pros

..Our data describe a transit-amplifying lineage in the Drosophila nervous system and suggest that different vulnerabilities in intermediate cell types can affect the outcome of tumor suppressor loss in stem cell lineages...

..The identification of Drosophila intestinal stem cells with striking similarities to their vertebrate counterparts will facilitate the genetic analysis of normal and abnormal intestinal function...

..number of cells, which have molecular features of undifferentiated progenitor cells that lack nuclear Prospero (Pros)...

..Stau, as one component of this complex, is required only for RNA localization. Hence staufen also acts zygotically, downstream of inscuteable, to effect aspects of neuroblast asymmetry...

..Our studies demonstrate that a class VI myosin is necessary for basal protein targeting and spindle orientation in neuroblasts...

..The Inscuteable protein localizes to the apical cell cortex before mitosis, suggesting that Inscuteable functions in establishing polarity for asymmetric cell division...

..Thus one way Grh could regulate pNBs is through expression of E-cadherin, a protein that is thought to mediate interactions with the glial niche...

..The ability to identify, manipulate and genetically trace cell lineages in the midgut should lead to the discovery of additional genes that regulate stem and progenitor cell biology in the gastrointestinal tract...

..We show that the homeodomain transcription factor Prospero (Pros) acts as an intrinsic signal for the specification of cell fates within the mechanosensory lineage...

..Single neuroblast clones lacking Prospero have a similar phenotype. We conclude that Brat suppresses neuroblast stem cell self-renewal and promotes neuronal differentiation...

..Moreover, our data suggest that the fate of some sibling neurons may be regulated by signals that do not require lateral interaction between the sibling cells...

..Type II lineages allow more neurons to be produced faster than Type I lineages, which may be advantageous in a rapidly developing organism like Drosophila...

..We propose that PON is one component of a multimolecular machinery that localizes Numb by responding to polarity cues conserved in neural precursors and epithelial cells...

..prospero encodes a large nuclear protein with multiple homopolymeric amino acid stretches and is expressed in neuronal precursors early during their formation. It is probably generally required for proper neuronal differentiation...

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..Similar defects are seen in lethal giant larvae (lgl) mutants where Brat and Prospero are not asymmetric. We have identified a molecular mechanism that may control self-renewal and prevent tumor formation in other stem cells as well...

..Thus, Notch signalling is likely to regulate MSI activity rather than its expression. Our results define cell-type-specific translational control of ttk69 by MSI as a downstream event of Notch signalling in asymmetric cell division...

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..These studies highlight a mechanism for transcriptional control by a Runt Domain protein and a redundant pair of partners in the specification of cell fate during development...

..Our results indicate that neuroepithelial cells have all the necessary components to execute asymmetric division, but that this pathway is normally overridden by the planar polarity cue provided by adherens junctions...

..This study establishes for the first time the function of Inscuteable in the PNS, and provides the basis for studying the mechanisms controlling planar and apical-basal cell polarities in the embryonic sensory organ lineages...

..Mammalian epithelia also use this complex to regulate apical/basal polarity. Recent results have allowed us to compare the mechanisms regulating asymmetric cell division in Drosophila neuroblasts and the C. elegans zygote...

..Thus, Lgl and Dlg act in a common process that differentially mediates cortical protein targeting in mitotic neuroblasts, and that creates intrinsic differences between daughter cells...

..These data suggest that Dapaf-1/cytochrome c-dependent cell death-inducing machinery is present in Drosophila, and the requirement of Dapaf-1/Apaf-1 in neural cell death is conserved through evolution...

..We show that Sevenless activates prospero independent of the enhancer and involves targeted degradation of Tramtrack, a transcription repressor...

..Loss of pros results in aberrant expression of multiple cell-cycle regulatory genes and ectopic mitotic activity...

..We propose that upregulated Lozenge acts as a cofactor to alter Pointed affinity, by a mechanism that is recapitulated in mammalian development...

..In sensory organ precursors, Bazooka/DaPKC and Pins/G alpha i localize to opposite sides of the cortex and function in opposition to generate a symmetric spindle...

..In addition, we present evidence that Numb has a novel function in endosomal recycling and intracellular trafficking of receptors...

..These studies identify the timing mechanism ending CNS proliferation and reveal how aging progenitors transduce bursts of transcription factors into long-lasting changes in cell proliferation and cell identity...

..Thus, ISCs control daughter cell fate by modulating Notch signaling over time. Our studies suggest that ISCs actively coordinate cell production with local tissue requirements by this mechanism...

..In some tissues cell fate appears to dictate the type of cell division, whereas in other tissues it is thought that stochastic variation in spindle position dictates subsequent sibling cell fate...

..Taken together, our results suggest that while spalt is required for R7 differentiation during larval stages, spalt and senseless promote terminal R8 differentiation during pupal stages, including the regulation of rhodopsin expression...

..Our data indicate that Sec15 mediates a specific vesicle trafficking event to ensure proper neuronal fate specification in Drosophila...

..We suggest that during eye development, Lozenge isoforms function in divergent roles, either interacting with Pointed on downstream targets or by functioning independently to establish distinct cell fates...

..These transformations in cell identity suggest that, although synchronized, cell cycle and fate determination are independent phenomena in the bristle lineage...

..This enables prospero-expressing cells alone to divide further upon elimination of neurons and to adjust glial number to axons during development...

..We show that N specifies the R7 fate by a novel branched pathway: N represses Svp expression, thereby exposing an underlying stochastic choice between the R7 and R8 fates, and then tips this choice towards the R7 fate...

..Taken together, these results reveal novel activities for pod-1 and show that proper levels of Dpod1, an actin/MT crosslinker, must be maintained in the growth cone for correct axon guidance...

..This study provides a mechanistic basis for the dual function of Runx proteins that is likely to be conserved in mammalian systems...

..An understanding of the lineage and development of olfactory sense-organs provides a handle for the analysis of how olfactory neurons acquire distinct terminal fates...

..inserted upstream of the pan-neural gene prospero (pros) causes several neural and behavioral defects in the Voila(1) strain...

..These results as a whole uncover a distinct regulatory mechanism of self-renewal and differentiation of the MB progenitors that is different from the mechanisms found in other progenitors...

..prospero is therefore a novel type of gene expressed in neuroblasts and known to specify neuronal fate...

..This difference in cell-division orientation is largely independent of the identity of the secondary precursor cells, and is regulated by Frizzled-independent mechanisms...

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..The prospero (pros) mRNA and the RNA-binding protein Staufen (Stau) are asymmetrically localized in mitotic neuroblasts and are ..

..These studies reveal that Suppressor of Hairless is required for only a subset of the asymmetric divisions that depend on the function of numb and Notch...

..miranda thus creates intrinsic differences between sibling cells by mediating the asymmetric segregation of a transcription factor into only one daughter cell during neural stem-cell division...

..Here we use in vitro culture of neuroblasts to investigate the role of intrinsic and extrinsic cues and the cytoskeleton in asymmetric localization of Inscuteable, Prospero and Staufen proteins...

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..Our results suggest that miranda functions downstream of inscuteable and works as an adapter that connects Prospero to the basal cell membrane during asymmetric cell division...

..Loss of sanpodo leads to an aberrant F-actin distribution and causes differentiation defects of actin-containing sensory structures. Our data suggest that an actin-based process is involved in Notch signaling...

..This leads to Ttk expression in the daughter cell that does not inherit Numb. Thus, the inherited determinant Numb bestows a bias in the machinery for cell-cell communication to allow the specification of distinct daughter cell fates...

..prospero (pros) is not expressed in the muscles or their precursors...

..The asymmetric cortical localization of prospero at mitosis is a mechanism for rapidly establishing distinct sibling cell fates in the CNS and possibly other tissues...

..Thus Miranda, which localizes Prospero protein, also localizes prospero RNA through its interaction with Staufen protein...

..Among genes known to control neurogenesis, prospero (pros) was recently identified as a gene required for gene expression specifying properties of some identified neurons...

..Fragmentation was blocked after overexpression of the caspase inhibitor p35 or removal of the pro-apoptotic genes reaper, hid and grim, showing that the glial cell undergoes apoptosis...

..The proposed modification in lineage has important implications for previous studies on sibling cell fate choice and cell fate specification in sensory systems...

..This revised description of the sense organ lineage provides the basis for future studies on how polarity and fate are regulated in asymmetrically dividing cells...

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

..These findings are illuminating in understanding the general mechanism of stem cell division...

..This suggests either that the role of condensin proteins in interphase differs from their expected role in mitosis or that the way we envision condensin's activity needs to be modified to accommodate alternative possibilities...

..We have identified a novel mechanism for controlling the balance between self-renewal and neuronal differentiation during the asymmetric division of Drosophila larval NBs...

..These results imply a novel role for caspases in modulating cell signaling pathways through substrate cleavage in neural precursor development...

..Our results suggest that two classes of asymmetric cell division exist, each with different requirements for asymmetric inheritance of cell-fate determinants...

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..Expression is switched when EGFR signaling transiently triggers Yan degradation. This two-tiered mechanism explains how signal transduction activity can robustly generate a stable change in gene-expression patterns...

..Our understanding now extends to the molecular nature of the cell polarity that underlies asymmetric divisions. This polarity is conserved among neural stem cells, epithelial cells and fertilized eggs...

..Molecular isolation and analysis of the genes identified by these second-site mutations should define the molecular basis for the genetic redundancy...

..Recently we identified the prospero (pros) gene, which is expressed in embryonic neuroblasts...

..Thus, huckebein regulates aspects of GMC and neuronal identity required for proper motoneuron axon pathfinding in the NB 4-2 lineage...

..This observation contradicts the widely held hypothesis that the cleavage furrow is always placed midway between the two centrosomes...

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..Therefore, some changes in scaffold formation may have reflected changes in the placement and differentiation of other cells of the VNC. In all mutants, alterations in scaffold formation preceded longitudinal axon tract formation...

..This is the first reported case of symmetric division in the sensory organ lineage. These data indicate that the organization of the fly peripheral nervous system is more complex than previously thought...

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..These findings begin to reveal the molecular mechanisms controlling dendritic morphogenesis...

..Our results implicate Dachs as a crucial downstream component of a Fat signaling pathway that influences growth, affinity and gene expression during development...

..Immunohistochemical detection of Mam on polytene chromosomes revealed binding at > 100 sites. Chromosome colocalization studies with RNA polymerase and the groucho corepressor protein implicate Mam in transcriptional regulation...

..These results indicate that the ninaG oxidoreductase acts in the biochemical pathway responsible for conversion of retinal to the rhodopsin chromophore, 3-hydroxyretinal...

..Our findings suggest a model in which Numb inhibits Notch signaling through the regulation of Sanpodo membrane localization...

..Furthermore, ectopic midline cells are able to induce enhanced expression of some lateral CNS cell markers. We thus conclude that the CNS midline plays an important role in the differentiation or maintenance of the lateral CNS cortex...

..As Bazooka is also responsible for the maintenance of apical-basal polarity in epithelial tissues, it may be the missing link between epithelial polarity and neuroblast polarity...

..None of the genes identified so far that are involved in these processes seems to have been conserved between flies and nematodes...

..What triggers the asymmetric localization of Numb at the onset of mitosis is unclear...

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..Receptor-independent activation of heterotrimeric G proteins by the Drosophila GoLoco protein Partner of Inscuteable seems to represent a novel mechanism to control these events...

..The mutations recovered are not random and might provide insights into possible mechanisms for mutagenesis in eukaryotes...

..Explicit incorporation of the relevant environmental gradient can result in a simple and powerful test of selection. For the Australian cline, our analysis provides strong internal evidence that the cline is due to selection...

..The orientation of these divisions is under the control of the Frizzled pathway that generates planar polarity in a number of cell types...

..We propose that COMM is an essential part of the dynamic cell surface remodeling needed by postsynaptic cells in coordinating synaptogenesis initiation...

..Many of the same molecules participate in the guidance of both vertebrate and fly motor axons. It is less clear, however, whether the same molecular mechanisms establish vertebrate and fly motoneuron identities...

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..We propose that this association is required for proper chromosomal segregation by facilitating the decatenation of chromatids at anaphase...

b>Voila(1), an enhancer-trap strain in Drosophila melanogaster, expresses GAL4 in most gustatory neurons, both before and after metamorphosis. Voila(1) expression starts at embryonic stage 10...

..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. ..

..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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..For one of these genes we will determine the relative importance of adhesion versus signal transduction for the mutant phenotype. ..

..The combination of cellular, molecular and genetic studies proposed in this project will provide new and in-depth insight into mechanisms of primitive heart tube morphogenesis. ..

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..Understanding of such mechanisms may allow us to manipulate stem cell behavior;for example, normal stem cells can be expanded in culture for transplantation, or we can inhibit the expansion of cancerous stem cells. ..

..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. ..

..Our proposed studies will help reveal mechanisms that regulate motoneuron differentiation and survival, thus providing insights that should facilitate new therapies for treatment of motoneuron diseases and injury. ..

..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. ..

..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. ..

..Our proposed studies will provide insights that should facilitate new therapies for treatment of motoneuron diseases and injury. ..

..We will learn whether death of a specific motoneuron can be prevented, and we will learn its fate when it survives. We will learn whether motoneurons that do not typically behave as an equivalence pair can be induced to do so...

..Parallel simulation studies are also in progress which complement the combined empirical and model buttressed exploratory methodology that we are developing...

..We will further investigate rare and frequent words, motifs, or compositional biases. Finally, we will continue the development of versatile code that implements all our computational and statistical methods for sequence analysis. ..

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

..Aim 2 will test the specific hypothesis that the serpentine receptors activate heterotrimeric G proteins. Aim 3 will use an elegant genetic screen to identify new genes in the Wg signaling pathway. ..

..We will also carry out experiments designed to distinguish between models proposed to explain the function of the fz signaling/signal transduction pathway in the development of tissue polarity. ..

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

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