The steroid hormone 20-hydroxyecdysone (ecdysone) is the key regulator of postembryonic developmental transitions in insects and controls metamorphosis by triggering the morphogenesis of adult tissues from larvae. The Rho GTPase, which mediates cell shape change and migration, is also an essential regulator of tissue morphogenesis during development. Rho activity can modulate gene expression, in part, by activating LIM kinase (LIMK) and consequently affecting actin-induced SRF transcriptional activity. A link has been established between Rho-LIMK-SRF signaling and the ecdysone-induced transcriptional response during Drosophila development. Specifically, Rho GTPase, via LIMK, regulates the expression of several ecdysone-responsive genes, including those encoding the ecdysone receptor itself, a downstream transcription factor (Br-C), and Stubble, a transmembrane protease required for proper leg formation. Stubble and Br-C mutants exhibit strong genetic interactions with several Rho pathway components in the formation of adult structures, but not with Rac or Cdc42. In cultured SL2 cells, inhibition of Rho, F-actin assembly, or SRF blocks the transcriptional response to ecdysone. Together, these findings indicate a link between Rho-LIMK signaling and steroid hormone-induced gene expression in the context of metamorphosis and thereby establish a novel role for the Rho GTPase in development (Chen, 2004).
The malformed legs in DlimkD522A flies closely resemble leg defects in flies in which Rho signaling is perturbed through genetic disruption of Rho1, DrhoGEF2 (a guanine nucleotide exchange factor for Rho1), sqh (myosin light chain), and zipper (nonmuscle myosin heavy chain). Sqh and zipper are downstream targets of Drok and regulate actomyosin contractility. Loss-of-function mutants of Rho1 or DrhoGEF2 strongly suppress the severity of wing defects associated with Dlimk expression. Reducing Rho activity by overexpressing the potent Rho inhibitor, p190 RhoGAP, also efficiently suppresses Dlimk-induced wing defects. Moreover, reducing levels of Diaphanous or Drok, two Rho targets that promote actin assembly, also substantially reduces the severity of Dlimk-induced wing defects. A loss-of-function allele of blistered, the Drosophila SRF ortholog, also suppresses the Dlimk-induced wing defects, suggesting that regulation of SRF-dependent transcription by Rho-LIMK signaling plays a role in wing morphogenesis. Significantly, in mammalian cells, LIMK and Diaphanous cooperate to regulate SRF activity. Reducing levels of the Rho-related GTPases, Rac1, Rac2, and Cdc42, or the Rac activator, Myoblast city (Mbc), or the Rac/Cdc42 effector target, PAK, has very little effect on the Dlimk-induced wing phenotype. Thus, it appears that in the developing leg and wing, Dlimk specifically mediates a Rho-actin signaling pathway required for imaginal-disc morphogenesis (Chen, 2004).
Morphogenesis of the Drosophila embryo is associated with a dynamic reorganization of the actin cytoskeleton that is mediated by small GTPases of the Rho family. Often, Rho1 controls different aspects of cytoskeletal function in parallel, requiring a complex level of regulation. The guanine triphosphate (GTP) exchange factor DRhoGEF2 is apically localized in epithelial cells throughout embryogenesis. DRhoGEF2, which has previously been shown to regulate cell shape changes during gastrulation, recruits Rho1 to actin rings and regulates actin distribution and actomyosin contractility during nuclear divisions, pole cell formation, and cellularization of syncytial blastoderm embryos. It is proposed that DRhoGEF2 activity coordinates contractile actomyosin forces throughout morphogenesis in Drosophila by regulating the association of myosin with actin to form contractile cables. These results support the hypothesis that specific aspects of Rho1 function are regulated by specific GTP exchange factors (Padash Barmchi, 2005; full text of article).
Guanine nucleotide exchange factors regulate the activity of the small GTPase Rho1, which is thought to act as a molecular switch in a broad spectrum of morphogenetic processes that require a complex reorganization of the actin cytoskeleton. However, the manner in which different aspects of Rho1 function are regulated by RhoGEFs is not well understood. This study found that DRhoGEF2 protein is broadly distributed in epithelia during oogenesis and embryonic development and concentrated at the apical surface of cells, suggesting that it may regulate Rho1 throughout morphogenesis. The defects of DRhoGEF2 mutants are less severe than those of Rho1 mutants, suggesting that DRhoGEF2 regulates specific aspects of Rho1 function (Padash Barmchi, 2005).
