corkscrew

DEVELOPMENTAL BIOLOGY

Embryonic, Larval and Adult

Maternal CSW functions in terminal development. Zygotically expressed csw is implicated in the establishment of ventral cell fates, plays a role in commissure formation in the central nervous system, is required for tracheal development, and is involved in the formation of adult structures, including eyes, aristae (the terminal antennal segment), wing veins, tarsal claws, specific macrochaetae, male sex combs and female genital disc derivatives. In addition, CSW is required during oogenesis in follicle cell development (Perkins, 1996 ). This is also discussed in the Biological Overviewsection of corkscrew.

Effects of Mutation or Deletion

corkscrew is maternally required for normal determination of cell fates at the termini of the embryo. Determination of terminal cell fates is mediated by a signal transduction pathway that involves Torso (a receptor tyrosine kinase), components of the Ras pathway, and the transcription factors Tailless and Huckebein. Double mutant and cellular analyses among csw, torso, D-raf and tailless indicate that csw acts downstream of torso and in concert with D-raf to positively transduce the Torso signal via tailless, to downstream terminal genes (Perkins, 1992).

csw is required maternally, since embryos derived from females lacking csw activity during oogeneisis die during embryogenesis. Externally these embryos, referred to as csw mutant embryos, though twisted or U-shaped, appear like wild type. However, mutant embryos show abdnormal development of their internal terminals structures that include disruption anterior to the cephalopharyngeal skeleton and dorsal bridge and posterior to the posterior midgut and Malpighian tubules (Perkins, 1992).

The role in patterning of quantitative variations of MAPK activity in signaling from the Drosophila Torso (Tor) receptor tyrosine kinase (RTK) has been examined. Activation of Tor at the embryonic termini leads to differential expression of the genes tailless and huckebein. Using a series of mutations in the signal transducers Corkscrew/SHP-2 and D-Raf, it has been demonstrated that quantitative variations in the magnitude of MAPK activity trigger both qualitatively and quantitatively distinct transcriptional responses. When terminal activity is progressively removed, there is a corresponding progressive malformation and eventual loss of terminal cuticular structures. The first terminal cuticular elements that are malformed or lost require the highest terminal activation (e.g., the anal tuft and posterior spiracles visualized by the presence of Filzkorper material). The next elements that are malformed or lost require intermediate levels of terminal signal (e.g., the abdominal 8 (A8) denticle belt and the posterior spiracles). Finally, the last elements that are malformed or lost require the lowest levels of terminal activity (e.g., posterior A7). While in the absence of D-raf activity, no activated MAPK (dp-ERK) is observed at the posterior pole. In csw null mutant embryos, where the tll and Hb expression domains are present though mispositioned, reduced levels of dp-ERK reactivity are observed. Collectively, these results reveal that a precise transcriptional response translates into a specific cell identity (Ghiglione, 1999).

Two chimeric receptors, Torextracellular-Egfrcytoplasmic and Torextracellular-Sevcytoplasmic, cannot fully functionally replace the wild-type Tor receptor, revealing that the precise activation of MAPK involves not only the number of activated RTK molecules but also the magnitude of the signal generated by the RTK cytoplasmic domain. For example, analysis of Torextracellular-Egfrcytoplasmic reveals that the posterior domain of Hunchback does not retract from the posterior pole, but rather remains as a terminal cap. Further, the anterior border of this posterior Hb domain is shifted posteriorly. Altogether, these results illustrate how a gradient of MAPK activity controls differential gene expression and thus, the establishment of various cell fates. The roles of quantitative mechanisms in defining RTK specificity are discussed. It is possible that in some instances, the generation of differing magnitudes of activity from the cytoplasmic domains of specific RTKs might be dependent on the specific affinities of the downstream signal transducers to the receptor. Csw binds through one of its SH2 domains to only one phosphotyrosine on Tor. Perhaps a higher or lower affinity of Csw to this site, or addition of another site that would also engage the second SH2 domain of Csw, would increase or decrease signal output. Presumably, in each individual cell there exists a mechanism built into the enhancer elements of the promoters of both tll and hkb that acts to read directly the magnitude of Tor signaling. In the tll promoter, a Tor-response element that mediates the repression of tll has been identified, indicating that the Tor signal activates tll by a mechanism of derepression. A putative candidate for this repressor activity is encoded by the transcription factor Grainyhead. Grainyhead binds to the Tor-response element and can be directly phosphorylated by MAPK in vitro: a decrease in Gh activity has been shown to cause tll expansion in early embryos. Further, the transcriptional corepressor Groucho is required for terminal patterning. Further characterization of how Gh and/or Gro activities are regulated by activated MAPK should clairify how differing levels of phosphorylation translate into derepression of terminal target genes (Ghiglione, 1999).

