse, they represent a general theme now apparent in the field of developmental biology, which has transformed the experimental approach applied to understanding cell differentiation and development. Also, this conservation of molecular mechanisms offers the opportunity of using systems that can be manipulated experimentally in organisms whose genetics would be intractable. This includes systems such as the limb bud of the chick embryo and Spemann's organizer in amphibian embryos. Thus, newly discovered genetic interactions now can be integrated quickly into a developmental model that can be tested by direct experimentation (e.g., Quiring et al., 1994). 18 Genome Sequencing Project The third advance in new information has been provided by the genome sequencing projects that are transforming the identification of the components of cellular and developmental processes. Today, the field of developmental biology is focused on a small number of model organisms that allow for detailed analysis of development at the cellular, genetic, and molecular levels. In combination with the considerable new information available as a consequence of the genome project, comparative molecular studies of yeast, plants, worms, flies, fish, and mammals will become the dominant theme for future studies. Because of the power of this type of analysis, most future studies of developmental phenomena will be conducted on organisms for which there is complete knowledge of the genome. In the field of development, where sea urchins, frogs, and chicks (three classical experimental organisms) are not subjects for the genome project, these models will lack the level of completeness that can be achieved from organisms such as yeast, flies, and worms, whose full genetic and molecular composition have been analyzed. However, the existence of genetic homologies makes investigations of the classical organisms still practical, as recently exemplified by the study of chick limb development.19 New technologies, such as differential displays and differential cDNA libraries of cells and tissues at various stages of development, also provide potential avenues for integrating the classical organisms into the genetic analysis of development.
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--> Major Issues In Space Developmental Biology As stated in the 1987 Goldberg report,20 the two objectives for developmental biology studies remain unchanged: to identify areas of fundamental research in space biology that are important to pursue in space, and to develop a knowledge base for long-term manned space habitation and/or exploration. Although significant progress has been made on a number of research projects proposed in that report, it is clearly impossible to test the wide range of possible effects of microgravity on biological development. In this report the importance of two types of future studies is stressed. First, complete life cycles in space should be used as an approach to determining whether there are developmental events affected by reduced gravity. In addition, continued analysis of the development of the gravity-sensing systems, including the vestibular system and other systems that interact with it in vertebrates, should be carried out to determine the importance of gravity in their normal development and maintenance. Complete Life Cycles in Microgravity Critically testing hypotheses regarding the effect of microgravity on specific developmental processes continues to be extremely difficult because of the engineering demands and the difficulty of repeating experiments in space. The latter reflects the high cost of performing experiments and the limited access to in-flight experimental animals. For example, a number of land-based experiments conducted on frog embryos during the first cell cycle after fertilization had suggested that the reorganization of yolk during rotation of the newly fertilized egg is responsible for establishing polarity of the early embryo. In experiments in which the rotation was prevented, axis formation was impaired. This led to the hypothesis that a gravity-induced movement of yolk was important for establishing the initial polarity. This was a natural experiment to test in microgravity. Costly in-flight experiments were performed in which the frog eggs were fertilized in space, and the embryos were allowed to develop to the tadpole stage before returning to Earth. Surprisingly, most of these embryos were normal, and some even developed to the adult stage and were fertile.21 Thus, although there was a clear indication that this developmental step depended on gravity, experiments in microgravity had ruled this out. Unfortunately, because of the difficulty of observing experimental animals in space, it is not yet known whether the reorientation of yolk occurred in microgravity through an endogenous contractile system, or whether the polarity was established independently of yolk movement. This example illustrates both the utility and the limitations of conducting experiments in space relating to specific developmental issues. Because of the extraordinary expense and technical limitation of in-flight experiments, requiring extensive engineering backup and preflight