fushi tarazu

DEVELOPMENTAL BIOLOGY

Embryonic

The seven ftz stripes arise individually in a distinct, non-linear order along the anterior-posterior axis of the embryo, in even numbered stripes starting just anterior to the cephalic furrow [Images]. The indentation that will become the posterior midgut invagination forms behind the posterior most stripe. The pattern is complementary to that of even-skipped. In addition, the stripes develop differentially along the dorsal-ventral axis; most stripes emerge on the ventral side and then gradually spread dorsally until they surround the entire circumference of the embryo (Carroll, 1985, Hafen, 1984 and Yu, 1995). In addition to expression in the epidermis, ftz is transiently expressed in neuroblasts and glia of the developing CNS. In the absense of ftz CNS expression, the RP2 neuron extends a growth cone along an abnormal pathway, mimicking its sibling (RP1), suggesting a transformation in neuronal identity. evenskipped is expressed in this same neuron (Doe, 1988).

See Chris Doe's Hyper-Neuroblast map site for information on the expression of fushi tarazu in specific neuroblasts.

For more information on Drosophila neuroblast lineages, see Linking neuroblasts to their corresponding lineage, a site carried by Flybrain, an online atlas and database of the Drosophila nervous system.

Asymmetric mRNA localization targets proteins to their cytoplasmic site of function. The mechanism of apical localization of wingless and pair-rule transcripts in the Drosophila blastoderm embryo has been elucidated by directly visualizing intermediates along the entire path of transcript movement. After release from their site of transcription, mRNAs diffuse within the nucleus and are exported to all parts of the cytoplasm, regardless of their cytoplasmic destinations. Endogenous and injected apical RNAs assemble selectively into cytoplasmic particles that are transported apically along microtubules. Cytoplasmic dynein is required for correct localization of endogenous transcripts and apical movement of injected RNA particles. It is proposed that dynein-dependent movement of RNA particles is a widely deployed mechanism for mRNA localization (Wilkie, 2001).

To study the mechanism of apical localization, whether actin and/or MTs are necessary for localization of injected mRNA was tested by preinjecting cytoskeletal inhibitors 10 min before injecting the RNA. It was found that preinjection of Cytochalasin B, at concentrations that disrupt the organization of actin filaments, has no affect on Runt mRNA localization. However, a similar disruption of nuclear position has been observed in the cortical cytoplasm. In contrast, preinjection of colcemid, which destabilizes blastoderm MTs, disrupts runt, wingless, and fushi tarazu RNA localization almost entirely. It is concluded that an intact MT cytoskeleton is required for apical localization of injected RNA and that actin does not play a major role in the process. However, some minor role for actin in apical localization of RNA cannot be excluded (Wilkie, 2001).

Whether the localization of injected RNA occurs by minus end directed MT-dependent motor movement was tested by preinjecting embryos with antibodies against Drosophila cytoplasmic dynein heavy chain (dhc). Two independently raised monoclonal antibodies against dhc are each sufficient to inhibit RUN, FTZ, and WG mRNA apical localization in most, or all, embryos. Either one, the anti-dynein antibody or the colcemid injections, is sufficient to cause apical RNA to partly diffuse away from the site of injection in a similar manner to embryos injected with HB RNA alone. Injected apical RNA does not diffuse in the absence of anti-dynein antibodies or Colcemid preinjections. These results suggest that apical RNA is tethered to MTs by dynein and that dynein is required for the transport of RNA particles (Wilkie, 2001).

To further test the involvement of cytoplasmic dynein in apical transcript localization, RNA was injected into mutant cytoplasmic dynein heavy chain (Dhc64C) embryos. A marked reduction was found in the speed of movement of injected apical targeted RNAs in dynein mutants. Cytoplasmic dynein is essential for many cellular processes, so strong mutations in Dhc64C are homozygous lethal in Drosophila and cannot be studied at the blastoderm stage. Instead hypomorphic allelic combinations of Dhc64C, which are viable in trans due to intragenic complementation, were used. In two different allelic combinations of Dhc64C, injected RNA particles move at speeds 60% to 70% slower than they do in wild-type. Staining Dhc64C mutant embryos with anti-tubulin antibodies showsthat MT distribution is indistinguishable from wild-type, indicating that the reduced speed of localization is not due indirectly to a disruption of the MTs. Instead, the reduction in speed is likely to show a direct requirement for dynein in particle transport (Wilkie, 2001).