An Enhancer of sevenless mutation acts as a dominantly inhibiting allele of csw. csw function is essential for Sevenless signaling. Expression of a membrane-targeted form of CSW can drive R7 photoreceptor development in the absence of sevenless function. The dominantly inhibiting CSW shows a substitution of glutamate for glycine at codon 547. In mutant eye discs, prepared by transducing the dominantly inhibiting CSW, elav expression appeares to be normal at the stage when R8, R2 and R5 express elav. However, subsequent staining for Elav is abnormal. Staining of cells occupying the normal position of R3 and R4 was only rarely observed. Transduction of normal CSW suppresses the dominant negative mutant. The dominantly inhibiting csw allele was used to examine the role of CSW during signaling by activated forms of Ras1 and Raf. csw function is still required during signaling by activated Ras1 and Raf proteins. These results define a function for CSW that is either downstream of Ras1 activation or in a parallel pathway that acts with activated Ras1/Raf to specify R7 photoreceptor development (Allard, 1996).

Vertebrate Src can be activated by specific mutations to become oncogenic. Analogous mutations in Drosophila Src oncogene 1 induce abnormal differentiation of photoreceptor cells when expressed ectopically in the developing Drosophila adult eye. The roles played in this process by the adapter protein Downstream of receptor kinases (Drk), and the SH2 domain-containing tyrosine phosphatase Corkscrew (Csw), have been examined. Dominant-negative mutations in either the drk or csw genes ameliorate the developmental abnormalities induced by activated Src64. This suggests that Drk and Csw are required downstream of, or parallel to, Src64. Csw does not act solely as an upstream activator of Scr64. The results are discussed in relation to potential roles for the vertebrate homologs of Drk and Csw (Grb2 and SHP2, respectively) in the transformation of fibroblasts by vertebrate Src (Cooper, 1996).

Transgenic Drosophila models of Noonan syndrome causing PTPN11 gain-of-function mutations

Mutations in the PTPN11 gene, which encodes the protein tyrosine phosphatase SHP-2, cause Noonan syndrome (NS), an autosomal dominant disorder with pleomorphic developmental abnormalities. Certain germline and somatic PTPN11 mutations cause leukemias. Mutations have gain-of-function (GOF) effects with the commonest NS allele, N308D, being weaker than leukemia-causing mutations. To study the effects of disease-associated PTPN11 alleles, transgenic fruitflies were generated with GAL4-inducible expression of wild type or mutant csw, the Drosophila orthologue of PTPN11. All three transgenic mutant CSWs rescued a hypomorphic csw allele's eye phenotype, documenting activity. Ubiquitous expression of two strong csw mutant alleles was lethal, but did not perturb development from some CSW-dependent receptor tyrosine kinase pathways. Ubiquitous expression of the weaker N308D allele causes ectopic wing veins, identical to the EGFR GOF phenotype. Epistatic analyses have established that the csw^N308D ectopic wing vein phenotype requires intact EGF ligand and receptor, and that this transgene interacts genetically with Notch, DPP and JAK/STAT signaling. Expression of the mutant csw transgenes increases RAS-MAP kinase activation, which is necessary but not sufficient for transducing their phenotypes. The findings from these fly models provided hypotheses testable in mammalian models, in which these signaling cassettes are largely conserved. In addition, these fly models can be used for sensitized screens to identify novel interacting genes as well as for high-throughput screening of therapeutic compounds for NS and PTPN11-related cancers (Oishi, 2006).

CSW is the Drosophila orthologue of SHP-2 and works as a positive regulator of multiple RTK pathways. The amino acid sequence of SHP-2's PTP domain is 63% identical to CSW excluding an insertion of unknown consequence in the latter and is 76% similar in the SH2 domains. Since the amino acids altered by the mutations in PTPN11 are conserved in the fly, it was hypothesized that transgenic Drosophila expressing mutant CSW would model the GOF effects on signal transduction observed in cell culture and frog animal cap systems. This study demonstrated that the mutant CSW proteins were biologically active in the eye rescue experiment and that they altered development. One NS transgene, N308D, had a GOF effect on wing vein formation, while two stronger GOF transgenes caused lethality when expressed ubiquitously (Oishi, 2006).

Among patients with NS who harbor PTPN11 mutations, no significant correlation between genotype and phenotype has been established, although the statistical power of those studies has been limited. Biochemical and cell physiologic studies, however, have documented that the GOF effects of NS-associated SHP-2 mutants vary, with the N308D allele being weakest. More strikingly, there are clinical, genetic and biochemical data showing that mutant SHP-2's causing hematopoietic proliferative disorders tend to have greater GOF effects than those associated with isolated NS. Juvenile myelomonocytic leukemia (JMML) occurring in the context of NS can be a milder disease than when it occurs in an otherwise normal child. NS with JMML is caused by specific germline PTPN11 mutations (i.e., most NS-associated PTPN11 mutations including the commonest N308D allele have never been associated with JMML). In contrast, somatic PTPN11 mutations result in JMML, ALL and AML. The molecular lesions also differ from those in NS with generally less conservative amino acid substitutions that are almost entirely restricted to the N-SH2 domain. In vitro biochemical analyses revealed that the phosphatase activities of the leukemia-associated SHP-2 proteins are generally greater than the NS-associated ones. Finally, the leukemia-associated PTPN11 mutations appear to result in embryonic lethality in humans when transmitted through the germline. Thus, it has been hypothesized that the GOF effects of PTPN11 mutation on signal transduction would be graded with leukemia mutants --> NS/JMML mutants --> NS mutants. The results of the present work with the transgenic csw GOF fly models are consistent with this hypothesis (Oishi, 2006).

The leukemic allele, E76K, caused the earliest lethality when expressed ubiquitously. The A72S allele, which has been shown to be a relatively strong NS allele biochemically, was also lethal. The weakest NS allele, N308D, was not lethal until the dose was increased through transgene homozygosity. Similarly, exposing developing embryos to lower ambient temperatures, which decreases transgene expression, shifted the lethality of the A72S allele to later stages and permitted a few to survive to adulthood; of interest, surviving A72S adult flies had ectopic wing veins. The molecular basis of the GOF strength differences among SHP-2 mutants has been attributed to relative effects on the molecular switching mechanism, an idea that still awaits experimental confirmation. The data presented here provide the first proof that the disease-associated PTPN11 mutations have graded effects on development (Oishi, 2006).

Ubiquitous expression of the csw^N308D transgene results in ectopic wing vein formation. This closely resembles the phenotype resulting from an Egfr GOF allele. Consistent with the well-defined role of EGFR signaling and its activation by ligand stimulation in wing vein development, LOF alleles of nearly all extra- and intra-cellular members of the EGFR-RAS-MAP kinase signaling cascade that promote signaling suppress the csw^N308D-associated phenotype, while loss of negative regulators enhance it. Despite the fact that most disease-associated SHP-2 mutant proteins including N308D have increased basal activity, the data from the fly model reveals that the N308D-induced perturbation of wing development requires an intact ligand and RTK. This is consistent with findings from in vitro studies showing Egf-dependent and Gab1-mediated ERK2 prolonged kinase activity, as well as from frog animal cap studies in which expression of a dominant-negative Fgfr quenched the induction of dorsolateral mesoderm from mutant SHP-2 expression. While the precise basis for this reliance on ligand-induced RTK stimulation has not been elucidated, it is speculated that there are two critical factors. (1) Signaling through RTKs such as EGFR requires ligand-induced phosphorylation of the receptor that then results in recruitment of numerous signaling and docking proteins including SHP-2 and CSW to the plasma membrane. In this context, basally activated SHP-2 or CSW is not physically associated with its requisite signaling partners unless and until the relevant RTK engages ligand. (2) SHP-2 is a positive regulator of signal transduction for many RTK-RAS-MAP kinase pathways, which primarily rely on phosphorylation to propagate their signals. This is true despite the fact that SHP-2 and CSW dephosphorylate RTKs such as PDGFR and Torso. While the elucidation of the full range of bona fide SHP-2 substrates continues to be pursued, two defined SHP-2 substrates, PAG/cbp and Paxillin, negatively regulate RTK-RAS signaling. SHP-2 dephosphorylates these substrates, preventing them from recruiting Csk, which, in turn, is a negative regulator of Src family kinases. While loss of SHP-2 activity reduces RAS signaling, SHP-2 GOF should not be sufficient to initiate it. Taken together, these two factors provide a rationale for the finding that reduction of EGFR or its ligand, Vein, suppresses the formation of ectopic wing veins from N308D (Oishi, 2006).

Another striking finding observed with the csw GOF alleles was the pleomorphism of effects among RTK pathways in which CSW participates. Development of the trachea, dorsal tube and photoreceptor R7, structures dependant upon Breathless, Heartless and Sevenless signaling, respectively, were not altered. The domains of tailless expression in the anterior and posterior poles, which have been used as a read out of Torso signaling and diminish with loss of maternal CSW, showed no augmentation from CSW GOF. The pleomorphism was also present among structures whose development is EGFR-signaling dependent: N308D expression altered wing vein formation but did not affect photoreceptor development. Thus, it is concluded that the CSW GOF mutants alter signal transduction in a selective and specific manner. This is consistent with the findings in NS, in which the GOF SHP-2 protein is ubiquitously expressed but the phenotype reflects developmental abnormalities occurring in a tissue- and stage-specific manner. In addition to that specificity, increased MAP kinase activation in the Ptpn11D61G knock-in model mice was noted only in specific tissues (Oishi, 2006).

What is the basis for the specificity in developmental abnormalities arising from SHP-2/CSW GOF? (1) GOF SHP-2 might dephosphorylate substrates promiscuously, thereby recruiting non-canonical signaling affecting specific developmental processes. In support of this, MAP kinase activation proved necessary but not sufficient for generating the CSW GOF phenotypes. Moreover, N308D expression recruited JAK/STAT signaling in the context of wing vein development, a non-canonical interaction. Of note, a similar phenomenon was observed for Torso signaling in which the effects of a torso GOF allele required STAT activation even though the JAK/STAT pathway plays no role in Torso signaling ordinarily. (2) There may be a critical developmental window that is dependent upon the dosage of SHP-2/CSW and/or MAP kinase activity. The tolerance to variability in these activities may differ among signaling pathways and between tissues for a given pathway. A comparison of the phenotypes observed in the N308D transgenic and the GOF Egfr^E1 flies provides an example of the latter. Although both alleles increase MAP kinase activation in the context of EGFR signaling, the former resulted in ectopic wing veins while the latter exhibited ectopic veins and a rough eye phenotype. The rough eye phenotype in Egfr^E1 flies is a LOF EGFR phenotype as a result of negative feedback caused by high expression of a negative regulator, Argos, which is induced by GOF EGFR activity. Argos inhibits EGFR signaling by binding to an activating ligand, Spitz. In contrast, the NS GOF CSW appears to cause high, nonconstitutive EGFR signal activation, which apparently does not increase the argos expression level enough to induce the EGFR LOF phenotype during photoreceptor development. It is likely that there is a distinct difference (although it may be subtle) in the levels of EGFR signaling activity between these two models and it determines the phenotypic pattern. In particular, specificity of the developmental abnormality seems to be established by the level of increased signaling activity caused by the NS alleles in a given pathway and by a specific requirement of a fine-tuned signaling activity for normal development in a given tissue and/or cell type. This idea is supported by work showing that there are multiple distinct thresholds of required EGFR signaling activity in different cell types during retinal development. In contrast, EGFR signaling in wing vein specification predominantly uses the ligand, Vein, a neuregulinlike molecule. Vein is a relatively weak ligand, which is proposed to be required for the tight basal control of the level of EGFR/RAS/MAP kinase pathway signaling during wing vein specification. Thus, the more modest increased EGFR signaling induced by CSW GOF alleles is still sufficient to induce ectopic veins (Oishi, 2006).

The N308D allele interacts genetically with several genes from the EGFR/RAS/MAP kinase pathway as well as some from the Notch, DPP (BMP), and JAK/STAT pathways. The degree of the suppression or enhancement of the interacting genes varies. While some of this variability could be attributed to allelism (e.g., null vs hypomorphic alleles for a single gene), it is apparent that there are differences in the intensity of the epistatic effects between interacting genes. A fuller elucidation of these epistatic genes might provide clues for understanding the clinical variability in NS. The phenotype of NS is variable among patients sharing the same PTPN11 mutation, even within families. Phenotypic variability was also observed in Ptpn11D61G knock-in mice, in which the cardiac phenotype was dependent upon the genetic background. While stochastic effects may explain some of the variability in NS patients, the results of epistatic studies underscore the fact that the PTPN11 mutant alleles are interacting with a variety of signal pathways, some finely balanced, such that relatively minor differences in gene expression or protein activities might significantly alter the phenotype (Oishi, 2006).

Congenital heart disease is a prominent feature of NS. Pulmonary valve stenosis is the most common cardiac defect and is particularly prevalent among NS patients with PTPN11 mutations. To date, the specific molecular mechanism underlying pulmonary stenosis in NS is unknown. Recent cardiac embryologic studies have shown that a delicate regulation of a variety of signaling pathways including VEGF, Notch, Wnt/ß-catenin, TGFß, BMP, and EGFR are important for valvulogenesis. Altered signaling leads to aberrant endothelial-mesenchymal transformation during cardiac valve cushion formation or remodeling of those cushions. Interestingly, the critical pathways for valvulogenesis are conserved in Drosophila and play essential roles for wing vein development (Oishi, 2006).

he phosphatase SHP2 regulates the spacing effect for long-term memory induction

A property of long-term memory (LTM) induction is the requirement for repeated training sessions spaced over time. This augmentation of memory formation with spaced resting intervals is called the spacing effect. In Drosophila, the duration of resting intervals required for inducing LTM is regulated by activity levels of the protein tyrosine phosphatase corkscrew (Csw). Overexpression of wild-type Csw in mushroom body neurons shortens the inter-trial interval required for LTM induction, whereas overexpression of constitutively active Csw proteins prolongs these resting intervals. These gain-of-function csw mutations are associated with a clinical condition of mental retardation. Biochemical analysis reveals that LTM-inducing training regimens generate repetitive waves of Csw-dependent MAPK activation, the length of which appears to define the duration of the resting interval. Constitutively active Csw proteins prolong the resting interval by altering the MAPK inactivation cycle. This study thus provides insight into the molecular basis of the spacing effect (Pagani, 2009).

This work began with the study of the effects of clinically relevant GOF csw mutations on learning and memory and led to the discovery that Csw plays a critical role in the regulation of the spacing effect for induction of LTM. Several measures were employed to minimize biologic variation, including the use of an isogenic background for all genotypes examined, identical rearing and testing conditions, and batching the analysis for all data presented in the same figure. In addition, multiple mutant alleles were used to support any phenotypes observed. Finally, alternative approaches such as pharmacologic inhibition or RNAi were used when possible to bolster the initial observation (Pagani, 2009).

Among the several functions of Csw, its phosphatase activity seems to be critical for LTM induction. Pharmacological phosphatase inhibition in wild-type fruit flies disrupted LTM, overexpression of phosphatase-dead Csw had no effect on memory formation, and NS- and leukemia-associated Csw mutants share the biochemical feature of having elevated phosphatase activity (Pagani, 2009).

The adverse effects of the GOF Csw on LTM formation are likely mediated through Csw-regulated Ras/MAPK activity. Csw is a key signaling relay in pathways in C. elegans, Drosophila, Xenopus and mammals. The data indicated that GOF Csw deregulated the training-dependent MAPK activation/inactivation. Thus, the most parsimonious interpretation is that csw GOF mutations alter the time course of the activity of the MAPK pathway in such a way that a longer resting period between training sessions is required for promoting normal memory formation (Figure 6D) (Pagani, 2009).

Although the Ras/MAPK pathway is crucial for growth and differentiation, it was interesting to note that the defects in LTM formation associated with GOF Csw were not developmental. Thus, this study together with an increasing body of evidence suggest that the receptor tyrosine kinase-activated Ras/MAPK pathway might be a conserved mechanism from Drosophila to vertebrates and even humans in mediating memory formation (Pagani, 2009).

This study has shown that genetic manipulation can modify the resting interval needed for the induction of LTM. In Drosophila, the spacing effect is well defined phenomenologically and it is used as a behavioral strategy to induce protein synthesis-dependent LTM. It was previously established that LTM can be elicited with 10 repetitive training trials with an optimal spacing of 15 min, and this study showed that LTM is equally well formed as the rest interval is lengthened to 30-40 min. More strikingly, the minimum duration was shortened to 150 sec for transgenic fruit flies overexpressing wild-type csw, but was prolonged to 40 min in transgenic fruit flies with overexpression of GOF Csw mutants. Of note, even though a 150-sec inter-trial was enough to induce LTM in fruit flies overexpressing wild-type csw, a longer interval did not produce more memory as only a small increase in performance was detected by using 30 or 40 min of spacing (Pagani, 2009).

A biochemical correlate of this resting-interval dependence for LTM induction emerged from the analysis of MAPK activation patterns (see Schematic Representations of Training-Regulated MAPK Activity Correlated with Training Protocol and Genotype). For clarity, For wild-type flies subjected to spaced training, MAPK is activated during each 15-min rest interval and is reset to the basal level by the following training cycle. Thus, there is a wave of MAPK activity after each training trial, making for 10 peaks in all. In contrast, in massed training, there is only one peak of MAPK activity, which occurs 15-20 min after finishing the 10th training trial. For fruit flies overexpressing wild-type Csw, however, massed training does create 10 waves of MAPK activation due to the faster MAPK activation combined with a normal post-trial resetting mechanism. Although MAPK may also be activated faster in transgenic fruit flies overexpressing GOF Csw mutants, this activity is not reset by the subsequent training trial, apparently due to the slower kinetics for its decay. Therefore, the standard spaced training protocol with 15 min rest intervals engenders altered MAP activity peaks in these mutant Csw transgenic fruit flies, resulting in an LTM deficit. This is supported by the observation that lengthening the inter-trial interval to 40 min, which presumably provides more time for the decay of the MAPK activity, rescues LTM formation by restoring MAPK activation waves. Taken together, these finding suggests that Csw-dependent MAPK activation is involved in defining the duration of resting intervals necessary for LTM induction (Pagani, 2009).

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date revised: 20 December 2012

 

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