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A transplant between genetically distinct individuals of the same species is called an allogeneic graft cholesterol pathway order zetia 10 mg free shipping, or an allograft cholesterol medication without muscle pain generic zetia 10 mg otc. The immune response to an allograft requires three elements: recognition of foreign antigens cholesterol ranges buy zetia 10mg on-line, activation of antigen-specific lymphocytes cholesterol levels nursing buy zetia 10mg otc, and the effector phase of graft rejection. Ischemia-reperfusion injury in the graft leads to the production of inflammatory cytokines and recruitment of macrophages, and acute rejection episodes are more common in grafts with prolonged ischemia times. Acute rejection of an allograft is believed to be primarily dependent on direct allorecognition, whereas the indirect pathway may play a larger role in chronic rejection. The calcineurin pathway has been best characterized, and involves the activation of calcineurin (a phosphatase) by an increase in cytosolic calcium. Although the specificity of the immune response is determined by signal 1, a costimulatory signal, or signal 2, which occurs though accessory molecules, is essential for T cell activation. However, in most in vivo models of B7 blockade, anergy has been difficult to demonstrate, possibly due to the complexity of costimulation that involves multiple stimulatory and inhibitory signals. In addition to T cells, B cells and the humoral arm of the immune system play a major role in acute and chronic graft injury. Antibodies produced by the differentiation of B cells into plasma cells cause cell injury through complement fixation or antibody-dependent cellular cytotoxicity. Subsequently, azathioprine was introduced in the early 1960s, and soon thereafter was routinely accompanied by prednisolone in an immunosuppressive regimen. The polyclonal antilymphocyte antibody preparations became available in the mid-1970s. In 2011, belatacept was approved as the first biologic agent for use in maintenance immunotherapy. Commonly used immunosuppressants and their mechanisms of action are listed in Table 63. First, multiple agents directed at different molecular targets within the alloimmune response are used simultaneously to maximize synergy and efficacy while minimizing toxicity. Second, greater immunosuppression (induction) is needed for early engraftment or to treat established rejection than for long-term graft maintenance. And third, continuous vigilance is essential to identify rejection, drug toxicity, and infection so that the immunosuppressive regimen can be modified appropriately. The three signal model of T-cell activation and subsequent cellular proliferation provides a useful guide to the sites of action of the major immunosuppressive agents. Therapies targeting antibody-mediated injury are directed against B cells, plasma cells, and complement activation. In general, all drugs in current clinical use have been more effective at suppressing primary than memory immune responses. Induction therapy with biologic agents is used to delay the use of nephrotoxic calcineurin inhibitors and/or to intensify the initial immunosuppressive therapy in patients at high immunologic risk. Biologic agents for induction therapy are currently used in over 80% of kidney transplant recipients, and are divided into two groups: depleting agents and immune modulators. Alemtuzumab is also increasingly used off-label as induction therapy (in about 10% of kidney transplants), particularly as part of steroid-sparing protocols. It is usually given as a single dose of 30 mg intraoperatively when infusion-related events are often masked by general anesthesia. Depleting agents can elicit major side effects, including fever, chills, and hypotension. Cell death and cytokine release peak with the first infusion and diminish substantially with subsequent doses. Premedication with corticosteroids, acetaminophen, and an antihistamine along with slow infusion (over 4-6 hours) through a large-diameter vessel minimize reactions. Other side effects include leukopenia, thrombocytopenia, serum sickness, glomerulonephritis, and rarely, anaphylaxis. Both drugs are fairly well tolerated, and no cytokine release syndrome has been observed, although anaphylaxis may occur rarely. The long-term use of steroids is associated with several adverse effects, including growth retardation in children, avascular osteonecrosis, osteopenia, increased risk for infection, poor wound healing, cataracts, hyperglycemia, and hypertension. Steroid minimization (avoidance and withdrawal) protocols are associated with improved metabolic parameters at the cost of higher acute rejection rates and unknown long-term effects on the graft. CsA, a lipophilic and highly hydrophobic cyclic polypeptide of 11 amino acids, is produced by the fungus Beauveria nivea. CsA supplied in the original soft gelatin capsule (Sandimmune) is absorbed slowly, with 20% to 50% bioavailability. A modified microemulsion formulation (Neoral) with improved bioavailability has become the most widely used preparation. Generic preparations of both are