The Language of Life How Cells Communicate in Health and Disease (2005) / Chapter Skim
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3 Plaiting the Net
Pages 81-138

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From page 81...
... Just in case you ever manage to turn back time, those words are "fibroblast growth factors." Vertebrate limbs begin as little hillocks of undifferentiated tissue known as "limb buds" that erupt at precise spots along the lateral edge of the embryo. More than 50 years ago, embryologists analyzing the development of legs and wings in the chick embryo discovered that the outgrowth of these limb buds was masterminded by a lip of tissue curving around the leading edge of the bud, the apical ectodermal ridge: If the ridge was cut away, the limb stopped growing; if it was rotated 90 degrees to the left or right, the limb grew outward from the body at right angles to its normal orientation.
From page 82...
... "You get a complete limb," says developmental biologist Cliff Tabin, "a humerus, a radius and ulna, a wrist, and digits." A B 48-hour 10-day chicken embryo Front Extra limb limb Hind Front limb limb region FGF bead inserted into interlimb region Hind limb How to make an extra limb. A region bead impregnated with fibroblast growth factor, implanted in the side of a 48-hour-old chick em bryo, triggers the development of an extra wing or leg.
From page 83...
... In that case, you should have added "bone morphogenetic protein number four," or "BMP4," to your vocabulary. In collaboration with FGF, BMP4, secreted by the optic vesicle (a pedestal of tissue protruding from the embryonic brain)
From page 84...
... Metazoans embarked on a building program as ambitious as that undertaken by any ancient civilization and as equally dependent on effective communication. Much as the progression from tents to pyramids went hand in hand with the invention of the floor plan and the square grid, the progression from single-celled organism to a multicellular body correlated with the evolution of mechanisms for stipulating the spatial relationships between specialized tissues dedicated to the administration of distinct physiological functions.
From page 85...
... "If organic form is not original, but is produced, what accounts for regularity and directedness of process? And how do all individuals of the species end up with the same body plan, the same organization of the internal organs, the same proportions of each type of cell?
From page 86...
... In 1901, Hans Spemann, a lecturer in zoology at the University of Würzburg and one of the new evangelists of the experiment, published a paper explaining how the tadpole got its eyes. In the frog Rana fusca, as in other vertebrates, development of the eye begins with the optic vesicles, situated on either side of the primordial brain.
From page 87...
... But if the vesicle was cut free of the brain and moved so that it contacted the ectoderm of the trunk instead, why, a lens formed there, in the belly of the tadpole! Spemann concluded that lens development was directed by a very private and specific conversation, in which the optic vesicle induced the production of a lens through some sort of exchange with the receptive ectoderm.
From page 88...
... In the cellular world, personality is based on proteins. Each type of cell is characterized by the unique constellation of proteins it synthesizes: neurons make ion channels and pumps that control the concentrations of ions and the propagation of electrical impulses, muscle cells string cables of protein fibers and mount protein motors to crank them taut, red blood cells pack themselves with hemoglobin for carrying oxygen, cells lining the gut produce enzymes to break down food.
From page 89...
... To make proteins, DNA needs proteins, a corps of mechanics and decision makers that biologists call "transcription factors." These proteins come in two flavors. So-called general transcription factors assemble at the promoter sequence where transcription begins; they recruit the polymerase and orient it correctly.
From page 90...
... Just as scaffolding proteins contain interaction domains that correspond to consensus sequences, transcription factors have evolved structural motifs that "read" DNA sequences by interacting with the surface features of the bases contained in that sequence. Some sport a coil, or a loop closed with an atom of zinc that fits into a groove of the helix.
From page 91...
... The imposition of additional constraints not only afforded eukaryotic cells an exquisite degree of control over gene activity but also offered unlimited opportunities to customize gene expression at different times and in different places, merely by increasing or decreasing levels of the gene regulatory proteins that collectively determine whether the gene is turned on or switched off. In addition, by integrating transcription factors into signaling pathways, gene expression could be placed under the aegis of external signals, granting a cell's neighbors the power to induce long-standing changes in its behavior, its activity, or even its identity.
From page 92...
... During development, each cell's contractors and homeowners -- transcription factors and the extracellular signals that boss them -- page through thousands of options to select the right genes, first to frame and then to finish the organism. Just as the configuration of the plumbing determines the placement of the sink, the size and shape of the sink affect cabinet selection, the finish on the cabinets determines the best tile color, and the amount still left in the bank dictates whether it will be paint or paper, the decisions cells make at one phase of development determine their options in the next phase.
From page 93...
