Scientific Frontiers in Developmental Toxicology and Risk Assessment (2000) / Chapter Skim
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6 Recent Advances in Developmental Biology
6 Recent Advances in Developmental Biology
Pages 108-150
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From page 108... ...
Protein components are identified, their functions in developmental processes are known, and the time and place in the embryo of expression of the genes encoding them are known. This knowledge greatly benefits elucidating the mechanisms of developmental toxicity.
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From page 109... ...
Vertebrate development, including that of mammals, had become comprehensible as a branching succession of inductive interactions among neighboring members of an increasingly large number of different cell groups of the embryo. Developmental mechanisms, as understood even in the 1970s, were descriptions of the movements and interactions of cells or groups of cells.
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From page 110... ...
All of their insights made possible the invention of techniques for gene isolation and amplification, for in vitro expression of genes, for genome analysis, and, thereafter, for the new developmental biology. With so little molecular information about developmental processes, there was scarcely any understanding of the action of developmental toxicants.
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From page 111... ...
· The signaling pathways involved in this information transfer are known to be of 17 types (a few more may remain undiscovered)
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From page 112... ...
. The response of developing cells to signals involves activation or repression of the expression of specific genes by transcription factors contained within genetic regulatory circuits.
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From page 113... ...
and to deduce plausible developmental pathways in which the actions of the encoded gene products could be related and ordered. By the late 1980s, a solid base of observations of Drosophila mutant phenotypes and gene locations had been built, and ordered pathways of function based on the mutant interactions had been proposed.
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From page 114... ...
transmembrane motif. Transcription factors could be recognized by the sequence motifs of their deoxyribnucleic acid (DNA)
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From page 115... ...
Regarding the function of these developmental genes, many were found to encode proteins with familiar motifs, such as those for receptor tyrosine kineses or various transcription factors. In fact, a surprisingly large number turned out to be transcriptional regulators.
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From page 116... ...
The graded transcription factors, called members of the "coordinate class" or "eggpolarity class" of gene products, activate at least eight gap genes in nuclei along the egg's length at different positions, each position unique in terms of the local quantity of transcription factors of the coordinate class. (The terms "coordinate," "egg polarity," and "gap" also derive from mutant phenotypes.)
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From page 117... ...
Similar conclusions apply to the development of the term~ni and the dorsoventral dimension, which also rely on initially asymmetric signals. The developmental mechanisms of the term~ni and dorsoventral dimension are of additional interest, because the signals bind to transmembrane receptors and activate signal transduction pathways, eventually leading to the activation of transcription factors and new gene expression.
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From page 118... ...
The graded transcription factors activate eight gap genes, and different factor concentrations activate different gap genes. The gap proteins are also transcription factors.
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From page 119... ...
The activated receptor, via several intracellular steps, activates the Dorsal protein, a transcription factor, which enters local nuclei and activates two genes, Twist and Snail, which also encode transcription factors. Those activate other genes for gastrulation and for mesoderm formation on the ventral side.
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From page 120... ...
One of the first significant similarities between vertebrate and fly development came from work on homeotic genes, now called Hox genes. As mentioned before, the Hox genes are expressed in eight broad bands or spatial compartments in the anteroposterior dimension of the body shortly after gastrulation but prior to organogenesis and cytodifferentiation.
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From page 121... ...
That sequence encodes the DNA-binding motif of the encoded proteins, which are members of a large and ancient family of transcription factors. The other six Hox genes were soon isolated from Drosophila, and those too had closely related homeobox sequences.
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From page 122... ...
Lines extending from each paralogous group to the schematic brain and cranial spinal cord show the rostral limits of expression of members on each group. Note, again, the colinearity between expression sites and relative chromosomal position of most Hox genes.
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From page 123... ...
, and in other ways less similar (e.g., having a highly invariant cell lineage and a fixed small number of cells, no Sonic Hedgehog signaling pathway, and few HOX genes)
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From page 124... ...
Humans, flies, and even roundworms are less different than widely thought just 10 years ago. Signaling Pathways in Development An important realization to come from the Drosophila research concerns the pervasive use of cell-cell signaling in most aspects of development, starting with the termini and dorsoventral dimension (see Figures 6-1A-D)
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From page 125... ...
125 ~ o i ~ ca ca C)
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From page 126... ...
That is, particular transcription factors are phosphorylated or proteolyzed as a signal transduction step of the pathway, changing their activity in activating or repressing particular genes. The pathways are used repeatedly at different times and places of development in Drosophila, nematode, and vertebrates, as listed in Table 6-3.
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From page 127... ...
In some cases, the mutant mice live to adulthood and reproduce. Are the signaling pathways less important in vertebrate development than in Drosophila?
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From page 128... ...
The active ligand is shown on the left, approaching the transmembrane receptor protein. Inside the cell is a multistep signal transduction pathway composed of switch-like intermediates, A, B
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From page 129... ...
development; spermatogenesis Notochord induction of floor plate of neural tube; notochord and floor-plate induction of sclerotome of somite and the dorsoventral organization of neural tube; prechordal mesoderm induction of prosencephalon; inhibit cyclopia; ZPA induction of anteroposterior axis of fin or limb development; gut and visceral mesoderm development; hair development Mesoderm maintenance; limb (apical ectodermal ridge) , vasculogenesis; hair follicle, inner ear, retinotectal projection; astrocyte differentiation, branchial arch signal to neural crest; heart, lung, and tooth development Several steps of neurogenesis; oligodendrocyte differentiation, retina development; somitogenesis, inner-ear development; feather-bud development; blood-cell development (e.g., thymocytes)
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From page 130... ...