To test whether cytoplasmic dynein is also required for apical localization of endogenous transcripts, the effects of Dhc64C hypomorphic mutants and anti-dhc antibodies on the apical localization of endogenous FTZ transcripts was tested by in situ hybridization. As expected, hypomorphic Dhc64C mutants show no detectable effects on FTZ apical mRNA localization since injected RNA localizes correctly, but more slowly. In contrast, injection of anti-dhc antibody disrupts endogenous FTZ localization, leading to unlocalized stripes of ftz mRNA 20–30 min after injection. Given that FTZ mRNA has a half-life of 6 min in the blastoderm, the FTZ transcripts observed are likely to have been synthesized after the injection. It is concluded that endogenous apical mRNA localization is also dynein dependent (Wilkie, 2001).

Dynactin is a protein complex that is involved in coordinating the activities of cytoplasmic dynein, and is thought to be required for most forms of dynein-based transport. To test whether dynactin is also required for apical RNA localization, a large excess of p50/dynamitin is preinjected into embryos 10 min before injecting apically targeted RNA. p50/dynamitin causes a significant reduction in the speed of RNA particle movement. p50/dynamitin is a subunit of dynactin whose overexpression is a widely used method of disrupting the dynactin complex and demonstrating conclusively dynein-dependent motility. Dynactin is required for some cargo binding and for dynein processivity. It is concluded that apical transcript localization in the blastoderm embryo occurs by cytoplasmic dynein- and dynactin-mediated transport along MTs toward their minus ends (Wilkie, 2001).

It is thought that export and localization of apical mRNA in the blastoderm embryo can be divided into six distinct steps. (1) During or after completion of transcription and processing, transcripts are assembled into particles, which contain various hnRNPs and export factors, some of which may form part of the cytoplasmic localization machinery. (2) mRNA particles diffuse freely after release from the site of transcription and processing until they reach nuclear pore complexes (NPCs) on the nuclear periphery. (3) mRNA particles are exported through NPCs in all parts of the nuclear envelope. (4) The composition of the particles probably changes during export from the nucleus and in the cytoplasm to recruit dynein, dynactin, and associated proteins. (5) Particles attach to MTs and are actively transported to the apical cytoplasm. (6) Particle movement arrests in the apical cytoplasm, where they may associate with other particles and become anchored (Wilkie, 2001).

The first three steps of apical localization are thought to be common to most mRNAs, because they are essential universal processes in eukaryotic cells. However, the last three steps of the localization pathway are likely to vary among different kinds of transcripts, since the key determinant in sorting different mRNAs to their correct cytoplasmic destinations is presumably RNP particle composition in the cytoplasm. It is possible that some components required for cytoplasmic sorting are preassembled in the nucleus, as suggested by studies showing that the localization of injected FTZ mRNA depends on preincubation with the hnRNPA1 protein Squid. Indeed, a requirement for hnRNPs has also been shown for GRK mRNA localization in the oocyte, for myelin basic protein mRNA in rat oligodendrocytes, and for Vg1 transcripts in Xenopus oocytes. However, the data in this study show that injected protein-free apical RNA assembles in the cytoplasm into particles that localize correctly, arguing that all the factors needed to assemble competent localization particles can also be recruited in the cytoplasm (Wilkie, 2001).

Effects of Mutation or Deletion

ftz mutation is lethal. Comparison of the cuticular segmentation pattern of wild type and ftz mutant larvae shows the presence of denticle belts from only the odd numbered segments (Hafen, 1984).

Recently, double-stranded RNA (dsRNA) has been found to be a potent and specific inhibitor of gene activity in the nematode Caenorhabditis elegans (Fire, 1998). The potential of dsRNA to interfere with the function of genes in Drosophila, termed RNA inhibition or RNAi) has been investigated. Injection of dsRNA into embryos resulted in potent and specific interference of several genes that were tested. dsRNA corresponding to four genes with previously defined functions was introduced. dsRNA is shown to potently and specifically inhibits the activities of wg, fushi tarazu (ftz), even-skipped (eve), and tramtrack (ttk). The reception mechanism of the morphogen Wingless was determined using dsRNA. Interference of the frizzled and Drosophila frizzled 2 genes together produces defects in embryonic patterning that mimic the loss of wingless function. Interference with the function of either gene alone has no effect on patterning. Epistasis analysis indicates that frizzled and Drosophila frizzled 2 act downstream of wingless and upstream of zeste-white3 in the Wingless pathway. These results demonstrate that dsRNA interference can be used to analyze many aspects of gene function (Kennerdell, 1998).

To determine whether dsRNA-mediated interference can occur in Drosophila, RNA was synthesized in vitro, allowed to anneal, and then injected into syncytial blastoderm embryos. The ftz and eve genes were chosen for initial characterization of this method based on several criteria. Both genes are required for embryonic segmentation. Transcription of ftz and eve begins approximately 90 to 120 min after egg laying, which corresponds to a time 10 to 60 min after dsRNA injection. Although both genes function in the first few hours of embryogenesis, null mutant animals survive to the end of embryogenesis and exhibit segmentation defects in their cuticle. Finally, mutants with reduced activity of either ftz or eve produce increasingly severe phenotypes, such that a semiquantitative relationship exists between genotype and phenotype. Antisense and sense RNAs for each gene were synthesized and annealed. Injection of either ftz- or eve-annealed RNA into wild-type embryos effectively interfers with gene activity as demonstrated by cuticle phenotypes characteristic of ftz or eve mutants. In contrast, antisense or sense RNAs injected separately have an order-of-magnitude weaker interference activity than annealed RNA. When a decreasing amount of ftz-annealed RNA is injected, interference activity declines also, though interference was still detectable at the lowest dose. The abundance of each RNA strand at this dose was calculated to be about 2 million molecules per injected embryo. Assuming uniform distribution of RNA, the original injected material is diluted to about 30 molecules per cell. Thus, dsRNA is a robust inhibitor of gene activity in Drosophila, comparable in its potency to that observed in C. elegans (Kennerdell, 1998).

The phenotypes produced by ds-ftz and ds-eve RNAs are highly specific. Injected animals exhibit cuticle defects indistinguishable from ftz and eve loss-of-function mutants. The phenotypes vary significantly among individuals, possibly due to variability in the injected dose. At high doses of ds-ftz RNA, the majority of animals exhibit the null mutant phenotype. At lower doses of ds-ftz RNA, the majority of animals exhibit localized or patchy interference. This localized phenotype is consistent with loss of ftz activity. Even within a group of animals given the same dose, variation in phenotype is apparent. Some ds-eve RNA-treated animals exhibit a lawn of denticles characteristic of the known null mutant, while the remaining animals exhibit a complete pair-rule phenotype or localized pair-rule phenotype characteristic of partial loss of eve function. Since both ftz and eve are expressed in cells spanning 60% the embryo's length, the complete phenotypes observed indicate that interference can occur in cells throughout the embryo. The observed interference is at the level of gene expression. Little or no endogenous Ftz protein is observed in embryos injected with ds-ftz RNA. In contrast, embryos injected with buffer exhibit a normal pattern of Ftz protein expression (Kennerdell, 1998).