... To "ensure that the lower parts of the building will suit the parts to be put upon them," the embryos' floor plan must answer fundamental questions about orientation and layout, or its project will collapse before it ever sees the light of day. Specifically, developmental biologist Marc Kirschner says, the nascent embryo must accomplish three critical tasks.
From page 94...
... Finally, Kirschner argues, the embryo must mark out a system of compartments that will be the basis for all subsequent differentiation; having laid the foundation, it must frame out the rooms, as it were, by manipulating gene expression to subdivide the front-toback and top-to-bottom axes specified in the first step. Embryos, he says, need "mechanisms to set up an `invisible anatomy' of signaling pathways, often in a sort of segmental pattern, anterior to posterior, and another invisible anatomy to set up an invisible pattern from dorsal to ventral." For example, patterning mechanisms might mark out 20 segments from head to tail and 10 divisions from back to front, a total of 200 individual domains.
From page 95...
... But until the mid-1980s, every geneticist's favorite organism, the fruit fly Drosophila melanogaster, was hardly the ideal subject for studying the genetics of early development. Flies with odd eye colors or extra wings can survive and breed in the sheltered environment of the laboratory, but a fly embryo with a mutation in a gene critical to development -- a gene, for example, that differentiates its head from
From page 96...
... The bicoid transcript, tethered to a complex of anchoring proteins at one end of the ovoid egg encodes one of these maternal morphogens. In the dialect of Drosophila, "bicoid" means "head." Translated into protein, bicoid yields a transcription factor that diffuses away from this end of the egg to form a concentration gradient
From page 97...
... The fruit fly gets around the awkward fact that transcription factors typically could not diffuse across plasma membranes because for the first four hours of its life the only plasma membrane is the one surrounding the egg itself. The first 13 "cell" divisions after fertilization are actually nuclear divisions -- after DNA replication, each nucleus divides, but no membranes form to isolate them into new cells.
From page 98...
... Just as gradients of Bicoid and the others polarize the embryo in the head-to-tail direction, this gradient of nuclear Dorsal points the way from the bottom of the embryo to its back. Using just a handful of transcription factors and RNA-binding proteins -- a natal gift from its mother -- the fruit fly embryo has sketched a floor plan for a body.
From page 99...
... Fingers of plasma membrane separate and surround the nuclei, putting a stop to this nonsense of using transcription factors as morphogens. It's time to break out the signaling proteins.
From page 100...
... The maternal effect genes, the gap genes, and the pair-rule genes are transient phenomena, but once the Hox genes are activated they will not be turned off. Regulatory proteins included among their targets maintain the status quo in each segment, locking the subset associated with that segment in the "on" position and mothballing the rest.
From page 101...
... Once activated, the Type I receptor kinase then phosphorylates a relay protein called "Smad." Two Smads make a transcription factor; so the Smad decorated with phosphate by the receptor recruits a confederate -- a different SMAD -- and the two sashay into the nucleus, ready to translate the BMP message into changes in gene expression. When Decapentaplegic and Dorsal are finished flipping genes on and off, the fly embryo has been partitioned into a series of compartments that run perpendicular to the compartments mapped out by the maternal effect genes and their successors.
From page 102...
... Finally, near the equator, Dorsal's whisper activates the short gastrulation, or "sog." For Decapentaplegic, running into the Sog compartment is like running into a brick wall -- Sog hates the bone morphogenetic protein and silences it immediately. Cells able to hear Decapentaplegic give rise to the ectoderm of the fly's back.
From page 103...
... Hydra doesnt' have a skin; it's just a pair of epithelial sheets, rolled up into a tube and crowned with a fringe of tentacles, and its muscle power doesnt' come from organized cohesive organs like our biceps but from primitive contractile cells, outfitted with elastic protein fibers able to contract and pump the animal along. These muscle-like cells are not even grouped together; they're distributed randomly throughout the animal, both the outer epithelium, or ectoderm, and the inner layer, known as the endoderm.
From page 104...
... What's more, nearly a century before Hans Spemanns' experiments with lens induction, Christian Pander, who discovered the germ layers, contemplated the possibility that the fates of the three layers might be interwoven, that "although already destined for different ends, all three influence each other collectively until each has reached an appropriate level." Today, we know that the migration of cells and the determination of their identities that occur during the formation of the mesoderm -- the central element in the dance of gastrulation -- are indeed the result of intimate conversations. The induction of the mesoderm, the first steps in the construction of the head, the migration of cells, and the partitioning of the ectoderm into cells that will form skin and cells that will form brain are all
From page 105...
... The slipping and sliding transform the ball of cells into a hollowed-out plum, with the cells of the primordial endoderm lining the pit, those representing the immature ectoderm forming the skin, and, sandwiched between the two, the soft fruit of the future mesoderm, idling in anticipation of further instructions from the neighbors. Contact with the embryonic optic vesicle could persuade cells undecided about their futures to devote themselves to forming the lens.