130 cam be be · ~ v: ca an A v: o ¢ o c z 0 be .= 0 -i ~ cq A ~ ~ ~z JO 0 A .
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From page 131... ...
131 an .= o C)
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From page 132... ...
132 3 ad Cq .~ an · _4 s°Em o an C)
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From page 134... ...
134 ca C)
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From page 135... ...
135 ~ ~ ~ ~ ~ ~ ~ =` . ~ ED torus ~So ca .ca ~ ~ ~ ~ ° ~ 0 ~ 0 ~ jig 8,~ ~ a ma ca .
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From page 136... ...
Toxicants upsetting these feedbacks would upset development. Molecular-Stress Pathways and Checkpoint Pathways Molecular-stress pathways and checkpoint pathways are not pathways of intercellular signaling but of intracellular signaling, reflecting an individual cell' s
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From page 137... ...
137 ~ ca ~ ~ o ca ca R ~ ~ ¢ ;^ ;~ ca ca a ~~ O Ed ~ ~ ¢ ;^ ca O ¢ Cq 3 be ·_4 be ·_4 VO o Cq Cq .s o be ¢ Ct Ed ;^ ~ .~ ~ t,.4 EM ¢ .= o .o ;^ ~ ~ C ·0 a; ~ o ·= ~ ca o , hi=, ~ Vl ~ ·0 ~ o o t.4 ~ ¢ U ~ ~ O = · ~ ~ C)
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From page 138... ...
In checkpoint pathways, the cell's response is one of delaying certain synthetic processes until other processes are complete. These controls are important in coordinating the timing and extent of cellular processes, such as ensuring the completion of DNA synthesis before mitosis begins or ensuring the attachment of chromosomes to the spindle before anaphase begins.
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From page 139... ...
Broadly acting toxicants are likely to show up as triggers of stress responses. · The intercellular signaling pathways of metazoa probably arose in evolution as elaborations and reworkings of the more ancient molecular-stress and checkpoint pathways of single-celled eukaryotic ancestors.
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From page 140... ...
Some mouse mutants, such as Hammertoe, fail to initiate the normal amount of programmed cell death in normal limb development, and an abnormal limb results (Zakeri et al.
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From page 141... ...
They are expressed in the postanal tail, which is a chordate structure not shared by arthropods, and also in the developing vertebrate limb. Still, the difference between chordates and arthropods is a modification of a shared feature, namely, the use of HOX genes to divide the anteroposterior dimension of the animal into nonequivalent spatial compartments.
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From page 142... ...
In light of the extensive conservation of developmental processes found thus far, it is expected that in most cases what is true for fish development, as learned from those mutants, will be true for mammalian development, down to the level of molecular details of components and processes. That is not meant to deny differences among organisms (e.g., mammals undergo placental development with extensive extra-embryonic tissues not found in a zebrafish)
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From page 143... ...
Their innovations include abundant cell-cell signaling, extracellular matrix, cell junctions, and a wide range of responses to intercellular signals based on complex genetic regulatory circuits and protein phosphorylation.
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From page 144... ...
Extensive molecular descriptions and cellular and genetic analyses have defined key regulatory pathways that facilitate the development of many vertebrate systems, including the following: . Neural tube: regionalization of forebrain, midbrain, hindbrain, and spinal cord (for reviews, see Wassef and Joyner 1997; Brewster and Dahmane 1999; Dasen and Rosenfeld 1999; Veraksa et al.
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From page 145... ...
, TGF0, BMP, and WNT signaling families. Although the signaling pathways involve the same or closely related signaling molecules, the responses made by cells are distinct because of the genes and gene products they express prior to and in response to the many different combinations of these signaling factors.
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From page 146... ...
Surprisingly, many homologous genes and signaling pathways are conserved between the vertebrate limb and the developing leg or wing of Drosophila. The researchers who followed the seemingly remote leads from the early Drosophila work on appendages have made rapid progress on vertebrate limb development in the past few years.
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From page 147... ...
The ventral epidermis does not secrete WNT7A, because the cells express the En gene encoding a transcription factor inhibiting the Wnt7a gene from expression. See text for further information and references.
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From page 148... ...
It remains to be learned how the signaling pathways of each axial dimension are coordinated with those of the other dimensions, and how the integration of these pathways leads to the formation of unique skeletal structures in precise locations within the limb. The limb exemplifies the advanced understanding of vertebrate organogenesis at a molecular genetic level (i.e., of the signal pathways and the genetic regulatory circuits involved in changing transcription and regulating cell proliferation)
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From page 149... ...
It seems self-evident that the knowledge about the basic processes of development provides developmental biologists with an understanding of normal development not even thought possible a decade ago, and also provides developmental toxicologists with improved tools to understand the mechanisms by which chemicals cause abnormal development. In the last decade, great advances have been made in the understanding of developmental processes on a molecular level in model organisms, such as Drosophila and C
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From page 150... ...
The number of allelic variants that exist in these human genes remains to be studied. These pathways are conserved among animal phyla, as are many of the genetic regulatory circuits involved in the responses of cells to signals.
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