available and are bioequivalent to the original formulation, but not to each other. The elimination of cyclosporine from the blood is generally biphasic, with a terminal TЅ of 5 to 18 hours. CsA and its metabolites are excreted principally through the bile into the feces, with 6% being excreted in urine. Dosage adjustments are required for hepatic dysfunction, but not for reduced glomerular filtration rate. The principal adverse reactions to CsA therapy are kidney dysfunction and hypertension. Tremor, hirsutism, hyperlipidemia, hyperuricemia, and gingival hyperplasia are also frequently encountered. Nephrotoxicity occurs in the majority of patients, and is the major reason for cessation or modification of therapy. It causes a dose-related, reversible renal vasoconstriction that particularly affects the afferent arteriole. Protocols employing rapid steroid withdrawal (within 1 week) are being used in over a third of kidney transplant recipients with good short-term results, although the effects on long-term graft function are unknown. Azathioprine has mostly fallen out of favor, but it is still used during pregnancy and sometimes as part of low-cost regimens. Maintenance biologic therapy with belatacept, in combination with a steroid and an antiproliferative agent, permits complete avoidance of calcineurin inhibition and has been associated with superior kidney function and improved metabolic parameters in recipients with low immunologic risk. Steroids exert broad antiinflammatory effects on multiple components of cellular immunity, but have little effect on humoral immunity. They lyse (in some species) and redistribute lymphocytes, causing a rapid transient lymphopenia. Neutrophils and monocytes display poor chemotaxis and decreased lysosomal enzyme release. It is indicated for the prophylaxis of solid-organ allograft rejection, and is also used as rescue therapy in patients who develop rejection episodes despite maintaining therapeutic levels of CsA. Dose requirements and trough levels are similar between brand and generic tacrolimus, but postconversion monitoring is prudent because patients may require dose titration. Diarrhea and alopecia are common in patients on both tacrolimus and mycophenolate. These interactions have been better characterized for CsA, but usually apply to both drugs. CsA and tacrolimus also affect the concentration of other drugs by competing for the hepatic microsomal system and plasma protein binding, and they decrease the clearance of drugs such as statins, digoxin, and methotrexate. Close monitoring of drug levels and attention to dosage is required when such combinations are used. A phase 2 study showed similar efficacy and comparable kidney function in patients receiving voclosporin as compared with tacrolimus, with a lower incidence of hyperglycemia. It remains unclear whether it will be further developed and marketed for use in transplantation. Cell proliferation is thereby inhibited, impairing a variety of lymphocyte functions. Azathioprine was the first chemical immunosuppressive agent used in organ transplantation, but it has been mostly superseded by mycophenolate in current clinical practice. Oral bioavailability of azathioprine is about 50%, and it is metabolized by oxidation and methylation in the liver and/or erythrocytes. The major side effect is myelosuppression, which can be severe if it is used in combination with allopurinol.
These data support the view that corticosteroids alone are not effective in slowing the progression rate in this high risk-of-progression patient cholesterol levels range chart cheap zetia 10 mg mastercard. In sum cholesterol guidelines chart generic zetia 10 mg free shipping, specific treatment as well as therapy directed toward secondary effects of the disease may need to be started before the end of the intended conservative monitoring period in these patients especially if there is associated deterioration in glomerular filtration rate total cholesterol chart uk order zetia 10 mg. These studies have either been small or uncontrolled low cholesterol diet definition cheap 10 mg zetia with mastercard, or the series have included patients in a variety of risk categories. Debiec H, Guigonis V, Mougenot B, et al: Antenatal membranous glomerulonephritis due to anti-neutral endopeptidase antibodies, N Engl J Med 346:2053-2060, 2002. This should replace labeling the patient as a treatment failure, because even a partial remission is associated with significantly improved kidney survival. Alexopoulos E, Papagianni A, Tsamelashvili M, et al: Induction and long-term treatment with cyclosporine in membranous nephropathy with the nephrotic syndrome, Nephrol Dial Transplant 21:3127-3132, 2006. The time course is characteristic, with hematuria appearing within 24 hours of the onset of the symptoms of infection. Visible hematuria resolves spontaneously over a few days in nearly all cases, but microscopic hematuria may persist between attacks. Most patients only experience a few episodes of gross hematuria, and such episodes typically recur for a few years at most. The highest worldwide incidence is in Southeast Asia, but this may reflect different approaches