experiments, it is clear that only a few critical tests of hypotheses concerning the role of gravity in normal developmental events can be performed. An alternative approach is to maintain a number of key organisms in space for two complete generations. The basis for this is the assumption that if organisms can grow successfully and reproduce in space, there are no specific stages during the life cycle that rely critically on a gravity-dependent process. A second generation is required to ensure that the processes of gamete production (particularly the development of the oocyte) can be accomplished in microgravity. Of course, in applying this approach small effects of gravity may be overlooked, such as the finding that amphibian embryos grown in microgravity possess a thicker blastula roof than normal.22 However, this difference must be compensated for later on, since these embryos did develop into normal tadpoles. The maintenance of life and the capability to reproduce do not necessarily ensure that higher brain functions have developed normally and are functional in organisms raised in space (see specific systems below). This would be
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--> most apparent in vertebrate animals. A major focus for space experiments should therefore be to maintain animals through successive generations, followed by detailed analyses to determine whether deficiencies detected are produced routinely. During the past 10 years fruitflies23 and nematodes24 have been grown successfully in microgravity through more than one generation with no significant developmental abnormalities. Although further repetition of the experiments in flies might be necessary because some abnormalities were observed, these results basically indicate that no major developmental process in these simple organisms critically depends on gravity. There are no comparable results with vertebrate animals, and such experiments should have high priority. The zebrafish, the current favorite of developmental geneticists for performing studies in lower vertebrates, may be difficult to rear in space because of its finicky environmental requirements. But the medaka fish, which is the favorite of the developmental biology community in Japan, may be more suitable for this experiment. In terms of avian development, some efforts have been made to grow chick or quail embryos in space, but these have been unsuccessful when embryos were brought into space during the earliest stages.25 It seems that the high content of yolk in these eggs requires the embryos to reach a stage of organization at which the yolky mass is segregated within membranes before normal development can be achieved in space. Recommendation Key model organisms should be grown through two complete life cycles in space to determine whether there are any critical events during development that are affected by space conditions. Because no critical effects have been seen in model invertebrates, the highest priority should be given to testing vertebrate models such as fish, birds, and small mammals such as mice or rats. If developmental effects are detected, control experiments must be performed on the ground and in space, including the use of a space-based 1-g centrifuge, to identity whether gravity or some other element of the space environment induces the developmental abnormalities. Development of the Vestibular System Neurobiologists working on space research are concerned about whether that part of the vestibular system that is sensitive to gravity can develop in microgravity. The vestibular sensory receptors that are sensitive to gravity are called, collectively, the otolith organs. This includes the utricle and saccule. A principal role of the vestibular system is to relay signals from the otoliths regarding linear acceleration, and from the semicircular canals regarding rotation or angular acceleration, to the brain in order to control the motor output of the extrinsic eye muscles and those muscles in the neck (collic) and body (vestibulospinal) concerned with posture and balance.26 In every other sensory system known, especially those that makeup the neural space maps in the brainstem,27 sensory stimulation has been implicated in the initial specification of the connections28 and physiological properties29 of the constituent neurons. Another example is the development of the visual system, where activity in the retinal pathway influences the specification of the connections determining how visual information is processed in the cerebral cortex.30 31 Only in the otolithic gravitational pathway has it been impossible to study the role of sensory deprivation, because there is no way to deprive the system of gravitational stimulation on Earth. Therefore, experiments should be planned to be carried out in space that will test the hypothesis that gravity itself plays a role in the development and maintenance of the components of the peripheral and central vestibular system. Structures whose development may depend at least in part on exposure to gravitational stimuli
