P N Adler

..Mutations in components of the fz signal transduction pathway disrupt tissue polarity; on the wing, hairs normally point distally but their polarity is altered by these mutations...

..These complexes appear to recruit downstream proteins that function to spatially restrict the activation of the cytoskeleton in wing cells. This leads to the formation of the array of distally pointing hairs found on wings...

..Selected cells in the arista (the terminal segment of the antenna) elaborate a lateral projection that shares characteristics with both hairs and bristles...

..Tricornered function requires interacting with the large Furry protein (3479 amino acid)...

..We suggest that fz and Vang clones result in altered levels of a locally acting signal and the domineering non-autonomy results from wild-type cells responding to this abnormal signal...

..A comparison of the function of these gene products in the different cell types suggests cell-specific modifications of the pathway...

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

..The direction of this domineering nonautonomy was coincident with the direction of the abnormal hair polarity. We conclude that dachsous causes a tissue polarity phenotype because it alters the direction of frizzled signaling...

..We conclude that both of these cellular systems are limited in their ability to scale to accommodate larger cell size...

..These data indicate that accumulation of proteins at the proximal side of wing cells is a key event for the distal activation of the cytoskeleton to form a hair...

..This cortical mark leads to the local activation of downstream gene products and the subsequent activation of the cytoskeleton to form a hair...

..We have also found that fz function is not required for normal fz expression. We have further found that mutations in several other tissue polarity genes do not noticeably alter the expression or the modification state of the Fz protein...

..Our data argue that fz has a regulatory function in specifying where the prehair forms, but no role in the actual morphogenesis of the prehair...

..We used a P-element insertion allele as a tag to clone the furry gene and found it to be a large and complicated gene that encodes a pair of large conserved proteins of unknown biochemical function...

..Our findings suggest that dsh may have a general role in signal transduction, perhaps as a component of a receptor complex...

..This is a conserved ser/thr protein kinase found in Caenorhabditis elegans and humans that is related to a number of kinases that have been found to be important in controlling cell structure and proliferation...

..This suggests that the tissue polarity genes function in or on a pathway that controls hair polarity by regulating the subcellular location for prehair formation...

..The ability of an in cDNA, the expression of which is driven by the basal activity of the hsp70 promoter to rescue an in mutation suggests that patterned expression of in is unlikely to play a role in the function of the gene...

..In both cases the domineering nonautonomy was suppressed consistent with Van Gogh being essential for frizzled signaling...

..Other results show that a second, low affinity, non-specific chromosome binding function is localized outside the HR in the Su(z)2 protein, and that the Su(z)2 protein contains at least two nuclear localization signals...

..That the temperature during hair morphogenesis is irrelevant for the phenotype of in is consistent with the hypothesis that the only role that in has in wing hair development is to regulate the initiation of hair morphogenesis...

..In addition, we found that grh has frizzled pathway independent functions during the development of the adult cuticle...

..Based on their behavior in genetic mosaics, it has proved possible to determine that individual genes are required either for the generation of an intercellular polarity signal and/or the transduction of that signal to the cytoskeleton...

..virilis. Conceptual translation of the D. virilis open reading frame indicates that the Fz protein is unusually well conserved. Indeed, in the putative cytoplasmic domains the Fz proteins of the two species are identical...

..This is a phenocopy of mutations in crinkled, and suggests mutations that cause branched hairs will be in genes that encode products that interact with the actin cytoskeleton...

..g., abdomen) the inturned-like genes were epistatic to the frizzled-like genes, but in other body regions (e.g., eye) that was not the case. Thus, the genetic control of tissue polarity is body region specific...

..Immunostaining of pupal wings showed that the Fz protein is evenly distributed throughout the wing arguing that the Fz protein does not act as a graded morphogen...

..However, we have found that mutations in Su(z)2 do interact in a variety of interesting ways with mutations in Pc group genes...

..We conclude that the arista laterals are a valuable complementary cell type system for studying the morphogenesis of polarized cellular extensions in Drosophila...

