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Especially transcripts coding for transcription factors such as grh and CrebA are affected. Likewise, the expression of CG and CG , both encoding factors involved in the synthesis of the dolichol-anchored oligosaccharide, is down-regulated in wol maternal and zygotic mutant larvae.
Reduction in Knk amounts may result from proteasome-mediated degradation of the protein caused by the unfolded protein response pathway that occurs in wol mutant embryos Supplementary Data ; Haecker et al.
The unfolded protein response has also been reported to induce decay of mRNA associated with the ER membrane coding for proteins to be loaded into the ER Hollien and Weissman Mutations in wol reduce the expression of caudal mRNA that codes for a homeobox containing transcription factor Haecker et al.
The amounts of grh and CrebA transcripts are lowered in these embryos. Taken together, Wol activity has an influence on grh and CrebA transcript levels.
In conclusion, through downscaling of mRNA of especially transcription factors, the suppressed activities of a plethora of differentiation factors may contribute to wol -dependent defects observed in epidermal cells involved in cuticle production.
Wol is a key enzyme for glycosylation taking place in the ER. To inspect whether wol mutations have an influence on ER morphology, we examined the ultrastructure of the ER in stage 16 embryos, which have initiated cuticle production.
In the respective embryos suffering loss of maternal and zygotic Wol activity, in contrast, ER tubules are rather smooth.
Wol is associated with the ER and influences its capacity. Ultrastructure of the epidermal ER of wild-type and wol mutant stage 16 embryos by electron microscopy.
During cuticle production, the epidermal cell contains cystic ER tubules C. In the absence of Wol activity, the ER fails to form cysts and consists rather of straight tubules D.
In wol mutant embryos, N -glycans contain markedly less glucose units than in wild-type embryos, especially the second and the third Glc residues are almost undetectable in wol mutant embryos.
The significance of this observation is not obvious. Wol activity is crucial for glycan composition and amounts. Terminal Glc residues are almost eliminated in wol mutant larvae.
The addition of fucoses to the oligosaccharide is normal in wol mutant embryos. This finding suggests that hypoglucosylated proteins are correctly passed through the secretory pathway.
Modification of N -glycans in the Golgi apparatus is not affected in embryos with eliminated Wol activity. N, N -acetylglucosamine; H, hexose mannose or galactose ; F, fucose.
N -Glycan nomenclature is according to the Proglycan system http: Taken together, Wol activity is needed for full glucosylation of proteins, underlining that it is indeed the Drosophila Alg5 ortholog.
An early role of N-glycosylation in the ER is to initiate the folding reaction of proteins for correct localization and function.
Recognition of the yet unfolded protein depends on a single glucose residue at the N -glycan. The importance of glucosylation of N -glycans has mainly been investigated in yeasts and cultured cells.
To understand the role of the N -glycan glucose in a multicellular organism, we have studied the role of Drosophila Wol DAlg5 and Gny DAlg6 that regulate early steps of glucosylation at the ER membrane.
Mutations in wol in Drosophila disrupt the architecture of the larval cuticle, which is an apical ECM produced by the epidermal cells.
Stepwise reduction in Wol activity results in a gradual worsening of cuticle defects ranging from small lesions in the procuticle of zygotic mutant larvae, over mislocalized cuticle proteins in maternally mutant but zygotic wild-type larvae to chitin disorganization and protein depletion upon additional removal of zygotic enzyme activity.
These observations signify that the amount of Wol activity provided by zygotic expression alone is not sufficient but nevertheless necessary to support embryogenesis, whereas maternal supply of Wol only is despite some tolerable errors adequate for development until after first moulting of the larva.
Hence, the rate of glucosylation is critical for embryogenesis and development in general and cuticle differentiation in particular.
One may postulate that hypoglucosylation yields fewer biochemically active extracellular and membrane-bound proteins, a situation that may retard especially secretion-related aspects of differentiation.
However, perturbed plasma membrane and cuticle organization cannot be satisfactorily explained by slower development.
This is a similar scenario encountered when chitin synthesis is decreased but not abrogated upon application of insecticides Gangishetti et al.
In brief, the epidermal system is unable to cope with biochemical attenuation of chitin synthesis implying that the activities of the cooperating factors are tightly adjusted and coordinated.
Full interpretation of the wol phenotypes, thus, probably also calls for the assumption of problems in coordination between effectors.
Our molecular data discussed in the following deal with these genetic arguments. N -Glycans are hypoglucosylated in wol mutant embryos that concomitantly suffer reduced glycosylation.
One can envisage two explanations for these observations. A simple one is that the glucose residues of the oligosaccharide have an influence on the rate of glycosylation.
In yeast, indeed, glucose residues on the oligosaccharide have been demonstrated to enhance the activity of the OST Burda et al. Problems with glucosylation possibly lower the output of the ER that exhibits a depleted morphology in epidermal cells at the onset of cuticle deposition in wol mutant embryos.
In addition, elimination of Wol function induces lessening of transcripts coding for enzymes involved in dolichol-anchored oligosaccharide synthesis, an effect that contributes to the attenuated ER flow-through.
The activity of the ER luminal UDP-glucose transferase adding a glucose to the unglucosylated N -glycan and the supply with auxiliary chaperones incited by the unfolded protein response apparently do not suffice to normalize ER function.
At the contrary, unfolded protein response is probably also responsible for reduced N -glycans and perturbed differentiation.
Indeed, the consequences of the unfolded protein response—suppression of transcription and translation Ruddock and Molinari ; Malhotra and Kaufman —constitute the second explanation for the defects including O -glycan decimation caused by wol mutations.
Despite the initial problems at the gate of secretion, reduced glycosylation and hypoglucosylation seem not to interfere with modifications of proteins in the Golgi apparatus and correct localization of N-glycosylated proteins to the plasma membrane or the extracellular space.
Consequently and in agreement with our genetic argument stated in the previous section Glucosylation promotes cuticle differentiation , the wol mutant phenotype could be described as the sum of reduction in membrane and extracellular protein activities through hypoglucosylation and the unfolded protein response.
This argument implies that passage through the secretory route per se does not depend on glucosylation. Consistently, in Saccharomyces cerevisiae cells, deletion of either alg5 or alg6 does not result in growth defects indicating that secretion is normal despite hypoglucosylation Heesen et al.
A particular feature of wol mutant defects is the lowering of Knk amounts and the accumulation of Crb in the apical plasma membrane.
Decrease in Knk may in part be responsible for loss of chitin orientation and procuticle organization in wol mutant larvae Moussian, Tang et al.
Hence, if we generalize our findings, one may argue that Wol activity contributes to equilibrate the activity of factors that direct epidermal differentiation.
In other words, glucosylation is critical for balanced and robust differentiation, either directly as a step of glycosylation or indirectly by preventing the unfolded protein response.
Attenuated translation and protein degradation may conceivably explain the consequences of wol mutations on Knk, but not on Crb.
The behavior of Crb in wol mutant embryos rather exemplifies that some proteins may gain function out of their normal context through the deleterious effects of wol deficiency.
In the case of Crb, this may indirectly follow from depletion of a factor participating at the complex mechanisms of Crb positioning in the apical plasma membrane.
In line with this view, absence of the recycling endosome syntaxin Avalanche causes accumulation of Crb in the apical plasma membrane of various epithelial cells in Drosophila Lu and Bilder Alternatively, deviation of normal apical plasma membrane dynamics may start with aPKC that has been shown to support Crb localization by phosphorylation Sotillos et al.
In this scenario, the wol -induced unfolded protein response may by an unknown mechanism lead to the concentration of aPKC at the apical plasma membrane and thereby stabilize Crb localization.
In any case, the differential response of proteins to glycosylation including Wol function may reflect a glycosylation-dependent mechanism of adjusting the stoichiometry of factors that assemble the cuticle in a certain time window during differentiation.
Elaborate genetic tools comprising wol will be required to test this hypothesis. Mutations have been identified in the human alg6 , but not in the human alg5 gene Jaeken and Matthijs , ; Freeze Patients carrying alg6 mutations suffer a plethora of developmental and physiological defects, but survive at least a few years.
Hence, these mutations either do not eliminate enzyme activity completely or like in Drosophila the putative maternal product are sufficient to support development.
In cultured fibroblasts of alg6 mutant patients, the amounts of the non-glucosylated dolichol-linked oligosaccharide Man 9 GlcNAc 2 are increased at the expense of the fully glucosylated Glc 3 Man 9 GlcNAc 2.
By consequence, serum transferrin is hypoglycosylated and therefore probably inactive in these patients. In Drosophila , in contrast, as demonstrated for Knk, extracellular and membrane-associated proteins are probably not hypoglycosylated.
This difference may point to a species-specific substrate affinity of the OST that transfers the oligosaccharide to the protein in the ER lumen.
Even though the presence of glucose has a greater importance for glycosylation in humans, the trace amounts of dolichol-linked oligosaccharide argue that reduced Alg6 function may lead to a dampened and disordered secretion as it occurs in Drosophila as well.
Thus, the use of Drosophila as a model system may help to elucidate the molecular basis of human CDG. A P-element inserted into the third exon of the gene is available at the Bloomington stock centre.
Following Drosophila practice to baptize mutations, this mutation was called gny , Swedish for wool ball, which means Wollknäuel in German.
The gny P-element was recombined to the FRT site on the cytologic position 42D for generation of germline clones as described in the next paragraph.
For collection of homozygous mutant embryos and larvae, fly stocks segregating the respective mutation balanced over CyO , Kr: GFP were kept in cages on apple juice agar plates spotted with fresh yeast paste.
For subsequent experiments, embryos were staged after Hartenstein and Campos-Ortega The day before transfection, 0.
On the day of transfection, cells were incubated with serum-free medium. For optimizing the transfection efficiency, transfection was done using two different ratios 8: For transfection, the solution was added drop wise to the cells.
Seventy-two hours after transfection, S2 cells were plated on 0. Permeabilization was done with 0. Cells were washed with PBS. The slides were observed by confocal microscopy as described in the next section.
For immunohistochemical experiments, dechorionated embryos were fixed at the interface of heptane and 3. The fixative was removed and replaced by methanol, and embryos were devitellinized by vigorous shaking.
The following day, the embryos were rehydrated gradually with PBS supplemented with 0. Embryos were then washed five times with PBST and deposited on a slide.
Laser scanning confocal microscopy of immunodetected epitopes was performed on an Olympus confocal microscope. For transmission electron microscopy, specimens were prepared and analyzed according to the method described previously Moussian, Seifarth et al.
Data analysis was performed using MassLynx 4. After gel electrophoresis, proteins were transferred to a nitrocellulose membrane Whatman, Dassel, Germany by the semi-dry method.
Western blots using Knk antiserum were performed as described previously Moussian, Tang et al. Oxford University Press is a department of the University of Oxford.
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Close mobile search navigation Article navigation. The Alg5 ortholog Wollknäuel is essential for correct epidermal differentiation during Drosophila late embryogenesis Khaleelulla Saheb Shaik.
Glycobiology , Volume 21, Issue 6, 1 June , Pages —, https: Abstract The formation of an extracellular matrix ECM presupposes an ordered delivery of its components to ensure its stereotypic architecture.
View large Download slide. Glycosylation is reduced in wol maternal and zygotic mutant embryos. A novel carbohydrate-deficient glycoprotein syndrome characterized by a deficiency in glucosylation of the dolichol-linked oligosaccharide.
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Congenital disorders of glycosylation: A rapidly expanding disease family. Allosteric regulation provides a molecular mechanism for preferential utilization of the fully assembled dolichol-linked oligosaccharide by the yeast oligosaccharyltransferase.
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Review of their molecular bases, clinical presentations and specific therapies. Recent advances in understanding mechanisms of insect cuticle differentiation.
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