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--> include the vestibular sensory receptors of gravity themselves—the hair cells situated in the utricle and saccule, vestibular ganglion cells that form synapses with vestibular hair cells and vestibular neurons in the brainstem vestibular nuclei, vestibular nuclei neurons themselves, and motor neurons receiving input from axons of vestibular nuclei neurons composing the vestibular reflex pathways. These reflex pathways include the vestibulo-ocular, vestibulospinal and vestibulocollic fibers whose pathways, connections, and development have been investigated most extensively within the last 10 years.32 33 34 Moreover, other sensory systems are known to interact with the vestibular pathway. For example, the gravity-driven otoliths function in producing basic postural adjustments by interacting with signals from the semicircular canals.35 36 The vestibular system also receives inputs from the proprioceptive system, involved in the control of muscle length and tension,37 and from the visual system, involved in the control of eye movements.38 Little is known about the exact nature of these interactions and virtually nothing concerning the development of these connections. As a consequence, there is a need to understand more about these basic topics through ground-based studies before evaluating the potential for space-based experiments. In addition, there is some evidence that the vestibular system plays a role in regulating the autonomic nervous system.39 In particular, the vestibular system may influence cardiovascular output40 and pulmonary function. 41 The pathways subserving vestibuloautonomic connections are complex and have not yet been fully characterized either structurally or functionally. Moreover, how these connections develop is still not understood. Recommendation The following experiments should be performed first in ground-based studies to identify appropriate experiments to be performed in space. Because in ovo rather than in utero experiments afford the possibility of manipulating the embryo, using an avian system is most appropriate. Studies should be performed to identify the critical periods in vestibular neuron development, including proliferation, migration, differentiation, and programmed cell death. This information is essential to design and interpret subsequent flight experiments on the effects of microgravity on vestibular development. Neural Space Maps Neural Space Maps in the Brainstem Vertebrate brains form and maintain multiple neural maps of the spatial environment, which provide distinctive, topographical representations of different sensory and motor systems. For example, visual space is mapped onto the retina in a two-dimensional coordinate plan.42 This plan is then remapped in the central nervous system in several places, including the superior colliculus (optic tectum).43 Likewise, the surface of the body is mapped in a somatotopic plan onto the superior colliculus.44 In addition, there is a map relating the localization of sounds in space45 46 and one that corresponds to oculomotor activity. 47 During development, all of these maps must be established. In the adult, the neural maps must be maintained in register so that appropriate perceptual and motor adjustments can occur. There are several reasons to suspect that gravitational stimuli may have special importance in the development and maintenance of space maps and neural tracts that act in position-sensing in mammalian brains. Apparently this system of neural maps must have appropriate information regarding the location of the head in the gravitational field, and so it follows that the vestibular system must play a key
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--> role in the organization of these maps. Thus, from a theoretical point of view, it can be predicted that important interactions must occur between sensory and motor systems on the one hand, and the vestibular system on the other. To understand how the status of the space maps relates to gravitational perturbations, it will be necessary to acquire detailed information from ground-based investigations on their structure and function in different species, including those with specialized adaptations (e.g., owls). This should permit researchers to frame testable hypotheses on the role of gravity in the assembly and maintenance of neural space maps. Neural Space Maps in the Hippocampus An analogous multisensory space map has been demonstrated in the mammalian hippocampus, which has the important function of providing short-term memory for an animal's location in a specific spatial venue.48 This neural map is particularly focused on body position and makes use of proprioceptive as well as visual cues. It is used by the animal to resume its location at a previous site. For theoretical reasons, it can be predicted that head position must be involved in this function. It is important to determine how the vestibular system, especially the otolithic component, is related to this neural space map. Neural Space Maps in the Sensory and Motor Cortices and the Corpus Striatum Other topographical maps of the body are found in the neocortex49 50 and neostriatum,51 which could be expected to interact with the vestibular system. In particular, the caudate nucleus of the corpus striatum has been implicated