Embryos of higher metazoans are divided into repeating units early in development. In Drosophila, the earliest segmental units to form are the parasegments. Parasegments are initially defined by alternating stripes of expression of the fushi-tarazu and even-skipped genes. How ftz and eve define the parasegment boundaries, and how parasegments are lost when ftz or eve fail to function correctly, has never been fully or properly explained. It is shown that parasegment widths are defined early by the relative levels of ftz and eve at stripe junctions. Changing these levels results in alternating wide and narrow parasegments. When shifted by 30% or more, the enlarged parasegments remain enlarged and the reduced parasegments are lost. Loss of the reduced parasegments occurs in three steps; delamination of cells from the epithelial layer, apoptosis of the delaminated cells and finally, apoptosis of inappropriate cells remaining at the surface. The establishment and maintenance of vertebrate metameres may be governed by similar processes and properties (Hughes, 2001).

Previous studies have shown that ftz and eve are the primary determinants of parasegmental boundaries and identities (even versus odd). Until quite recently, it was believed that the two genes perform these roles relatively late (stages 6-7), and that high levels and sharp anterior stripe boundaries are crucial. However, when in the right proportions, the absolute levels of ftz and eve are not particularly important. ftz and eve first define the positions of parasegment borders prior to the completion of cellularization (mid stage 5). At this time, ftz and eve stripes have a bell-shaped distribution across each stripe, and the stripes overlap with one another at their edges. It is suggested that parasegment boundaries occur at the points where stripes intersect and activity levels are equivalent. If the activity of one gene is raised while the other remains unchanged, these positions of equivalency move. The result is an alternating set of narrow and wide parasegments. These shifts become more pronounced with greater changes in activity or when both genes change in opposite directions. However, if both gene activities are increased or decreased at the same time the positions of equivalency do not change, and parasegments remain equal in width (Hughes, 2001).

It is suggested that the transition from overlapping stripe boundaries to sharp non-overlapping boundaries occurs via a combination of autoregulatory and mutually antagonistic functions. For example, if above a certain relative threshold level, ftz autoregulation dominates over repression by eve, and ftz expression rises to maximal levels while eve expression is lost. If below that relative threshold, repression by eve dominates over ftz autoregulation and ftz expression is lost while eve rises to maximal levels. The ability of ftz and eve to autoregulate and to mutually repress one another (directly or indirectly) has been well documented. Once the borders of ftz and eve stripes are established, combinatorial interactions with other segmentation gene products then determine where downstream targets such as en and wg are activated or repressed, thereby locking in the positions of the parasegment boundaries (Hughes, 2001).

ftz and eve pair-rule phenotypes have been described and explained in a number of conflicting ways. The remaining cuticle is not simply composed of every second parasegment, nor is it composed of double-width or homeotically re-transformed segments. A relative decrease in ftz or eve activity causes a decrease in width of alternate parasegments and a corresponding expansion of adjacent parasegments. The smaller parasegments are excised and the enlarged parasegments retained. Efficient deletion (greater than 90%) of the reduced parasegments occurs when they are reduced by 30% or more. Enlarged parasegments are 1.4-1.5 times wider than normal parasegments. This degree of enlargement remains the same when levels of ftz or eve are increased further or when the levels of ftz are reduced to zero (eve nulls affect all parasegments due to earlier roles). It is suggested that these maximal widths reflect the edges of stage 5 ftz and eve stripes, beyond which autoregulation cannot occur. Further expansion of these stripes may be limited by the actions of other pair-rule or gap gene products. The resulting larva is composed of half the normal number of segments, but these are 1.3-1.5 times wider than normal segments, giving an overall length that is about 65%-75% the length of a normal larva (Hughes, 2001).

Parasegments are considered to be the first 'compartments' to form within the embryo. Compartments are fields of cells that originate from a common group of founder cells and that remain defined in lineage thereafter. Cells within adjoining compartments do not mix, most likely due to differential adhesion properties. Compartments are further defined by unique gene expression patterns (e.g. ftz and eve) that respect their boundaries. Another property of compartments relevant to this study is that they are capable of sensing and modulating their size. Changes in size can be induced by injury, transplantation, irradiation, or genetic manipulation. In the case of reductions in size, compensation is most often in the form of increased cellular proliferation, and when increased in size, by programmed cell death. These studies show that parasegments can compensate for changes in size, but that this ability is relatively limited. Both reduced and enlarged parasegments showed changes in the normal numbers of apoptotic events. Dying cells are rarely seen in the ectoderm of reduced parasegments while higher than normal numbers are seen in enlarged parasegments. The numbers of dying cells and the time of onset are proportional to the degree of parasegment enlargement. These changes, however, are insufficient to compensate for the changes in widths induced in this study (Hughes, 2001).