DRhoGEF2 has been shown to regulate cell shape changes during gastrulation, and DRhoGEF2 is implicated in epithelial folding during imaginal disc development, a process that depends on cell shape changes that are similar to those driving invagination of the germ layers. This paper shows that DRhoGEF2 regulates cytoskeletal reorganization and function during pole cell formation and blastoderm cellularization. All of these processes require the contraction of actomyosin rings. It is proposed that DRhoGEF2 regulates Rho1 activity during cell shape changes requiring actomyosin contractility. The results support the hypothesis that individual RhoGEFs may regulate specific aspects of Rho1 function during development (Padash Barmchi, 2005).
Interestingly, DRhoGEF2 has been found to be nonessential during cytokinesis, which also involves the function of contractile actin rings. The function of Rho1 during cytokinesis is regulated by the RhoGEF pebble that initiates actin ring assembly. In pebble mutants, cytokinesis is blocked at mitotic cycle 14 and subsequent mitoses occur without cytokinesis, creating polyploid, multinucleated cells. Although large multinucleated cells are also observed in DRhoGEF2 mutants at the extended germ band stage it is not clear whether these cells are caused by a block in cytokinesis or are caused by earlier defects during cellularization. In contrast to pebble, DRhoGEF2 may not be required for the assembly of actin rings, but may play a nonessential role in the separation of daughter cells. This is reminiscent of observations during cellularization. Although the function of actin rings appears compromised throughout cellularization, the data suggest that some contractile activity remains that leads to the basal closure of blastoderm cells and is responsible for the cellularized appearance of DRhoGEF2 mutants at the onset of gastrulation (Padash Barmchi, 2005).
At the retracted germ band stage, DRhoGEF2 is enriched at the apical cortex of cells in the leading edge of the lateral epidermis, which is consistent with the view that it may regulate Rho1 during dorsal closure. Rho1 function is essential for dorsal closure, and the cuticles of zygotic Rho1 mutants show dorsal holes. In DRhoGEF2 mutants, the lateral epithelial sheets closed the embryo dorsally. This does not exclude the possibility that constriction of actin cables may contribute to dorsal closure and that DRhoGEF2 may play a role in this process. Overall, the data suggest that DRhoGEF2 function may not be essential for the generation of contractile force, but rather regulate the temporal and spatial coordination of actomyosin contractility (Padash Barmchi, 2005).
During syncytial nuclear divisions and cellularization, DRhoGEF2 is localized specifically at the invaginating furrows. In DRhoGEF2 mutants, actin is irregularly distributed and metaphase furrow formation is less uniform than in the wild type. The defects in furrow formation lead to mitotic defects and the subsequent elimination of abnormal nuclei from the cortex so that, at the onset of cellularization, ~20% of the nuclei have been lost. These phenotypes are reminiscent of the defects seen in mutants of the nonreceptor tyrosine kinase Abelson (Abl). The abnormalities in actin distribution observed in abl mutants are likely caused by the mislocalization of Dia, which leads to ectopic actin polymerization at the apical end of cells. Changes in Dia distribution were not observed in DRhoGEF2 mutants, suggesting that DRhoGEF2 may regulate actin distribution by a different mechanism . Perturbations in actin distribution are observed throughout early development in DRhoGEF2 mutants. During cellularization, significant amounts of actin fail to redistribute to the base of the furrow canal. These observations show that one of the roles of DRhoGEF2 is to regulate furrow assembly. The defects in actin distribution also affect the pole cells, which fail to reorganize their cortical actin cytoskeleton and remain embedded in the somatic nuclear layer rather than sitting on top of it. Consequently, they are obliterated during invagination of the cellularization front (Padash Barmchi, 2005).
It is speculated that DRhoGEF2 may have a function in the assembly of actin cables by regulating the association of actin with other proteins such as myosin II. The mislocalization of actin observed in DRhoGEF2 mutants may be caused by failure of actin to associate with myosin. Interestingly, although myosin II is present at the metaphase furrows, it plays no essential role in their formation, and this suggests that the function of DRhoGEF2 in furrow assembly may be independent of actomyosin contractility (Padash Barmchi, 2005).