in vestibular-related locomotion.52 Recommendations The role of otolithic stimulation on the development and maintenance of the different neural space maps—including those within the brainstem, hippocampus, sensory and motor cortices, and corpus striatum—should be investigated. Studies should be designed to address how neurons of the various sensory and motor systems interact with vestibular neurons in the normal assembly and function of the neural space maps. Studies should be performed to determine the influence of decreased stimulus (as experienced in microgravity) on the development and maintenance of the neural space maps. Neuroplasticity Neuroplasticity refers to the long-lived alterations in structure and function that neurons may undergo following changes in their activity. It occurs in both developing and in mature neurons. However, the degree of alteration depends in part on the type of lesion or change,53 the age of the animal at the time of the lesion or change (younger animals are usually more sensitive to loss),54 and the time during the development of the system that the change occurs (i.e., whether it occurs during critical developmental events).55 56 Such alterations range from gross to microscopic and molecular, involving cell death,57 cell atrophy,58 loss of dendrites,59 synaptic reorganization 60 and long-term potentiation (LTP) or depression (LTD) of synaptic transmission or its efficacy (synaptic modifiability).61 Various types of changes in stimuli may lead to neuroplasticity of the target neurons. These include eyelid closure in the
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--> visual system,62 cochlear deprivation63 or overstimulation in the auditory system,64 labyrinthectomy in the vestibular system,65 whisker removal in the somatosensory system,66 or simple nerve transection of any afferent input, in addition to changes in the frequency of stimulation of the afferent fibers.67 Neuroplasticity is especially important to characterize, because it may result in changes in function not only of a single target neuron but also of the entire pathway or system in which the target neuron participates.68 69 70 Thus, the effects on the organism can be profound. In some cases, neuroplasticity can result in enhanced performance. For example, LTP is thought to represent a mechanism subserving learning and/or memory.71 72 An important type of plasticity is exhibited by the central vestibular system in response to decreased inputs from the labyrinths, as with exposure to microgravity. Typically, this process is called vestibular compensation.73 Following diminished inputs from the labyrinths, the organism exhibits multiple symptoms such as disequilibrium, disorientation, and locomotor deficits, but after about a week the symptoms diminish or disappear to some extent in most adult mammals. The mechanisms underlying vestibular compensation are thought to be mediated by modifications in some synapses, most likely those within the vestibular brainstem nuclei,74 75 although other brainstem neurons and parts of the cerebellum have been implicated.76 It is important to distinguish between overstimulation and understimulation (sensory deprivation) as perturbational factors. Research on sensory systems (e.g., the auditory system) has shown that overstimulation can produce wholesale destruction of the sensory receptor cells and a toxic condition in neurons (excitotoxicity)77 resulting from overaccumulation of excitatory neurotransmitters such as glutamate.78 This can lead to catastrophic changes in calcium fluxes and even cell death.79 Long-term changes may be manifested in phenomena such as tinnitus, 80 which probably reflects a persistent state of hyperactivity or supersensitivity in the central nervous system. Neurological disturbances following overstimulation are seen in adults as well as juveniles. In contrast, the neurological effects of understimulation or sensory deprivation are generally quite different. In adults, the changes in the nervous system have been relatively minor81 compared with the effects on developing systems.82 In the adult (e.g., following auditory deprivation) there is some atrophy of neuronal cell size but seldom cell death and degeneration.83 In infants or embryos, however, such deprivation can result in cell death in the central nervous system and seriously disrupt the establishment of neural connections.84 85 In consideration of these observations made in many other sensory systems, it is important to study how microgravity, which probably represents decreased stimulation of the vestibular system, affects the vestibular neural pathway. Furthermore, it appears that the concept of a dose-response curve dose not adequately reflect how the nervous system responds biologically to changes in gravity. Consequently, it is unlikely that the mechanisms activated in hypergravity will resemble those operating in microgravity. In conclusion, the concept of a dose response does not adequately reflect the biology of the nervous system in its response to changes in gravity. Recommendations From ground-based studies, researchers know that there are compensatory mechanisms that function normally in the vestibulomotor pathways, and these mechanisms occur in space.86 87 What is the basis for the compensation on Earth and in space, and are the mechanisms the same? These experiments should be given the highest priority, because these compensatory mechanisms operate in astronauts entering and returning from space and may have a profound effect on their performance in space and their postflight recovery on Earth. Experiments are needed to critically test the role of gravity on the development and maintenance
