en

..Demonstration that stem cells can contribute to niche function has far-reaching consequences for stem cell therapies and may provide insight into how cancer can spread throughout an organism via populations of cancer stem cells...

..Thus, Debra defines the border of the Hh-responsive region in the A compartment by inducing the lysosomal degradation of Ci...

..The early role of wg is to stabilize engrailed (en) expression by initiating a phase of en autoregulation in the adjacent more posterior cells...

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..The results highlight the importance of genetic analysis in the study of proteins required for developmental regulation of gene expression...

..In addition, we show that Ptc(SSD) preferentially accumulates in endosomes of the endocytic compartment. All these results suggest a role of the SSD of Ptc in mediating the vesicular trafficking of Ptc to regulate Smo activity...

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..Where appropriate, wingless signaling will be compared to the activity of vertebrate Wnt proteins...

..Hence, hh and wg play opposing roles in mesoderm segmentation...

..Analysis of cell cycle regulators indicates that the PcG system also dynamically modulates the expression levels of certain genes, providing a possible explanation for the tumor phenotype of PcG mutants...

During segmentation of the Drosophila embryo, even skipped is required to activate engrailed stripes and to organize odd-numbered parasegments...

..Here, we review several recent reports that help to elucidate the regulatory principles used to control this pattern. Because organizers are conserved, the same fundamental principles might operate in other organizers...

..We present a model for the role of Armadillo stripes in transduction of wingless signal...

..We conclude that the spatial limits of btd expression are not instructive for metamerization of the head region and that btd activity does not contribute to a combinatorial code for specification of segment identity...

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..This demonstrates an unexpected level of specificity in the regulation of the distribution of extracellular signals by HSPGs...

..Our results demonstrate that dsRNA interference can be used to analyze many aspects of gene function...

..Hh inhibits proteolysis of Ci, and we suggest that this inhibition leads to the observed patterns of expression of key target genes at the compartment border...

..COS2 is cytoplasmic and binds microtubules. We find that CI associates with COS2 in a large protein complex, suggesting that COS2 directly controls the activity of CI...

..Both the domain of even-skipped function and the level of twist expression are regulated by sloppy-paired. sloppy-paired thus controls segmental allocation of mesodermal cells to different fates...

..Comparing the biological activities of secreted and membrane-tethered Hh provides evidence that Hh forms a local concentration gradient and functions as a concentration-dependent morphogen in the fly wing...

..parasegment boundary, cells expressing the Wnt family member Wingless confront cells expressing the homeoprotein Engrailed. The Engrailed-expressing cells normally differentiate as one of two alternative cell types...

Genetic analysis shows that Engrailed (En), a homeodomain-containing transcription factor, has both negative and positive targets...

..We have identified a sequence-specific DNA binding protein that interacts with a PRE from the Drosophila engrailed gene...

..Here, I review the work that demonstrated the existence of compartments. I then conjecture on why compartments exist and review the roles of various gene products in the maintenance of compartment boundaries...

..Finally, mutations in the Drosophila groucho gene also suppress wingless and armadillo mutant phenotypes as Groucho physically interacts with dTcf and is required for its full repressor activity...

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..Furthermore, overexpression of the mutant form has dominant negative effects on Hedgehog signaling. These data suggest that the importance of the N-terminal cysteine of mature Hedgehog in patterning appendages differs between species...

..The combination of independent progression of cell identity and arrest of progression by signals facilitates accurate patterning of an extremely plastic developing epidermis...

..PcG targets are highly enriched in genes encoding transcription factors, but they also include genes coding for receptors, signaling proteins, morphogens and regulators representing all major developmental pathways...

..Epistasis analysis indicates that Par-1 functions upstream of Notch and is critical for proper localization of the Notch ligand Delta...

..We conclude that RanBP3 is a direct export enhancer for beta-catenin, independent of its role as a CRM1-associated nuclear export cofactor...

..Our data further indicate that Shf interacts with Hh and the heparan sulfate proteoglycans. Therefore, we propose that Shf stabilizes the interaction between Hh and the proteoglycans, an unexpected role for a member of the WIF-1 family...

..We also show that human WIF inhibits Wg signaling in Drosophila without affecting the Hh pathway, indicating that different WIF family members might have divergent functions in each pathway...

In Drosophila, the subdivision into compartments requires the expression of engrailed (en) and hedgehog (hh) in the posterior cells and of cubitus-interruptus (ci) in the anterior cells...

..After gastrulation Htl is essential for the differentiation of dorsal mesodermal derivatives. It is not known how Htl is activated, because its ligand has not yet been identified...

In Drosophila embryos, segment boundaries form at the posterior edge of each stripe of engrailed expression...

..Our work furthers the hypotheses that a conserved pathway controls gonad sexual dimorphism in diverse species and that sex-specific cell recruitment and programmed cell death are common mechanisms for creating sexual dimorphism...

..The model gives important insights into the functioning of the segment polarity gene network, such as the crucial role of the wingless and sloppy paired genes, and the network's ability to correct errors in the pre-pattern...

..We propose that Arrow (LRP) recruits Axin to the membrane, and that this interaction leads to Axin degradation. As a consequence, Armadillo is no longer bound by Axin, resulting in nuclear signaling by Armadillo...

..Our results suggest that one of fru's sex-nonspecific roles is to regulate the pathfinding ability of axons in the embryonic CNS...

..Our data argue strongly that Pygopus is a new core component of the Wg signaling pathway that acts downstream or at the level of TCF...

..fate specification of a set of late delaminating neuroblasts, NB 6-4 and NB 7-3, both of which arise from the engrailed (en) expression domain, with NB 6-4 delaminating first...

..Our results provide a new neuroblast lineage for investigating temporal identity and reveal the importance of Pdm and Cas as timing factors that close temporal identity windows...

..Psc shows unusual effects on two of the targets, Ultrabithorax and abdominal-A. These results show that the PcG genes do not act only in a common complex or pathway; they must have some independent functions...

..We present evidence for four distinct phases of wg function in epidermal cells: (1) an early requirement in engrailed-expressing cells to establish and maintain stable expression of en, (2) a discrete period when wg and en gene ..

..We demonstrate that engrailed-expressing cells in the Drosophila epidermis have organizer properties...

..Their developmental roles are assessed in terms of their participation in conserved gene networks and mechanisms that establish positional information...

..to the evolution of this pattern; we find that the first step in patched regulation is under the control of engrailed whereas the second requires the activity of both cubitus interruptusD and patched itself...

..Two other segment polarity genes, porcupine and dishevelled, are required for this effect. We also show that arm protein is closely associated with the plasma membrane in virtually all cell types and often colocalizes with F-actin...

..We have established a hierarchical order among these genes: Antp less than Scr less than Ubx less than abd-A less than Abd-B. In addition, we show that the engrailed gene is ectopically active in Pc- imaginal cells.

..BSH9, BSH4, and prd are activated in cells that are in register along the anteroposterior axis of the embryo in the posterior parts of primordial segments comprising the posterior compartments of engrailed expression.

..the anterior and posterior compartments, which are distinguished by the activity of the selector gene engrailed (en) in posterior cells...

In Drosophila, Engrailed is a nuclear regulatory protein with essential roles in embryonic segmentation and in normal development of posterior compartments...

We show that maintenance but not initiation of engrailed (en) gene expression in the Drosophila embryo requires trithorax (trx), which is also required to maintain stable long-term expression of the homeotic genes throughout the ..

The engrailed gene helps to direct Drosophila melanogaster development by encoding a homeodomain-containing DNA binding protein...

The hedgehog gene product, secreted from engrailed-expressing neuroectoderm, is required for the formation of post-S1 neuroblasts in rows 2, 5 and 6...

..These results set the stage for investigating neuroblast specification and the mechanisms controlling neuroblast cell lineages...

..We conclude that the mesoderm is segmented in some way not dependent on the distribution of Wingless, suggesting a more permissive and less instructive role for the protein in this instance...

..We have analyzed embryos that are multiply mutant for five key patterning genes: wingless, patched, engrailed, naked and hedgehog...

..We have examined the pattern of expression of the Drosophila segment polarity gene, engrailed (en), in embryos mutant for several different members of the Pc group...

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..This suggests that loco and pros are targets of DRI transcriptional activation in some LG. We conclude that dri is an important regulator of the late development of longitudinal glia...

..The resulting pattern defects, and the patterns of en and Ubx activity, can be explained if h acts via ftz and other pair-rule genes in the establishment of stable en ..

..Teneurin function appears to be required for a fundamentally important signaling mechanism conserved between invertebrates and vertebrates having an impact on many processes relying on cell-cell contact throughout development...

..The non-cell autonomous nature of Ubx-mediated repression of CG32062 expression suggests that the novel component of D/V signaling is also negatively regulated during haltere specification...

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..These results confirm that proper pathway formation requires careful regulation of MLCK and/or myosin II activity and suggest that regulation occurs in direct response to attractive and repulsive cues...

..brain neuroblasts, we carried out a comprehensive analysis of the expression of segment polarity genes (engrailed, wingless, hedgehog, gooseberry distal, mirror) and DV patterning genes (muscle segment homeobox, intermediate ..

..In engrailed mutants, ci-D expression was derepressed in the posterior compartments of both embryos and imaginal discs...

..Dally-like, however, is strictly necessary for Hedgehog signal transduction. Epistatic experiments show that Dally-like is required for the reception of the Hedgehog signal, upstream or at the level of the Patched receptor...

We have found a fragment of engrailed regulatory DNA that has an unusual effect on expression of a linked marker gene, white, in the P element transposon CaSpeR...

..The existence of human orthologs for Rdx raises the possibility that this novel feedback loop also modulates Hh responses in humans...

..Loss of pros function results in aberrant expression of the homeobox genes fushi tarazu, even-skipped and engrailed in a subset of neuroblast progeny, suggesting that pros plays an early and fundamental role in the specification ..

..We propose that controlled degradation is an active mechanism important for Hh gradient formation...

..Xcad3 (Xcad-EnR) in which the activation domain of Xcad3 is replaced by the repression domain of the Drosophila Engrailed protein...

..Genetic evidence suggests that one of the functions of foi may be associated with hedgehog signaling...

..Our results suggest that modulation in Dpp expression and spread accounts, in part, for the different size of halteres and wings...

b>engrailed (en) is a segmentation gene expressed in a series of stripes throughout embryonic development. Here, I show that regulatory sequences for striped expression are present within the first intron of en...

..Src42A protein accumulates at sites of cell-cell or cell-matrix adhesion. Anti-Engrailed antibody staining of Src42A protein-null mutant embryos indicated that Src42A is essential for proper cell-cell ..

..These results illustrate potentially general rules about the homeotic control of target gene expression and suggest that subtractive hybridization can be used to isolate interesting homeotic target genes...

..The homeobox gene engrailed has been implicated in specification of posterior cell fate, whereas the LIM/homeobox gene, apterous, specifies ..

..Based on these results, and the segmental phenotypes generated by ectopic Odd, we suggest a number of new roles for Odd in the patterning of embryonic segments. These include gap-, pair-rule- and segment polarity-type functions...

..Genes that are known to be expressed in compartment-specific manners in other discs (engrailed, hedgehog, patched, decapentaplegic, wingless and cubitus interruptus) are expressed in analogous patterns in ..

..wing is divided into anterior and posterior compartments, the latter characterized by the expression of the engrailed gene...

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..We propose that an important role of wingless in this part of the developing brain is the determination of neural cell fate...

..This result provides evidence for functional cooperativity in vivo between the adhesion and signaling pathways controlled by neurotactin and the other three genes...

..Taken together, these data define a novel neuroectoderm to mesoderm signaling pathway and suggest that unique mesodermal cell types are specified by a combination of midline and segmental cues...

..In vivo, complexes formed at one genomic site can interact with those at other sites, suggesting that they, like heterochromatin complexes, affect the folding of chromatin and the organization of chromosomes in the nucleus...

..A recent paper shows that small clusters of cells in developing cell populations are in mitotic synchrony, but that the synchrony is transient. What is the significance of this mitotic synchrony?..

..The bHLH domain is sufficiently different from previously described bHLH domains to imply a novel function...

..dTCF transgene cause a segment polarity phenotype and affect expression of the Wingless target genes engrailed and Ultrabithorax. Epistasis analysis positions dTCF downstream of armadillo...

..Consequently, most Pax genes arose from a Paired-like ancestor, via fusion of a Paired-like homebox gene with a gene encoding only a paired domain; the Cnidaria appear to contain genes representing the 'before' and 'after' fusion events...

..However, Serrate does not require rhomboid function in the maxillary segment, suggesting that the Hox-Serrate pathway to segment-specific morphogenesis can be linked to more than one downstream function...

..2 target genes. This knowledge may be highly instructive in defining those regulatory networks required for beta islet specification. ..

..These studies address the structure and function of vnd, a critical regulator of early neuronal development, and may serve as a prototype for vertebrate vnd-like genes. ..

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..Together, these studies will further our understanding of the regulatory circuits that control gastrointestinal proliferation in normal development and carcinogenesis. ..

..The new resources generated through this project will be made available to the NIDDK-funded biotechnology centers and the diabetes research community at large. ..

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..Therefore, the mechanisms to be uncovered in this research will be relevant to human disease. ..

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..Such insight should help us understand the etiology of diseases in which this process is de-regulated and design new methods to treat these diseases. ..

..Together, this proposal will further our understanding of GI development and cancer, and allow for the development of novel diagnostic and possibly therapeutic tools in the future. ..

..Therefore, the mechanisms to be uncovered in this research will be relevant to human disease. ..

..Such insight should help us understand the etiology of diseases in which this process is de-regulated and design new methods to treat these diseases. ..

..The single active X chromosome in humans of both males and females must be up-regulated for viability. The proposed project will examine the type of mechanism responsible for this up-regulation. ..

..Thus, we propose to continue our investigation of temporal patterning in the Drosophila CNS, with the goal of providing insight into the mechanisms regulating temporal patterning during mammalian neurogenesis. ..

..single RD could provide all the activity required for a TF to function, but real TFs such as the Brinker (Brk), Engrailed (En) and C15 proteins of Drosophila possess multiple RDs and appear to be able to recruit more than one ..

..Thus, we propose to continue our investigation of temporal patterning in the Drosophila CMS,with the goal of providing insight into the mechanisms regulating temporal patterning during mammalian neurogenesis. ..

..Together, these studies will further our understanding of the regulatory circuits that control gastrointestinal proliferation in normal development and carcinogenesis. ..

..In addition, many of the genes regulating Drosophila development are homologous to vertebrate oncogenes and thus these studies should help to illuminate the molecular mechanisms behind oncogenesis...

..We wish to determine whether cell types are altered, and whether there are other effects on formation of neuronal circuits. ..

..We will do RNA and protein localization studies; our collaborator, Dr. G. Oliver will generate and assay the gene knock-out mice. ..

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..Apical constriction is an evolutionarily conserved process and therefore these studies will have direct implications to vertebrate systems. ..

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..Such information may provide useful clues into the various causes of neurological or neuromuscular dysfunctions. ..

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