to evaluation of kidney disease and different thresholds for kidney biopsy. Patients more commonly develop nephroticrange proteinuria, and this is principally seen in patients with advanced glomerulosclerosis. A number of case series have reported patients who, on kidney biopsy, have normal light microscopy, foot process effacement on electron microscopy, and electron-dense mesangial IgA deposits and in whom proteinuria resolved completely in response to corticosteroid therapy. Typically in these cases, following resolution of proteinuria, both microscopic hematuria and IgA deposits persist. The urine is usually brown rather than red and will often be described by the patient as looking like "tea without milk" or "cola-colored. There may be bilateral loin pain accompanying these episodes, which may be attributed to renal capsular swelling. This is a reversible phenomenon, and recovery of kidney function occurs with supportive measures. Mononuclear cell infiltration is associated with tubular atrophy and interstitial fibrosis, ultimately leading to a widening of the cortical interstitium. This is detected in kidney biopsy specimens by immunofluorescence or immunohistochemistry. Other immunoglobulins are also frequently detectable (IgG in 50% to 70%, IgM in 31% to 66%), but their presence does not appear to correlate with clinical outcome. Mesangial IgA is a common autopsy finding in patients with chronic liver disease; however, few patients have clinical manifestations of kidney disease other than microscopic hematuria. This is most commonly diffuse and global, but focal segmental hypercellularity is also seen. Focal segmental glomerulosclerosis is also described, and crescentic change may be superimposed on diffuse mesangial proliferation with or without associated segmental necrosis. Glomerular capillary wall deposits may also be seen in the subepithelial, or more commonly, subendothelial space. Glomerular basement membrane abnormalities are seen in 15% to 40% of cases and are associated with heavy proteinuria, more severe glomerular changes, and crescent formation. A group of patients experience thinning of the glomerular basement membrane indistinguishable from thin membrane disease. The predictive value of these biopsy features was similar in both adults and children. Studies are ongoing to validate this classification in different patient populations. It is predominantly present at mucosal surfaces and in secretions such as saliva and tears, where it protects against mucosal pathogens. The IgA molecule exists as two isoforms, IgA1 and IgA2, with each existing as monomers (single molecules) or polymers (most commonly dimeric IgA). The major difference between IgA1 and IgA2 is that IgA1 includes a hinge region that carries a variable complement of O-linked carbohydrates. The key change is an increase in the serum of IgA1 O-glycoforms that contains less galactose. IgA1 contains a 17 amino-acid hinge region that undergoes co/posttranslational modification by the addition of 6 O-glycan chains. Poorly galactosylated IgA1 O-glycoforms form high molecular weight circulating immune complexes, either through self-aggregation or through the generation of IgG and IgA hinge region specific autoantibodies. These high molecular weight immune complexes are prone to mesangial deposition resulting ultimately in mesangial cell proliferation, release of proinflammatory mediators, and glomerular injury. There is increasing evidence, predominantly from in vitro models, that circulating IgA immune complexes containing poorly galactosylated polymeric IgA1 are key drivers for all of these processes. Exposure to IgA immune complexes triggers mesangial cell activation, proliferation (M), and release of proinflammatory and profibrotic mediators. These mediators, along with the direct effects of exposure to IgA immune complexes, cause podocyte injury, a process fundamental to segmental glomerular scarring (S), and proximal tubule cell activation, which drives tubulointerstitial scarring (T). In addition, the systemic microenvironment is likely to be very different from the mucosal sites these plasma cells would normally inhabit, and it is possible that these plasma cells also receive cytokine signals promoting undergalactosylation of IgA1. It is contended that one of the most likely mechanisms for this displacement is incorrect homing of mucosal lymphocytes to systemic sites. However, there is now evidence in several ethnic backgrounds to suggest that genetic factors heavily influence the composition of circulating IgA O-glycoforms in the serum. This could be mediated through production of autoantibodies with specificity for the poorly galactosylated IgA1 hinge region. Approximately 25% to 30% of any cohort will require kidney replacement therapy within 20 to 25 years of presentation. Many studies have identified clinical, laboratory, and histopathologic features at presentation, which mark a poor prognosis (Table 20. Although the various prognostic factors listed may be informative for populations of patients, they do not as yet possess the specificity to identify an individual prognosis with complete confidence. There are a number of patients who will continue to experience proteinuria in excess of 0. In these patients, current evidence regarding additional therapy is controversial. Overall results have been equivocal, and reports showing positive outcomes have been criticized for inadequate trial design and the presence of multiple confounding factors. This may be the consequence of significant preexisting chronic damage at the time of a crescentic transformation, thereby reducing the chances of a response to immunosuppression. A kidney biopsy clearly is the key to distinguishing between these two extremes, and electron microscopy should be performed. Both diseases share similar findings on kidney biopsy, and they also share changes in the complement of serum IgA1 O-glycoforms. There is a similar association between mucosal infection and presentation of disease. On discharge from nephrology services, clear guidance should be provided to the primary-care physician regarding frequency of kidney function, urine dipstick, and blood-pressure monitoring. This will be dictated by local guidelines, although we would suggest this testing be performed at least annually. The rash is classically distributed on extensor surfaces, with sparing of the trunk and face. Abdominal pain is usually mild and transient, but it may be severe and lead to gastrointestinal hemorrhage, bowel ischemia, intussusception, and perforation. Most cases occur in the winter, spring, and autumn months, which may be because of its association with preceding upper respiratory tract infections. More severe complications, such as nephrotic syndrome or rapidly progressive deterioration of kidney function, occur less frequently and are more common in adults than in children. These women are at increased risk of developing hypertension and proteinuria during pregnancy. Pathogenesis Barratt J, Feehally J: Primary IgA nephropathy: new insights into pathogenesis, Semin Nephrol 31:349-360, 2011. Wang Y, Chen J, Chen Y, et al: A meta-analysis of the clinical remission rate and long-term efficacy of tonsillectomy in patients with IgA nephropathy, Nephrol Dial Transplant 26:1923-1931, 2011. Xu G, Tu W, Jiang D, Xu C: Mycophenolate mofetil treatment for IgA nephropathy: a meta-analysis, Am J Nephrol 29:362-367, 2008. Ronkainen J, Nuutinen M, Koskimies O: the adult kidney 24 years after childhood Henoch-Schцnlein purpura: a retrospective cohort study, Lancet 360:666-670, 2002.
This condition is maintained by the plasma membrane xanthoma cholesterol spots purchase 10 mg zetia otc, which steadfastly inhibits the entry of sodium ions into the oocyte and prevents potassium ions from leaking out into the environment cholesterol levels in fish discount zetia 10mg without a prescription. If we insert an electrode into an egg and place a second electrode outside it cholesterol en ratio purchase zetia 10mg visa, we can measure the constant difference in charge across the egg plasma membrane cholesterol foods to eat buy zetia 10 mg overnight delivery. This resting membrane potential is generally about 70 mV, usually expressed as 70 mV because the inside of the cell is negatively charged with respect to the exterior. Within 1 3 seconds after the binding of the first sperm, the membrane potential shifts to a positive level, about +20 mV (Longo et al. Although sperm can fuse with membranes having a resting potential of 70 mV, they cannot fuse with membranes having a positive resting potential, so no more sperm can fuse to the egg. It is not known whether the increased sodium permeability is due to the binding of the first sperm or to the fusion of the first sperm with the egg (Gould and Stephano 1987, 1991; McCulloh and Chambers 1992). The importance of sodium ions and the change in resting potential was demonstrated by Laurinda Jaffe and colleagues. They found that polyspermy can be induced if sea urchin eggs are artificially supplied with an electric current that keeps their membrane potential negative. Conversely, fertilization can be prevented entirely by artificially keeping the membrane potential of eggs positive (Jaffe 1976). The fast block to polyspermy can also be circumvented by lowering the concentration of sodium ions in the water (Figure 7. If the supply of sodium ions is not sufficient to cause the positive shift in membrane potential, polyspermy occurs (GouldSomero et al. It is not known how the change in membrane potential acts on the sperm to block secondary fertilization. Most likely, the sperm carry a voltage-sensitive component (possibly a positively charged fusogenic protein), and the insertion of this component into the egg plasma membrane could be regulated by the electric charge across the membrane (Iwao and Jaffe 1989). An electric block to polyspermy also occurs in frogs (Cross and Elinson 1980), but probably not in most mammals (Jaffe and Cross 1983). The eggs of sea urchins (and many other animals) have a second mechanism to ensure that multiple sperm do not enter the egg cytoplasm (Just 1919). The fast block to polyspermy is transient, since the membrane potential of the sea urchin egg remains positive for only about a minute. This brief potential shift is not sufficient to prevent polyspermy, which can still occur if the sperm bound to the vitelline envelope are not somehow removed (Carroll and Epel 1975). This removal is accomplished by the cortical granule reaction, a slower, mechanical block to polyspermy that becomes active about a minute after the first successful sperm-egg attachment. Directly beneath the sea urchin egg plasma membrane are about 15,000 cortical granules, each about 1 m in diameter (see Figure 7. Upon sperm entry, these cortical granules fuse with the egg plasma membrane and release their contents into the space between the plasma membrane and the fibrous mat of vitelline envelope proteins. These enzymes dissolve the protein posts that connect the vitelline envelope proteins to the cell membrane, and they clip off the bindin receptor and any sperm attached to it (Vacquier et al. Mucopolysaccharides released by the cortical granules produce an osmotic gradient that causes water to rush into the space between the plasma membrane and the vitelline envelope, causing the envelope to expand and become the fertilization envelope (Figures 7. A third protein released by the cortical granules, a peroxidase enzyme, hardens the fertilization envelope by crosslinking tyrosine residues on adjacent proteins (Foerder and Shapiro 1977; Mozingo and Chandler 1991). This process starts about 20 seconds after sperm attachment and is complete by the end of the first minute of fertilization. Finally, a fourth cortical granule protein, hyalin, forms a coating around the egg (Hylander and Summers 1982). In mammals, the cortical granule reaction does not create a fertilization envelope, but its ultimate effect is the same. Released enzymes modify the zona pellucida sperm receptors such that they can no longer bind sperm (Bleil and Wassarman 1980). Thus, once a sperm has entered the egg, other sperm can no longer initiate or maintain their binding to the zona pellucida and are rapidly shed. The mechanism of the cortical granule reaction is similar to that of the acrosomal reaction. Upon fertilization, the intracellular calcium ion concentration of the egg increases greatly. In this high-calcium environment, the cortical granule membranes fuse with the egg plasma membrane, releasing their contents (see Figure 7. Once the fusion of the cortical granules begins near the point of sperm entry, a wave of cortical granule exocytosis propagates around the cortex to the opposite side of the egg. In sea urchins and mammals, the rise in calcium concentration responsible for the cortical granule reaction is not due to an influx of calcium into the egg, but rather comes from within the egg itself. The release of calcium from intracellular storage can be monitored visually using calcium-activated luminescent dyes such as aequorin (isolated from luminescent jellyfish) or fluorescent dyes such as fura-2. When a sea urchin egg is injected with dye and then fertilized, a striking wave of calcium release propagates across the egg (Figure 7. Starting at the point of sperm entry, a band of light traverses the cell (Steinhardt et al. The calcium ions do not merely diffuse across the egg from the point of sperm entry. Rather, the release of calcium ions starts at one end of the cell and proceeds actively to the other end. The entire release of calcium ions is complete in roughly 30 seconds in sea urchin eggs, and the free calcium ions are resequestered shortly after they are released. If two sperm enter the egg cytoplasm, calcium ion release can be seen starting at the two separate points of entry on the cell surface (Hafner et al. Several experiments have demonstrated that calcium ions are directly responsible for propagating the cortical granule reaction, and that these calcium ions are stored within the egg itself. The drug A23187 is a calcium ionophore (a compound that transports free calcium ions across lipid membranes, allowing these cations to traverse otherwise impermeable barriers). Placing unfertilized sea urchin eggs into seawater containing A23187 causes the cortical granule reaction and the elevation of the fertilization envelope. Moreover, this reaction occurs in the absence of any calcium ions in the surrounding water. Therefore, A23187 must be causing the release of calcium ions already sequestered in organelles within the egg (Chambers et al. The calcium ions responsible for the cortical granule reaction are stored in the endoplasmic reticulum of the egg (Eisen and Reynolds 1985; Terasaki and Sardet 1991). In sea urchins and frogs, this reticulum is pronounced in the cortex and surrounds the cortical granules (Figure 7. In Xenopus, the cortical endoplasmic reticulum becomes ten times more abundant during the maturation of the egg and disappears locally within a minute after the wave of cortical granule exocytosis occurs in any region of the cortex. Free calcium is able to release sequestered calcium from its storage sites, thus causing a wave of calcium ion release and cortical granule exocytosis. The Activation of Egg Metabolism Although fertilization is often depicted as merely the means to merge two haploid nuclei, it has an equally important role in initiating the processes that begin development. These events happen in the cytoplasm and occur without the involvement of the nuclei. This activation is merely a stimulus, however; it sets into action a preprogrammed set of metabolic events. The responses of the egg to the sperm can be divided into "early" responses, which occur within seconds of the cortical reaction, and "late" responses, which take place several minutes after fertilization begins (Table 7. Early responses As we have seen, contact between sea urchin sperm and egg activates the two major blocks to polyspermy: the fast block, initiated by sodium influx into the cell, and the slow block, initiated by the intracellular release of calcium ions. The activation of all eggs appears to depend on an increase in the concentration of free calcium ions within the egg. Such an increase can occur in two ways: calcium ions can enter the egg from outside, or calcium ions can be released from the endoplasmic reticulum within the egg. In snails and worms, much of the calcium probably enters the egg from outside, while in fishes, frogs, sea urchins, and mammals, most of the calcium ions probably come from the endoplasmic reticulum. In both cases, a wave of calcium ions sweeps across the egg, beginning at the site of sperm-egg fusion (Jaffe 1983; Terasaki and Sardet 1991). The timing of events within the first minute is best known for Lytechinus variegatus, so times are listed for that species. The presence of calcium ions is essential for activating the development of the embryo.
The cleaved Spдtzle protein is now able to bind to its receptor in the oocyte cell membrane cholesterol medication that does not affect the liver buy zetia 10mg visa, the product of the Toll gene cholesterol free diet chart buy generic zetia 10 mg. Toll protein is a maternal product that is evenly distributed throughout the cell membrane of the egg (Hashimoto et al cholesterol levels video zetia 10 mg low cost. Therefore cholesterol levels in fresh eggs buy zetia 10 mg with mastercard, the Toll proteins on the ventral side of the egg are transducing a signal into the egg, while the Toll receptors on the dorsal side of the egg are not. Establishing the dorsal protein gradient Separation of the dorsal and cactus proteins. The crucial outcome of signaling through the Toll protein is the establishment of a gradient of Dorsal protein in the ventral cell nuclei. It appears that the Cactus protein is blocking the portion of the Dorsal protein that enables the Dorsal protein to get into nuclei. As long as this Cactus protein is bound to it, Dorsal protein remains in the cytoplasm. Thus, this entire complex signaling system is organized to split the Cactus protein from the Dorsal protein in the ventral region of the egg. When Spдtzle binds to and activates the Toll protein, the Toll protein can activate the Pelle protein kinase. Once phosphorylated, the Cactus protein is degraded, and the Dorsal protein can enter the nucleus (Kidd 1992; Shelton and Wasserman 1993; Whalen and Steward 1993; Reach et al. Since the signal transduction cascade creates a gradient of Spдtzle protein that is highest in the most ventral region, there is a gradient of Dorsal translocation into the ventral cells of the embryo, with the highest concentrations of Dorsal protein in the most ventral cell nuclei. Thus, the biochemical pathway used to specify dorsalventral polarity in Drosophila appears to be homologous to that used to differentiate lymphocytes in mammals (Figure 9. What does the Dorsal protein do once it is located in the nuclei of the ventral cells? A look at the fate map of a cross section through the Drosophila embryo at the fourteenth division cycle (see Figure 9. The next cell up from this region generates the specialized glial and neural cells of the midline. The next two cells are those that give rise to the ventral epidermis and ventral nerve cord, while the nine cells above them produce the dorsal epidermis. The most dorsal group of six cells generates the amnioserosal covering of the embryo (Ferguson and Anderson 1991). Large amounts of Dorsal instruct the cells to become mesoderm, while lesser amounts instruct the cells to become glial or ectodermal tissue (Jiang and Levine 1993). The first morphogenetic event of Drosophila gastrulation is the invagination of the 16 ventralmost cells of the embryo (Figure 9. All of the body muscles, fat bodies, and gonads derive from these mesodermal cells (Foe 1989). These genes are transcribed only in nuclei that have received high concentrations of Dorsal protein, since their enhancers do not bind Dorsal with a very high affinity (Thisse et al. The Twist protein activates mesodermal genes, while the Snail protein represses particular nonmesodermal genes that might otherwise be active. The rhomboid gene is interesting because it is activated by Dorsal but repressed by Snail. Both Snail and Twist are needed for the complete mesodermal phenotype and proper gastrulation (Leptin et al. The sharp border between the mesodermal cells and those cells adjacent to them that generate glial cells (mesectoderm) is produced by the presence of Snail and Twist in the ventralmost cells, but of only Twist in the next cell up (Kosman et al. In mutants of snail, the ventralmost cells still have the twist gene activated, and they resemble the more lateral cells (Nambu et al. In addition to activating the mesoderm-stimulating genes (twist and snail), it directly inhibits the dorsalizing genes zerknьllt (zen) and decapentaplegic (dpp). Thus, in the same cells, the Dorsal protein can act as an activator of some genes and a repressor of others. Thus, in wild-type embryos, the mesodermal precursors express twist and snail (but not zen or dpp); precursors of the dorsal epidermis and amnioserosa express zen and dpp but not twist or snail. Glial (mesectoderm) precursors express only snail, while the lateral neural ectodermal precursors do not express any of these four genes (Kosman et al. Thus, as a consequence of the responses to the Dorsal protein gradient, the axis becomes subdivided into mesoderm, mesectoderm, neurogenic ectoderm, epidermis, and amnioserosa. Axes and Organ Primordia: the Cartesian Coordinate Model the anterior-posterior and dorsal-ventral axes of Drosophila embryos form a coordinate system that can be used to specify positions within the embryo. Theoretically, cells that are initially equivalent in developmental potential can respond to their position by expressing different sets of genes. This type of specification has been demonstrated in the formation of the salivary gland rudiments (Panzer et al. First, salivary glands form only in the strip of cells defined by the activity of the sex combs reduced (scr) gene along the anterior-posterior axis (parasegment 2). Moreover, if scr is experimentally expressed throughout the embryo, salivary gland primordia form in a ventrolateral stripe along most of the length of the embryo. The formation of salivary glands along the dorsalventral axis is repressed by both Decapentaplegic and Dorsal. The cells that form the salivary glands are directed to do so by the intersecting gene activities along the anterior-posterior and dorsal-ventral axes. A similar situation is seen with tissues that are found in every segment of the fly. Neuroblasts arise from ten clusters of four to six cells each that form on each side in every segment in the strip of neural ectoderm at the midline of the embryo (Skeath and Carroll 1992). The cells in each cluster interact (in ways that are discussed in Chapters 8 and 12) to generate a single neural cell from the cluster. Skeath and colleagues (1993) have shown that the pattern of achaete and scute transcription is imposed by a coordinate system. Their expression is repressed by the Decapentaplegic and Snail proteins along the dorsal-ventral axis, while positive enhancement by pair-rule genes along the anterior-posterior axis causes their repetition in each half-segment. The enhancer recognized by these axis-specifying proteins lies between the achaete and scute genes and appears to regulate both of them. It is very likely, then, that the positions of organ primordia are specified throughout the fly through a two-dimensional coordinate system based on the intersection of the anterior-posterior and dorsal-ventral axes. Coda Genetic studies on the Drosophila embryo have uncovered numerous genes that are responsible for the specification of the anterior-posterior and dorsal-ventral axes. We are far from a complete understanding of Drosophila pattern formation, but we are much more aware of its complexity than we were five years ago. The mutations of Drosophila genes have given us our first glimpses of the multiple levels of pattern regulation in a complex organism and have enabled the isolation of these genes and their products. Moreover, as we will see in the forthcoming chapters, these genes provide clues to a general mechanism of pattern formation used throughout the animal kingdom. We are beginning to learn how the genome influences the construction of the organism. The genes regulating pattern formation in Drosophila operate according to certain principles: There are morphogens such as Bicoid and Dorsal whose gradients determine the specification of different cell types. There is a temporal order wherein different classes of genes are transcribed, and the products of one gene often regulate the expression of another gene. In Drosophila, boundaries of gene expression can be created by the interaction between transcription factors and their gene targets. Here, the transcription factors transcribed earlier regulate the expression of the next set of genes. Rather, there is a stepwise specification wherein a given field is divided and subdivided, eventually regulating individual cell fates. Gastrulation begins with the invagination of the most ventral region, the presumptive mesoderm. The germ band expands such that the future posterior segments curl just behind the presumptive head. Maternal effect genes are responsible for the initiation of anterior-posterior polarity. A gradient of Bicoid protein activates more hunchback transcription in the anterior. Bicoid and Hunchback proteins activate the genes responsible for the anterior portion of the fly; Caudal activates genes responsible for posterior development.
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