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--> of the vestibular system's capability for neuroplasticity. The process needs to be characterized at several different times following perturbations to determine the sequence of intermediate events leading to the plastic change.88 Controls for the effects of nongravitational stresses likely to be encountered in space (such as loud noise and vibration) must also be performed on the ground, so that space experiments can be designed to isolate the effects of microgravity form the effects of other stresses. From ground-based experiments, the vestibulo-oculomotor system is known to be capable of learning new motor patterns in response to sensory perturbations.89 Future investigation should focus on determining if and how these mechanisms are affected by exposure to microgravity. References 1. Space Science Board, National Research Council. 1987. A Strategy for Space Biology and Medical Science for the 1980s and 1990s. National Academy Press, Washington, D.C. 2. Wilson, C., Pearson, R.K., Bellen, H.J., O'Kane, C.J., Grossniklaus, U., and Gehring, W.J. 1989. P-element-mediated enhancer detection: An efficient method for isolating and characterizing developmentally regulated genes in Drosophila. Genes Dev. 3: 1301-1313. 3. Golic, K., and Lindquist, S. 1989. The FLP recombinase of yeast catalyzes site-specific recombination in the Drosophila genome. Cell 59: 499-509. 4. Xu, T., and Rubin, G.M. 1993. Analysis of genetic mosaics in developing and adult Drosphila tissues. Development 117: 1223-1237. 5. Feil, R., Brocard, J., Mascrez, B., LeMeur, M., Metzger, D., and Chambon, P. 1996. Ligand-activated site-specific recombination in mice. Proc. Natl. Acad. Sci. U.S.A. 93: 10887-10890. 6. Kenyon, C. 1994. A perfect vulva every time: Gradients and signaling cascades in C. elegans. Cell 82: 171-174. 7. Dickson, B., and Hafen, E. 1993. Genetic dissection of eye development in Drosophila. Pp. 1327-1362 in The Development of Drosophila melanogaster (M. Bates and A. Martinez Arias, eds.). Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y. 8. Haffter, P., Granato, M., Brand, M., Mullins, M.C., Hammerschmidt, M., Kane, D.A., Odenthal, J., Van Eeden, F.J.M., Jiang, J.-J., Heisenberg, C.-P., Kelsh, R.N., Furutani-Seiki, M., Vogelsang, E., Beuchle, D., Schach, U., Fabian, C., and Nusslein-Volhard, C. 1996. The identification of genes with unique and essential functions in the development of the zebrafish, Danio rerio. Development 123: 1-36. 9. Driever, W., Solnica-Krezel, L., Schier, A.F., Neuhauss, S.C.F., Malicki, J., Stemple, D.L., Stainier, D.Y.R., Zwartkruis, F., Abdelilah, S., Rangini, Z., Belak, J., and Boggs, C. 1996. A genetic screen for mutations affecting embryogenesis in zebrafish. Development 123: 37-46. 10. Mansour, S.L., Thomas, K.R., and Capecchi, M.R. 1998. Disruption of the proto-oncogene int-2 in mouse embryoderived stem cells: A general strategy for targeting mutations to non-selectable genes. Nature 336: 348-352. 11. Cordes, S., and Barsh, G.S. 1994. The mouse segmentation gene kr encodes a novel basic domain-leucine zipper transcription factor. Cell 79: 1025-1034. 12. Gerhart, J., and Kirschner, M. 1997. Cells, Embryos, and Evolution. Blackwell Science, Malden, Mass. 13. Holley, S.A., and Ferguson, E.L. 1997. Fish are like flies are like frogs: Conservation of dorsal-ventral patterning mechanisms. Bioessays 19: 281-284. 14. Tomarev, S.I., Callaerts, P., Kos, L., Zinovieva, R., Halder, G., Gehring, W., and Piatigorsky, J. 1997. Squid Pax-6 and eye development. Proc. Natl. Acad. Sci. U.S.A. 94: 2421-2426. 15. Quiring, R., Walldorf, U., Kloter, U., and Gehring, W.J. 1994. Homology of the eyeless gene of Drosophila to the small eye gene in mice and Aniridia in humans. Science 265: 785-789. 16. Laufer, E., Dahn, R., Orozco, O.E., Yeo, C.-Y., Pisenti, J., Henrique, D., Abbott, U.K., Fallon, J.F., and Tabin, C. 1997. Expression of radical fringe in limb-bud ectoderm regulates apical ectodermal ridge formation. Nature 386: 366-373. 17. Goodrich, J., Puangsomlee, P., Martin, M., Long, D., Meyerowitz, E.M., and Coupland, G. 1997. A Polycomb-group gene regulates homeotic gene expression in Arabidopsis. Nature 386: 44-51. 18. Quiring, R., Walldorf, U., Kloter, U., and Gehring, W.J. 1994. Homology of the eyeless gene of Drosophila to the small eye genein mice and Aniridia in humans . Science 265: 785-789. 19. Laufer, E., Dahn, R. Orozco, O.E., Yeo, C.-Y., Pisenti, J., Henrique, D., Abbott, U.K., Fallon, J.F., and Tabin, C. 1997. Expression of radical fringe in limb-bud ectoderm regulates apical ectodermal ridge formation. Nature 386: 366-373.
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Representative terms from entire chapter: