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1.
The microtubule-binding protein tau has been investigated for its contribution to various neurodegenerative disorders. However,
the findings from transgenic studies, using the same tau transgene, vary widely among different laboratories. Here, we have investigated the potential mechanisms underlying tauopathies
by comparing Drosophila (d-tau) and human (h-tau) tau in a Drosophila model. Overexpression of a single copy of either tau isoform in the retina results in a similar rough eye phenotype. However, co-expression of Par-1 with d-tau leads to lethality, whereas co-expression of Par-1 with h-tau has little effect on the rough eye phenotype. We have found analogous results by comparing larval proteomes. Through genetic
screening and proteomic analysis, we have identified some important potential modifiers and tau-associated proteins. These
results suggest that the two tau genes differ significantly. This comparison between species-specific isoforms may help to clarify whether the homologous
tau genes are conserved.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users.
This study was supported by the National Science Foundation of China (30270341; 30630028), the Multidisciplinary Program (Brain
and Mind) of the Chinese Academy of Sciences, the Major State Basic Research Program (“973 program”; G2000077800; G2006CB806600;
2006CB911003), the Precedent Project of Important Intersectional Disciplines in the Knowledge Innovation Engineering of the
Chinese Academy of Sciences (KJCX1-09-03). 相似文献
2.
Tauopathies are a group of neurodegenerative disorders characterised by altered levels of phosphorylation or mutations in
the neuronal microtubule protein Tau. The heterogeneous pathology of tauopathies suggests differential susceptibility of different
neuronal types to wild-type and mutant Tau. The genetic power and facility of the Drosophila model has been instrumental in exploring the molecular aetiologies of tauopathies, identifying additional proteins likely
contributing to neuronal dysfunction and toxicity and novel Tau phosphorylations mediating them. Importantly, recent results
indicate tissue- and temporal-specific effects on dysfunction and toxicity coupled with differential effects of distinct Tau
isoforms within them. Therefore, they reveal an unexpected richness of the Drosophila model that, coupled with its molecular genetic power, will likely play a significant role in our understanding of multiple
tauopathies potentially leading to their differential treatment. 相似文献
3.
4.
The Drosophila segment polarity gene fused, which encodes a serine threonine kinase, is required to transmit the Hedgehog (Hh) signal in imaginal discs. To explore the functional homology between the human protein FUSED (hFU) and the Drosophila protein fused (dFu), we have subjected hFU to a precise and well-defined Hh signalling assay of Drosophila wing development. In the wildtype, hFU affects the expression of Hh target genes leading thus to defects in adult wings. In fu mutants, overexpression of hFU cannot rescue the fu phenotype. These results suggest that hFU in Drosophila interferes with endogenous Hh signalling probably by competing with endogenous dFu when binding its partners but cannot perform the normal Fu function.Edited by C. Desplan 相似文献
5.
Heparan sulfate proteoglycans play a vital role in signaling of various growth factors in both Drosophila and vertebrates. In Drosophila, mutations in the tout
velu (ttv) gene, a homolog of the mammalian EXT1 tumor suppressor gene, leads to abrogation of glycosaminoglycan (GAG) biosynthesis. This impairs distribution and signaling
activities of various morphogens such as Hedgehog (Hh), Wingless (Wg), and Decapentaplegic (Dpp). Mutations in members of
the exostosin (EXT) gene family lead to hereditary multiple exostosis in humans leading to bone outgrowths and tumors. In this study, we provide
genetic and biochemical evidence that the human EXT1 (hEXT1) gene is conserved through species and can functionally complement the ttv mutation in Drosophila. The hEXT1 gene was able to rescue a ttv null mutant to adulthood and restore GAG biosynthesis. 相似文献
6.
Centromeres are specialized chromosomal domains that direct mitotic kinetochore assembly and are defined by the presence of
CENP-A (CID in Drosophila) and CENP-C. While the role of CENP-A appears to be highly conserved, functional studies in different organisms suggest that
the precise role of CENP-C in kinetochore assembly is still under debate. Previous studies in vertebrate cells have shown
that CENP-C inactivation causes mitotic delay, chromosome missegregation, and apoptosis; however, in Drosophila, the role of CENP-C is not well-defined. We have used RNA interference depletion in S2 cells to address this question and
we find that depletion of CENP-C causes a kinetochore null phenotype, and consequently, the spindle checkpoint, kinetochore–microtubule
interactions, and spindle size are severely misregulated. Importantly, we show that CENP-C is required for centromere identity
as CID, MEI-S332, and chromosomal passenger proteins fail to localize in CENP-C depleted cells, suggesting a tight communication
between the inner kinetochore proteins and centromeres. We suggest that CENP-C might fulfill the structural roles of the human
centromere-associated proteins not identified in Drosophila. 相似文献
7.
The Alhambra ( Alh) gene is the Drosophila homologue of the human AF10 gene. AF10 has been identified as a fusion partner of MLL, a human homologue of the fly gene trithorax, in infant leukemias. The endogenous function of human AF10 is not known, but may be vital to its role in acute leukemia. This prompted us to analyse Alh function. We describe here the genetic organisation of the Alh locus in D. melanogaster. We show that an independent lethal complementation group encoding a muscle protein ( Mlp84B) is located within an Alh intron. We have already shown that the leucine zipper (LZ) domain of ALH activates several Polycomb group-responsive elements. We further demonstrate that the LZ domain on its own bears the Alh vital function, since it is necessary and sufficient for rescue of Alh mutant lethality. Finally, we demonstrate that, in contrast to a previous report, Alh does not affect position-effect variegation.Communicated by G. Reuter 相似文献
8.
<Emphasis Type="Italic">Rab11</Emphasis> is required for embryonic nervous system development in <Emphasis Type="Italic">Drosophila</Emphasis> 总被引:1,自引:1,他引:0
In eukaryotes, membrane trafficking is regulated by the small monomeric GTPases of Rab protein family. Rab11, an evolutionary
conserved, ubiquitously expressed subfamily of the Rab GTPases, has been implicated in the regulation of vesicular trafficking
through the recycling of endosomes. To dissect out the role of this protein during embryonic nervous system development, we
have studied the expression pattern of Rab11 in the ventral nerve cord during neuronal differentiation in the Drosophila embryo. When the dominant-negative or constitutively-active mutant DRab11 proteins are expressed in neurons, or when homozygous
mutant Rab11 embryos are analyzed, defects are found in the developing central nervous system, along with disorganization
and misrouting of embryonic axons. Our results provide the first in vivo evidence that Rab11 is involved in the development of the nervous system during Drosophila embryogenesis.
This work was supported by the DST (to J.K.R.) and SRF from ICMR, New Delhi (to T.B.). 相似文献
9.
Seng-Sheen Fan Mei-Sue Chen Jui-Fen Lin Wei-Ting Chao Vivian Cheng Yang 《Journal of biomedical science》2003,10(6):766-773
The cell polarity gene,crumbs (crb), has been shown to participate in the development and degeneration of theDrosophila retina. Mutations inCRB1, the human homologue ofDrosophila crb, also result in retinitis pigmentosa and Leber congential amaurosis. In this study, we used the gain-of-function approach to delineate the roles ofcrb in developingDrosophila eye. In the third-instar larval stage, eye development is initiated with photoreceptor differentiation and positioning of photoreceptor nuclei in the apical cellular compartment of retinal epithelium. In the pupal stage, differentiated photoreceptors begin to form the photosensitive structures, the rhabdomeres, at their apical surface. UsingGMR-Gal4 to drive overexpression of the Crb protein at the third-instar eye disc, we found that differentiation of photoreceptors was disrupted and the nuclei of differentiated photoreceptors failed to occupy the apical compartment. Usinghs-Gal4 to drive Crb overexpression in pupal eyes resulted in interference with extension of the adherens junctions and construction of the rhabdomeres, and these defects were stage-dependent. This gain-of-function study has enabled us to delineate the roles of Crb at selective stages of eye development inDrosophila. 相似文献
10.
11.
Mecklenburg KL 《Molecular genetics and genomics : MGG》2007,277(5):481-489
The function of conserved novel human genes can be efficiently addressed in genetic model organisms. From a collection of
genes expressed in the Drosophila visual system, cDNAs expressed in vertebrates were identified and one similar to a novel human gene was chosen for further
investigation. The results reported here characterize the Drosophila retinophilin gene and demonstrate that a similar gene is expressed in the human retina. The Drosophila and human retinophilin sequences are 50% identical, and they share an additional 16% conserved substitutions. Examination
of the cDNA and genomic sequence indicates that it corresponds to the gene CG10233 of the annotated genome and predicts a
22.7 kDa protein. Polyclonal antibodies generated to a predicted retinophilin peptide recognize an antigen in Drosophila photoreceptor cells. The retinophilins encode 4 copies of a repeat associated with a Membrane Occupation and Recognition
Nexus (MORN) function first discovered in junctophilins, which may interact with the plasma membrane. These results therefore
show that Drosophila retinophilin is expressed in fly photoreceptor cells, demonstrate that a conserved human gene is expressed in human retina,
and suggest that a mutational analysis of the Drosophila gene would be valuable. 相似文献
12.
Ping Li Jianjian Peng Jiangbo Hu Zhongxin Xu Wei Xie Liudi Yuan 《Molecular biology reports》2011,38(1):355-358
MicroRNAs (miRNAs) are a kind of endogenous non-coding small RNAs whose specific functions in animals are generally important.
Although functions of some miRNAs have been identified, the role of miR-184 remains unknown. Here, we determined the temporal
and spatial expression pattern of miR-184 during the different development stages and tissues in Drosophila. Strikingly, miR-184 is expressed ubiquitously in Drosophila embryos, larvae and adults, its expression pattern shows a dynamic changes during the development of embryo, especially in
the central nervous system. This expression profile suggests that miR-184 may act important function in Drosophila development. 相似文献
13.
Rab11, an evolutionarily conserved, ubiquitously expressed subfamily of small monomeric Rab GTPases, has been implicated in
regulating vesicular trafficking through the recycling of endosomal compartment. In order to gain an insight into the role
of this gene in myogenesis during embryonic development, we have studied the expression pattern of Rab11 in mesoderm during
muscle differentiation in Drosophila embryo. When dominant-negative or constitutively active Drosophila Rab11 proteins are expressed or Rab11 is reduced via double-stranded RNA in muscle precursors, they cause partial failure
of myoblast fusion and show anomalies in the shape of the muscle fibres. Our results suggest that Rab11 plays no role in cell fate specification in muscle precursors but is required late in the process of myoblast fusion.
This work was supported by grants from the DST (to J.K.R.) and SRF from ICMR, New Delhi (to T.B.). 相似文献
14.
Casad ME Yu L Daniels JP Wolf MJ Rockman HA 《Molecular genetics and genomics : MGG》2012,287(4):351-360
Drosophila is a useful model organism in which the genetics of human diseases, including recent advances in identification of the genetics
of heart development and disease in the fly, can be studied. To identify novel genes that cause cardiomyopathy, we performed
a deficiency screen in adult Drosophila. Using optical coherence tomography to phenotype cardiac function in awake adult Drosophila, we identified Df(1)Exel6240 as having cardiomyopathy. Using a number of strategies including customized smaller deletions, screening of mutant alleles,
and transgenic rescue, we identified CG3226 as the causative gene for this deficiency. CG3226 is an uncharacterized gene in
Drosophila possessing homology to the mammalian Siah-interacting protein (SIP) gene. Mammalian SIP functions as an adaptor protein involved
in one of the β-catenin degradation complexes. To investigate the effects of altering β-catenin/Armadillo signaling in the
adult fly, we measured heart function in flies expressing either constitutively active Armadillo or transgenic constructs
that block Armadillo signaling, specifically in the heart. While, increasing Armadillo signaling in the heart did not have
an effect on adult heart function, decreasing Armadillo signaling in the fly heart caused the significant reduction in heart
chamber size. In summary, we show that deletion of CG3226, which has homology to mammalian SIP, causes cardiomyopathy in adult
Drosophila. Alterations in Armadillo signaling during development lead to important changes in the size and function of the adult heart. 相似文献
15.
Polycomb group (PcG) proteins are required to maintain a stable repression of the homeotic genes during Drosophila development. Mutants in the PcG gene Supressor of zeste 12 (Su(z)12) exhibit strong homeotic transformations caused by widespread misexpression of several homeotic genes in embryos and larvae.
Su(z)12 has also been suggested to be involved in position effect variegation and in regulation of the white gene expression in combination with zeste. To elucidate whether SU(Z)12 has any such direct functions we investigated the binding pattern to polytene chromosomes and
compared the localization to other proteins. We found that SU(Z)12 binds to about 90 specific eukaryotic sites, however, not
the white locus. We also find staining at the chromocenter and the nucleolus. The binding along chromosome arms is mostly in interbands
and these sites correlate precisely with those of Enhancer-of-zeste and other components of the PRC2 silencing complex. This
implies that SU(Z)12 mainly exists in complex with PRC2. Comparisons with other PcG protein-binding patterns reveal extensive
overlap. However, SU(Z)12 binding sites and histone 3 trimethylated lysine 27 residues (3meK27 H3) do not correlate that well.
Still, we show that Su(z)12 is essential for tri-methylation of the lysine 27 residue of histone H3 in vivo, and that overexpression of SU(Z)12 in somatic
clones results in higher levels of histone methylation, indicating that SU(Z)12 is rate limiting for the enzymatic activity
of PRC2. In addition, we analyzed the binding pattern of Heterochromatin Protein 1 (HP1) and found that SU(Z)12 and HP1 do
not co-localize. 相似文献
16.
The Drosophila melanogaster broad locus is essential for normal metamorphic development. Broad encodes three genetically distinct functions (rbp, br, and 2Bc) and a family of four zinc-finger DNA-binding proteins (Z1-Z4). The Z1, Z2, and Z3 protein isoforms are primarily associated with the rbp, br, and 2Bc genetic functions respectively. The Z4 protein isoform also provides some rbp genetic function, however an essential function for the Z4 isoform in metamorphosis has not been identified. To determine the degree of conservation of Z4 function between the tobacco hornworm Manduca sexta and Drosophila we generated transgenic Drosophila expressing the Manduca broad Z4 isoform and used this transgene to rescue rbp mutant lethality during Drosophila metamorphosis. We find that the Manduca Z4 protein has significant biological activity in Drosophila with respect to rescue of rbp-associated lethality. There was also some overlap in effects on cuticle gene expression between the Manduca Z4 and Drosophila Z1 isoforms that was not shared with the Drosophila Z4 isoform. Our findings show that Z4 function has been conserved over the 260-million-year period since the divergence of Diptera and Lepidoptera, and are consistent with the hypothesis that the Drosophila Z4 and Manduca Z4 isoforms have essential roles in metamorphosis.Edited by M. Akam 相似文献
17.
Mitochondria play essential roles in development and disease. The characterisation of mitochondrial proteins is therefore of particular importance. The slowmo (slmo) gene of Drosophila melanogaster has been shown to encode a novel type of mitochondrial protein, and is essential in the developing central nervous system. The Slmo protein contains a conserved PRELI/MSF1p domain, found in proteins from a wide variety of eukaryotic organisms. However, the function of the proteins of this family is currently unknown. In this study, the evolutionary relationships between members of the PRELI/MSF1p family are described, and we present the first analysis of two novel Drosophila genes predicted to encode proteins of this type. The first of these, preli-like (prel), is expressed ubiquitously during embryonic development, whilst the second, real-time (retm), is expressed dynamically in the developing gut and central nervous system. retm encodes a member of a novel conserved subclass of larger PRELI/MSF1p domain proteins, which also contain the CRAL-TRIO motif thought to mediate the transport of small hydrophobic ligands. Here we provide evidence that, like Slmo, both the Prel and Retm proteins are localised to the mitochondria, indicating that the function of the PRELI/MSF1p domain is specific to this organelle.Edited by P. Simpson 相似文献
18.
Overexpression of epidermal growth factor receptor (EGFR) is a common phenomenon observed in most cancers. Clinical treatment
of such cancer involves the use of chemotherapeutic agents such as gefitinib and erlotinib which are inhibitors of tyrosine
kinase (TK). These small molecules bind to the ATP-binding sites of the TK domain of EGFR. Our in silico analysis suggests that the TK domains of Drosophila and human EGFR are highly conserved. We therefore employed the Drosophila system to validate the in silico observations made with two important anticancer drugs. Since a large number of mutant flies are available, it was possible
to investigate the various components of the EGFR/Ras/Raf/ MAPK pathways and the phosphorylation status of diphosphorylated
extracellular signal-regulated kinase (dp-ERK1/2). These studies confirm the binding of the anilinoquinazolines to the Drosophila EGFR protein and modulation of its activity. Thus, Drosophila appears to be a robust and simple model system for screening newer anticancer drugs that act as TK inhibitors (TKIs).
Electronic Supplementary Material Supplementary material is available for this article at and is accessible for authorized users.
Supplementary figures and tables pertaining to this article are available on the Journal of Biosciences Website at http://www.ias.ac.in/jbiosci/dec2008/pp731-742-suppl.pdf 相似文献
19.
Every population possesses genetic variations which are achieved through gene mutation, genetic recombination, hybridization, gene duplication etc. These genetic variations provide raw materials for evolutionary forces to create a better surviving species. Genetic polymorphism is reflected at every level in the populations, for example, at phenotypic, chromosomal, protein and DNA levels. Protein or enzyme polymorphisms have been well studied in various organisms including Drosophila and humans. Drosophila has proven to be a good model organism for carrying out polymorphism studies. Among the different species of Drosophila, there is a wide variation in the levels of allozyme polymorphisms and heterozygosities which depends upon species, geographical regions, number and nature of loci in question etc. In Drosophila, the average polymorphic enzyme loci and average heterozygosity ranges from 35 to 70 percent and 10 to 20 percent respectively. The genetic differentiation as observed through allozyme or isozyme variation affords an important parameter in evaluating the phylogenetic relationships between different species of Drosophila and also for discussing the adaptive significance of allozyme polymorphisms. Therefore, this review attempts to compile all studies on allozyme polymorphism in Drosophila that have been undertaken so far. 相似文献
20.
O. B. Simonova D. A. Kulikova I. B. Mertsalov O. N. Umnova V. N. Bashkirov V. L. Buchman L. I. Korochkin 《Russian Journal of Genetics》2005,41(2):138-143
A newly found locus of the Drosophila melanogaster genome, named toothrin (tth) has been used to study the role of the conserved the 2/3 domain of genes from the d4 family. In contrast to all vertebrates studied (including humans), in which the 2/3 domain is always accompanied by the d4 domain, the tth gene contains the sequence encoding the 2/3 domain but lacks that encoding the d4 domain. The tth gene overexpression has been studied using the two-component system UAS-GAL4. It has been demonstrated that the tth overexpression at the third-instar larval (prepupal) stage decreases survival rate, simultaneously causing a substantial deceleration of development in Drosophila. It is known that the change of developmental stages in Drosophila is controlled by the rates of the expression of ecdysteroid and juvenile hormones (JHs). It is supposed that the overexpression of the tth gene causes either a shift in the ecdysterone-to-JH ratio (through a decreased JH decay rate or a delayed initiation of ecdysone synthesis) or a deceleration of the release of ecdysterones synthesized.Translated from Genetika, Vol. 41, No. 2, 2005, pp. 196–202.Original Russian Text Copyright © 2005 by Simonova, Kulikova, Mertsalov, Umnova, Bashkirov, Buchman, Korochkin. 相似文献