Phenotypic analysis suggests that DRhoGEF2 regulates actomyosin contractility during cellularization. Previously, the actin-binding protein Bnk has been implicated in the regulation of contractile forces. In bnk mutants, actin hexagons detach from each other and constrict prematurely. Based on this phenotype, it is suggested that, during the slow phase, cortical actin hexagons are linked to each other through Bottleneck (Bnk), and that actomyosin constriction causes the network to contract as a whole, thereby pulling the membrane front inwards. Once the cellularization front has reached the base of the nuclei and Bnk is degraded, actin hexagons detach from each other and contract as individual rings, thereby closing the blastoderm cells basally. It is proposed that DRhoGEF2-mediated activation of Rho1 may regulate the force that keeps actin hexagons under tension. Bnk counteracts contraction during the slow phase by linking individual actin rings to each other. Degradation of Bnk during the fast phase releases individual actin rings, and the DRhoGEF2-mediated contractile force now contributes to basal closure. Therefore, DRhoGEF2 and bnk act in concert to coordinate actin ring contraction during cellularization. In DRhoGEF2-bnk double mutants, the actin network disintegrates progressively, suggesting that DRhoGEF2 and bnk may play an additional role in the assembly or stabilization of actomyosin filaments (Padash Barmchi, 2005).
It has been proposed that actin network contraction contributes to the inward movement of the furrow canal. Although the data suggest that network tension is severely reduced in DRhoGEF2 mutants, the rate of membrane invagination is unaffected. This is consistent with reports on the role of myosin II during cellularization, suggesting that network tension may not contribute to membrane invagination. In the wild type, actin rings squeeze the nuclei slightly and push them basal-wards as the actin network moves over them. This may contribute to the parallel alignment of astral microtubules surrounding the nuclei and to nuclear elongation. In DRhoGEF2 mutants, nuclei are wider than in the wild type and irregularly aligned. It is proposed that network tension may create an ordered hexagonal array of actin rings that contributes to a parallel alignment of nuclei during cellularization. The force moving the actin network inward may be created by plus end-directed tracking of actin on astral microtubules and by membrane insertion as previously suggested. These observations suggest that actomyosin contractility plays a role in the spatial coordination of cytoskeletal function during cellularization (Padash Barmchi, 2005).
Two effector pathways have been implicated in the transduction of Rho1 activation to the actin cytoskeleton. During cytokinesis, which is mechanistically related to cellularization, a linear pathway including profilin and Dia have been proposed to link Rho1 to the contractile actomyosin ring. The maternally supplied Dia plays a role in a spectrum of cytoskeletal functions during early embryogenesis that also require DRhoGEF2 function, such as metaphase furrow formation, pole cell formation, and cellularization. Dia is localized at the cellularization front and is necessary for the recruitment of cytoskeletal components such as the actin-binding protein anillin and the septin homologue Pnut. The phenotypes of dia mutants suggest that dia is necessary for the assembly of contractile actin rings at sites of membrane invagination (Padash Barmchi, 2005).
The similarities between dia and DRhoGEF2 mutants might suggest dia as a downstream effector of DRhoGEF2. However, the defects of dia mutants are morphologically different from those of DRhoGEF2 mutants. In dia mutants, metaphase furrows do not form and contractile rings at the base of polar cytoplasmic buds fail to assemble. During cellularization, actin fails to condense into individual rings, and the network disintegrates during the second phase of cellularization. In DRhoGEF2 mutants actin rings form and remain largely intact but fail to constrict. In addition, the temporal and spatial localization of Dia and Pnut to the cellularization front was unaffected in DRhoGEF2 mutants and dia was not required for the localization of DRhoGEF2. These findings do not exclude that DRhoGEF2 activity may in part be mediated by dia, however, they suggest that some dia-dependent aspects of Rho1 function are still active in DRhoGEF2 mutants and that another pathway may be involved in transduction of the DRhoGEF2 signal (Padash Barmchi, 2005).
A well-characterized pathway regulating actomyosin contractility in mammalian cells and in C. elegans links Rho1 to actin via Rho kinase, the regulatory subunit of myosin light chain phosphatase (MBS) and myosin II. Rho kinase-mediated phosphorylation inhibits the activity of MBS and induces a conformational change in myosin II allowing it to form filaments that promote sliding of antiparallel actin filaments. The data are consistent with a model in which DRhoGEF2 regulates the association of actin with myosin II, thereby stabilizing actomyosin cables. It is proposed that failure to activate the Rho kinase pathway may compromise the recruitment of actin into contractile cables. This may destabilize actin cables and lead to the mislocalization of actin and to the defects in actomyosin contractility observed in DRhoGEF2 mutants. The Drosophila homologue of Rho kinase, Drok, and myosin II have recently been identified as downstream effectors of DRhoGEF2 during the regulation of actomyosin contractility in Schneider (S2) cells. In addition, myosin II is required for basal closure of blastoderm cells and the myosin II heavy chain encoded by zipper (zip) interacts genetically with DRhoGEF2. These data support the model that DRhoGEF2 may regulate actomyosin contractility through the Rho kinase pathway. Mutants in Drok and Drosophila myosin light chain phosphatase have been identified, however, their role during early embryogenesis has not been reported. Interestingly, inhibition of Drok activity by injection of the specific Rho kinase inhibitor Y-27632 into embryos before cellularization disrupts the localization of myosin II. Similar observations have been made in Drok mutant cell clones in imaginal discs. By contrast, DRhoGEF2 mutants reveal no significant changes in the localization of myosin II during cellularization. It is possible that the differences in myosin II localization between DRhoGEF2 and Drok mutants are due to different mechanisms of action at the molecular level. In mammalian cells myosin II phosphorylation is required for the generation of contractile force but not for its localization. Further investigations will be necessary to resolve how the DRhoGEF2 signal is transduced to the cytoskeleton (Padash Barmchi, 2005).
Little is known about the events that regulate the specific subcellular localization and activation of DRhoGEF2. It has recently been shown that DRhoGEF2 particles are transported from the cytoplasm to the cell periphery by tracking microtubule plus ends in Drosophila S2 cells. DRhoGEF2 particles have been observed during syncytial development that may be involved in a similar process in the embryo. It is speculated that DRhoGEF2 may be delivered to specific membrane subdomains at the cellularization front by microtubules. The G-protein α-subunit encoding gene concertina (cta) has been shown to regulate the dissociation of DRhoGEF2 from microtubules. cta has been implicated in the activation of DRhoGEF2 during gastrulation, but is not required during cellularization. It has been suggested that the force moving the actin network inward may be generated by plus end-directed crawling of actin on astral microtubules. It is speculated that DRhoGEF2 may regulate actin ring constriction during cellularization while associated with the tip of astral microtubules by recruiting Rho1 to the site of actin rings (Padash Barmchi, 2005).
DRhoGEF2 is concentrated in actin-rich regions throughout development and the human orthologue of DRhoGEF2, PDZ-RhoGEF, has been shown to bind to actin directly. Although the domain structure of DRhoGEF2 and PDZ-RhoGEF is very similar, the actin-binding region of PDZ-RhoGEF is not conserved in DRhoGEF2. Nevertheless, the localization of DRhoGEF2 is consistent with the view that it may associate with actin, however, further experiments are needed to corroborate this theory (Padash Barmchi, 2005).
A hallmark of epithelial invagination is the constriction of cells on their apical sides. During Drosophila gastrulation, apical constrictions under the control of the transcription factor Twist lead to the invagination of the mesoderm. Twist-controlled G protein signaling is involved in mediating the invagination but is not sufficient to account for the full activity of Twist. A Twist target was identified, the transmembrane protein T48, which acts in conjunction with G protein signaling to orchestrate shape changes. Together with G protein signaling, T48 recruits adherens junctions and the cytoskeletal regulator RhoGEF2 to the sites of apical constriction, ensuring rapid and intense changes in cell shape (Kolsch, 2007).
Apical constriction of cells can contribute to the invagination of epithelia, such as during gastrulation or organogenesis, and the closure of wounds. In the Drosophila embryo, apical constrictions occur along the ventral side of the blastoderm epithelium, leading to the formation of the ventral furrow and the invagination of the mesoderm. Proteins necessary for the mechanics of these cell shape changes include the Rho guanosine 5'-triphosphate-exchange factor RhoGEF2 and a heterotrimeric G protein. Whereas RhoGEF2 is essential for furrow formation, disruption of the heterotrimeric G protein, such as by loss of its α subunit Concertina (Cta), leads to a delay but no lasting defects in mesoderm morphogenesis. These maternally supplied proteins must be activated under the control of the zygotic genome in the embryo (Kolsch, 2007).
Twist is the zygotic transcriptional activator that is essential for the cell shape changes that produce the ventral furrow. One of its targets is the transcriptional repressor Snail, which is also essential for mesodermal morphogenesis (Kolsch, 2007).
However, the cell biological events responsible for the cell shape changes must ultimately be regulated by targets that are not transcription factors. Of the known Twist targets, only one, folded gastrulation (fog), is involved in mediating shape changes. Mutants in fog, which codes for a secreted peptide, show the same defects as embryos lacking Cta. Fog is therefore thought to act in the same pathway as Cta, which is referred to as Fog/Cta signaling (Kolsch, 2007).
Fog/Cta signaling is thought to cause changes in the actin cytoskeleton in conjunction with RhoGEF2. Recruitment of myosin from basal to apical in constricting ventral cells is partly dependent on Fog/Cta and absolutely dependent on RhoGEF2. Furthermore, the mammalian homologs of RhoGEF2 and Cta interact. Finally, binding of Drosophila RhoGEF2 to microtubules by means of EB1 is disrupted by activated Cta. Given that myosin recruitment and apical constriction are reduced but not abolished in the absence of Fog/Cta, there must be other factors regulated by Twist that explain its effects on apical constriction (Kolsch, 2007).
In a screen for genes that mediate the zygotic control of gastrulation, the region uncovered by the chromosomal deficiency Df(3R)TlP was found to be necessary for the proper formation of the ventral furrow. Phenotypic analysis and molecular mapping of a set of overlapping deficiencies identified the gene T48 as being responsible for the defects seen in Df(3R)TlP. T48 is expressed in the mesoderm. It codes for a predicted protein with a signal peptide and a potential transmembrane domain. When an internally hemagglutinin-tagged T48 protein (T48HA) was expressed in embryos, it localized at the peripheries of blastoderm cells, consistent with a close association with or insertion into the plasma membrane. Optical cross-sections showed that T48HA is targeted to the apical membrane (Kolsch, 2007).
No other structural motifs are recognizable in the protein. However, the C-terminal amino acid sequence -Ile-Thr-Thr-Glu-Leu (-ITTEL) conforms to the class I consensus for peptides that interact with PDZ domains. T48 has no obvious human ortholog but shows some similarity to the intracellular part of Fras1, which also has a PDZ-binding motif. To find candidates for PDZ domains that might interact with T48, the putative PDZ-binding sequence was analyzed with an algorithm designed to determine the PDZ domains that show the optimal fit for any given peptide. Of the predicted interactors, RhoGEF2 was particularly interesting in view of its role in ventral furrow formation. Furthermore, the mammalian ortholog of RhoGEF2 has been shown to bind to Plexin-B1 by means of a PDZ-binding motif (-Val-Thr-Asp-Leu) very similar to that of T48 (Kolsch, 2007).
Whether the C terminus of T48 is indeed able to interact with RhoGEF2 was tested. A 35S-labeled C-terminal peptide of T48 preferentially coprecipitated with the PDZ domain of RhoGEF2 rather than those of other PDZ domain-containing proteins, in contrast to Crumbs, which was used as a control and which preferentially coprecipitated with PDZ domains from its physiological interaction partner Stardust, as well as Bazooka. In Schneider S2 cells, a green fluorescent protein (GFP)-tagged RhoGEF2 PDZ domain or full-length RhoGEF2 was localized in the cytoplasm or formed intracellular aggregates when expressed alone, but localized to the plasma membrane when coexpressed with T48. In both assays, the interaction required the presence of the -ITTEL motif and was not seen with other PDZ domains. Thus, T48 interacts with RhoGEF2 by means of its PDZ-binding motif and is able to enrich RhoGEF2 to the plasma membrane (Kolsch, 2007).
To understand the function of T48 during gastrulation, the subcellular localization of RhoGEF2 and its dependence on T48 were studied in the developing embryo. Before gastrulation, the apical surfaces of the blastoderm epithelium are dome shaped and the developing adherens junctions are located subapically. RhoGEF2 is associated with the basally located furrow canals, whereas Armadillo is found just below this site and at a subapical position of the lateral cell membranes (Kolsch, 2007).
After cellularization was completed, these distributions changed specifically in ventral cells. Even before morphological changes occurred, RhoGEF2 and Armadillo disappeared from the basal ends. Subsequently, Armadillo disappeared from its subapical site and accumulated apically. A weak association of RhoGEF2 with the apical plasma membrane was seen at this stage (Kolsch, 2007).
As cells begin to flatten apically, high levels of both RhoGEF2 and Armadillo accumulate apically. Although they concentrated in the same region of the cell, Armadillo was restricted to the cell junctions, whereas RhoGEF2 was often more enriched between these sites. Notably, movement of the adherens junctions occurred not only in constricting cells but also in the more lateral mesodermal cells that flattened and became stretched on their apical sides (Kolsch, 2007).
To examine whether these processes depend on T48, stage-selected T48 mutant embryos were stained. Loss of RhoGEF2 and Armadillo from the basal side was unaffected in these embryos, as was the apical concentration of Armadillo. The cells flatten apically and lengthen, but the absence of constrictions results in a thick placode rather than an indentation. Localization of RhoGEF2 to the apical membrane is slightly delayed and possibly reduced. T48 therefore contributes to but is not essential for the recruitment of RhoGEF2 to the apical membrane. This is consistent with the observation that furrow formation is not completely abolished, but only delayed or weakened. Therefore other mechanisms were examined that might participate in RhoGEF2 localization (Kolsch, 2007).
As in the case of T48, mutations in the Fog/Cta pathway delay but do not abolish apical constriction and furrow formation. It was therefore considered whether Fog/Cta signaling might cooperate with T48 to recruit RhoGEF2. In embryos lacking Cta, the recruitment of RhoGEF2 was weakened. Combining mutations in cta and T48 resulted in much more notable effects. These cta,T48 embryos failed to make a furrow; the lack of apical constrictions was mirrored by a failure to accumulate RhoGEF2 apically. Thus, T48 and Fog/Cta signaling act in parallel to concentrate RhoGEF2 apically (Kolsch, 2007).
Severe defects were also observed in the behavior of the adherens junctions in the double-mutant embryos. Armadillo staining disappeared from its tight subapical localization but did not reaccumulate apically. Thus, movement of the junctions is not simply mediated by a tensile force from the constricting actin cytoskeleton: an independent step of at least partial disassembly must occur. It is speculated that this might be controlled by Snail, which regulates the disassembly of cell junctions in vertebrates. It was found that the disassembly of Armadillo from the subapical position was indeed blocked in snail (but not in twist) mutant embryos. Thus, Snail acts in parallel to Twist to direct the disassembly of subapical junctions, a process to which currently unknown Twist targets may also contribute (Kolsch, 2007).
Having observed that T48 and Fog/Cta activation are required for the apical localization of RhoGEF2 and Armadillo, whether T48, like Fog/Cta signaling, was able to trigger their relocalization in other cells was also tested. Ubiquitous expression of T48 in the embryo led to a concentration of RhoGEF2 at the apical membranes of lateral cells. Armadillo localization in ectodermal cells was no longer restricted to a distinct subapical domain but extended to the apical end of the lateral membranes in many cells. When T48 was coexpressed with activated Cta, this effect was slightly enhanced, and some embryos showed morphological defects (Kolsch, 2007).
With T48, a missing factor has been found in the control cascade from transcriptional regulation by Twist to the cell biological mediators of furrow morphogenesis. Two Twist targets, Fog and T48, appear to act in separate pathways that converge on RhoGEF2, which integrates the signal to activate myosin and modify the actin cytoskeleton. This model shows the maternally supplied RhoGEF2 is largely attached to microtubules by means of EB1. The onset of Twist expression has two effects. Fog is synthesized, which triggers the activation of Cta. This in turn releases RhoGEF2 from the microtubules that, by analogy to its vertebrate homologs, may bind to Cta through its RGS domain, allowing some myosin activation and constriction. In parallel, T48 is synthesized and targeted to the apical membrane, where it acts to concentrate RhoGEF2 through its PDZ-binding motif. In the absence of Fog-mediated displacement of RhoGEF2 from EB1, T48 can probably still recruit sufficient freely diffusible RhoGEF2 to allow slow constriction. Only when both mechanisms fail are the downstream events of constriction and junction reassembly abolished completely (Kolsch, 2007).
The utilization of Gα12/13 proteins and a microtubule-bound RhoGEF have also been reported in vertebrate gastrulation. The absence of an obvious homolog of T48 in vertebrates might suggest that this element of the control mechanism is unique to Drosophila gastrulation. However, the PDZ-binding motif in Plexin-B1 is similar to that of T48 and acts during neuronal growth cone remodeling by recruiting PDZ-RhoGEF. Therefore, this mechanism of controlling cell shape may operate in a variety of systems (Kolsch, 2007).
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