It was also found that changes in mitotic frequency, as an alternate form of compensation, do not occur. Once established, the ratio of the number of cells per mutant parasegment, as compared to wild-type segments, remains relatively constant until cells in the reduced segments begin to delaminate. This finding agrees with those obtained previously by increasing the number of copies of the bicoid gene. Reduced parasegments in the compacted middle of the embryo fail to compensate by increasing rates of mitosis. However, these changes in width were usually subtle enough (<20%) that most segments were able to recover by reducing their rates of apoptosis. These results show that once these changes reach 30% or higher, variations in apoptotic frequencies can no longer compensate (Hughes, 2001).

One of the most novel and intriguing findings of this study was the unstable nature of reduced parasegments and the manner in which they are removed. It was found that this occurs via a three-step process. First, large patches of cells move out of the ectodermal layer. Next, they pinch off from the overlying ectoderm and then programmed cell death is initiated. Finally, the fused engrailed stripes remaining at the surface are resolved by late and sporadic apoptotic events. Although the precise spatial and temporal details of this process vary between individual embryos and different mutant backgrounds, the general trends and final consequences are the same (Hughes, 2001).

The delamination of reduced parasegment cells occurs primarily during the late stages of germ band retraction. This coincidence between reduced parasegment delamination and germ band retraction suggests the possibility that cellular movement and adhesion may play a prominent role in the delamination process. During germ band retraction, normal parasegments are reduced in width by almost half (approx. 11 cells to 7). In reduced parasegments, the corresponding decrease results in an average width of just 3 cells. This reduced width means significantly fewer contacts with other reduced parasegment cells and more contacts with the cells of neighboring parasegments. This may drive the reduced parasegment cells to increase homogeneous contacts by forming spheres, much as observed in imaginal discs when small clones of anterior compartment identity are formed in the posterior compartment (Hughes, 2001).

The protein encoded by the Drosophila pair-rule gene fushi tarazu (ftz) is required for the formation of the even-numbered parasegments. The phenotypes were analyzed of ectopic expression of Ftz and Ftz protein deletions from the Tubulin alpha1 (Tubalpha1) promoter. Fusion of ftz to the Tubalpha1 promoter results in low-level ectopic expression of Ftz relative to Ftz expressed from the endogenous ftz gene. The effects of ectopic expression of four Ftz proteins, Ftz^1-413 (full length wild-type Ftz), Ftz^delta257-316 (a complete deletion of the HD), Ftz^delta101-150 (a deletion that includes the major Ftz-F1 binding site) and Ftz^delta151-209 were determined. Ectopic expression of Ftz^1-413, Ftz^delta257-316 and Ftz^delta101-151 did not result in an anti-ftz phenotype; however, ectopic expression of Ftz^1-413, and Ftz^delta257-316 did result in a ftz^Ual/Rpl-like phenotype. In addition, low-level ectopic expression of Ftz^1-413 and Ftz^delta257-316 rescued ftz phenotypes. This was an important observation because the even-numbered parasegment pattern of Ftz expression is considered important for normal segmentation. Therefore, the rescue of ftz phenotypes by low-level Ftz expression in all cells of the embryo suggests that the even-numbered parasegment expression pattern of Ftz is not the sole factor restricting Ftz action. Low-level ectopic expression of Ftz^delta151-209 resulted in the anti-ftz phenotype and rescued hypomorphic ftz-f1 phenotypes indicating that Ftz^delta151-209 is a hyperactive Ftz molecule. Therefore, the region encompassing amino acids 151-209 of Ftz is required in some manner for repression of Ftz activity. These results are discussed in relation to the current understanding of the mechanism of Ftz action (Argiropoulos, 2003).

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date revised: 20 May 2002

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