From page 106...
... A portion of this kind, transplanted in an indifferent place in another embryo of the same age did not develop according to its new environment but rather persisted in the course previously entered upon and con strained its environment to follow it. In one of the most celebrated experiments ever conducted by developmental biologists, Spemann and Mangold transplanted a piece of the dorsal blastopore lip taken from a newt embryo of a dark-colored species into the underside of an embryo of a light-colored species.
From page 107...
... , segregates the three germ layers and establishes the dorsal-ventral and anterior-posterior axes, while the interaction of bone morphogenetic proteins, made by the ventral mesoderm, and BMP inhibitors, made by the organizer, differentiates the cells that will give rise to the nervous system from those that will give rise to the epidermis. E, the completed tadpole.
From page 108...
... Dad offers the infant one hint: "dorsal" is the side opposite the point where the sperm pierces the egg. And Mother provides a second, in the form of mRNA encoding the gene regulatory protein -catenin, essential confederate of transcription factors currently idling in the cell nucleus.
From page 109...
... Members of the TGF- family of signals that includes the bone morphogenetic proteins, Nodal proteins can be heard on the air in all developing vertebrate embryos; frog, fish, bird, or mammal, they send the same message: make mesoderm. It's easy to spot XNR's loyal listeners.
From page 110...
... The ventral mesoderm, assigned the thankless job of posting the bad news, heaves buckets of the bone morphogenetic proteins BMP4 and BMP2, synonyms for "ventral" and "skin," at the ectoderm. But if everyone changes course and follows these instructions, the embryo will be all belly skin and no brain.
From page 111...
... The prelude to this dance is the appointment of cells to the mesoderm; its climax, the sorting and shifting of these cells and their compatriots to form the three germ layers. Along the way, the order of migration and the interactions between signals, particularly the bone morphogenetic proteins and their antagonists, have also patterned the anterior-posterior and dorsal-ventral axes and sketched the location of the nervous system.
From page 112...
... The embryos' construction project has also made considerable progress. Signaling pathways and teams of transcription factors have decided which end will lead and which will follow as well as which side will face the sky and which the ground, assigned cells to germ layers, rearranged cells to seal off the interior of the organism from the outside world and facilitate the further exchange of chemical signals, and divided the embryo into a system of compartments, each characterized by a unique pattern of gene expression.
From page 113...
... And the cellular territory labeled "neural ectoderm" by FGF and BMP antagonists like Chordin and Noggin doesnt' constitute a functioning nervous system any more than a stack of bricks and a pail of mortar constitute a finished wall. The developing embryo meets the challenge of later embryonic development the same way it met earlier challenges: by talking itself along toward maturity, linking signals to transcription factors that continue the task of "compartmentalizing" the genome, as Kirschner calls it.
From page 114...
... Hedgehog, in other words, may be a chimera, two prokaryotic enzymes fused into a single eukaryotic signaling protein. "What sort of organism this happened in or what pathway it took from primitive unicellular organism to patterned multicellularity, we dont' know," Beachy notes.
From page 115...
... , turning it into a gene repressor rather than a gene activator. When Hedgehog says "no" to Patched, Smoothened can tell the enzymes to leave the transcription factor alone; in its intact form, it can now turn genes on.
From page 116...
... But perhaps no tissue faces a more daunting challenge than the nervous system. Beginning only with the dorsal ectoderm rescued from a life as skin by the antagonists of the organizer, the vertebrate embryo must shape a brain at the head end and run a spinal cord down the back.
From page 117...
... If you detect something familiar about the notochord, youre ' not imagining things; the cells of this structure are descendents of the organizer, all grown up and done with baby talk. Now their vocabulary consists of the words "Sonic hedgehog," which they chant ceaselessly at the base of the neural tube.
From page 118...
... At the same time, the epidermis above the neural tube is also talking. It spews a cocktail of signaling molecules belonging to the TGF- "superfamily," in particular the bone morphogenetic proteins BMP4 and BMP7.
From page 119...
... This disembodied free end is the pathway's only intracellular signaling protein, and it hikes itself off to the nucleus to negotiate the exchange of transcription factors regulating so-called proneural genes. Whispers are followed by the muffled sound of the genes being wrapped for storage.
From page 120...
... 4 Notch tail absorbed by cell 3 Protease "beheads" 5 Notch Notch shuts down specialization 2 genes and Delta- gene expression Notch bind Notch Delta Delta "swallowed" 6 One cell gains the advantage 7 Neighboring cells are blocked from differentiation 8 The winner continues to express lots of Delta, 9 The losers respond to Delta, but down regulates Notch but down regulate their Delta production Lateral inhibition mediated by Notch-Delta signaling. Cells vying to become neurons begin as equals.
From page 121...
... As a consequence, the noisy cell gains the upper hand, while those surrounding it sink lower and lower into repression. Their proneural genes are turned off, and the loudmouth becomes the mother cell.
From page 122...
... They collapse and decay, turning off the feedback mechanism and resetting the clock in preparation for the next round of signaling. Notch oscillations are translated into a spatial pattern by another familiar signal, the growth factor FGF.
From page 123...
... -Catenin accumulates and "takes the Wnt signal to the nucleus," says Nusse. The cells designated muscle precursors by Wnt signals migrate into the developing limb and activate genes for the transcription factors MyoD and Myf-5.
From page 124...
... "When you implant an FGF bead, it induces FGF10 in the flank as if another apical ectodermal ridge was there. Youre coming in the middle of ' that feedback loop." Once the limb bud is established, the interaction of FGFs and other signals shape the limb as it grows, directing the formation of a cartilage template according to a pattern that is more or less the same in all four-legged animals.
From page 125...
... Just as the proximal-distal axis is specified by fibroblast growth factors, the anterior-posterior and dorsal-ventral patterns are spelled out for the growing limb by distinct signals. Back-to-palm patterning is the province of Wnts, specifically Wnt 7A, produced by cells in the ectoderm just above the apical ectodermal ridge.
From page 126...
... As the limb bud grows out from the body (a chick embryo illustrates the principle here) , FGFs made by a signaling center in the apical ectodermal ridge establish the proximal-distal (shoulder to fingers)
From page 127...
... That explains what happens if you remove the apical ectodermal ridge today and dont' get an elbow tomorrow -- the arm had specified up to the elbow," as Cliff Tabin explains it. Tabin, however, is convinced the model is wrong.
From page 128...
... 128 THE LANGUAGE OF LIFE cess. Instead of putting all their eggs in one basket, they spawn basketfuls of eggs.
From page 129...
... During development it whittles overstocked compartments down to size, cuts away superfluous cells to shape organs and body parts, thins tissues so that cells selected for further differentiation have the space they need, and matches the number of cells to the availability of precious resources. The suicide weapons of unwanted cells are a family of killer proteases.
From page 130...
... They kill the neighbors, they kill the kids, they blow up the whole society, and then they die themselves." Despite the precautions, eukaryotic cells were playing with fire, collecting lethal enzymes like caspases when they had black-hearted bacterial symbionts as permanent houseguests. Oxygen-loving prokaryotes may have withered away to mitochondria without a whimper, but one of their respiratory enzymes seems to have resented being put to work as slave labor.
From page 131...
... Read the clues for yourself: BMP2, BMP4, BMP7 in plain view at the scene, the third and final element of the limb (the "autopod," developmental biologists call it) , just before the collective suicide of thousands of cells.
From page 132...
... . FGF, whispered by the apical ectodermal ridge, induces a Wnt antagonist; without Wnt, "BMP" means "go kill yourself." If not for FGF's meddling, the BMPs will protest, they would have helped others rather than hurting them.
From page 133...
... Discovered in the 1950s by Rita Levi-Montalcini and colleagues Viktor Hamburger and Stanley Cohen, "NGF," like other growth factors, binds to a receptor tyrosine kinase called TrkA (and several other receptors as well)
From page 134...
... Growth factor dependence explains why removal of the apical ectodermal ridge truncates a developing limb, says Cliff Tabin. Critical to the regulation of outgrowth and patterning, FGF4 and FGF8 secreted by the ridge are also essential to survival: cells in the progress zone depend on these factors to dispel thoughts of suicide while they're making decisions and laying down templates for bones.
From page 135...
... Using a battery of transcription factors able to bind to DNA and turn genes on and off, eukaryotic organisms could choose the proteins made by their constituent cells and vary their selections from cell to cell to produce a wide variety of combinations from the same genes. What's more, thanks to a hermetically sealed internal environment made possible by the evolution of the epithelium and the discovery that these gene regulatory proteins could be integrated into signaling pathways, organisms could regulate gene expression from outside the cell as well as inside.
From page 136...
... In the amphibian, bone morphogenetic proteins and antagonists like Chordin and Noggin compete for control of the ectoderm; in the fly, Decapenta
From page 137...
... Using only a few dozen words, metazoan embryos compose bodies that are also great works of art. The vocabulary of development -- concise, adaptable, and powerful-stands as a tribute to how much can be accomplished with a handful of conserved patterns and a few well-chosen words.


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