..Overexpression of the hsfzI transgene resulted in two distinct tissue polarity phenotypes depending on the time of heat shock...

..One function involves the transmittance and/or generation of a polarity signal along the proximal-distal axis of the wing. The second function involves the cellular interpretation of a polarity signal...

..In all cases, it is nuclear, as is its mammalian homolog, the bmi-1 protein. On polytene chromosomes, we find Psc at 45 chromosomal loci where two other Pc-G proteins are present...

..We found a strong genetic interaction between mutations in these genes consistent with their having a close but parallel functional relationship...

..Conceptual translation of this mRNA indicates that it encodes an integral membrane protein that is likely to contain both extracellular and cytoplasmic domains...

..Surprisingly, we found that mutations in flr and tsr also result in greatly increased tubulin staining, suggesting a tight linkage between the actin and microtubule cytoskeleton in these cells...

..This is the first reported sequence for the protein product of a tissue polarity gene...

..These data suggest that the bristle abnormalities seen with overexpression of Su(z)2 and Psc may result from altered expression of genes involved in bristle sense organ development that are not normal regulatory targets of these genes...

..4% that is also conserved in the murine oncogene bmi-1. At the amino terminus of this domain is a cysteine-rich sequence that has been proposed as a novel type of zinc finger...

..Northern and in situ hybridization analyses show that the mutations result in increased accumulation of the Su(z)2 mRNA, which we argue is responsible for the bristle loss phenotype...

..Later in development exposure to chitinase caused a loss of normal prehair and bristle polarity, and high doses resulted in a severe disruption of the actin cytoskeleton...

..The upstream function may be an indirect one and associated with the requirement for normal apical basal polarity and adherens junctions for the accumulation of PCP protein complexes...

..The differences in the phenotypes of the doubly mutant embryos allow us to eliminate one class of molecular models to explain the dramatic synergism seen with mutations in this group of genes...

..The fusion protein localized to the proximal side of wing cells prior to hair formation and in growing hairs as expected if protein localization is a key for the function of these proteins...

..Our data suggest a feedback mechanism involving Trc activity regulates the accumulation of Fry in developing hairs...

..This later function appears to be a feedback mechanism that limits cytoskeleton activation to ensure a single hair is formed...

..Interestingly, these divisions were not typically oriented parallel to the axis of elongation. Our observations show that disc evagination involves multiple cellular behaviors, as is the case for many other morphogenetic processes...

..We also found that mutations that lead to lateral splitting typically alter the stereotypic arrangement of actin filament bundles and microtubules in laterals...

..We further provide evidence that Mo25, the Drosophila homolog of the RAM pathway hym1 gene does not function along with Trc...

..The bristle microtubules are less stable. The retrograde movement of the peripheral actin appears to be counterbalanced by the distally directed movement of cytoplasm in the center of the bristle...

..The collection of identified genes should be a valuable data set for future studies on hair and bristle morphogenesis, cuticle synthesis, and planar polarity...

..In addition, we showed that the effects on cell shape and the timing of differentiation appear to be not linked to changes in relative growth rate of cells compared to their neighbors...

..Genetic interaction and gain-of-function studies provide evidence that Tow acts downstream of Fz/Dsh and plays a role in restricting the number of hairs that wing cells form...

..Thus, the Trc/Fry signaling pathway plays a key role in patterning dendritic fields by promoting avoidance between homologous dendrites as well as by limiting dendritic branching...

..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. ..

..We propose to continue to study a group of planar polarity effector genes to understand how they function at the cellular level and the molecular genetic basis for their control of cell shape and morphology. ..

..DESCRIPTION: The long term goal is to understand the genetic basis for the formation of cellular projections by epithelial cells. Dr. Adler uses the wing imaginal epidermis of Drosophila as a model system. ..

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

..We propose to continue to study a group of planar polarity effector genes to understand how they function at the cellular level and the molecular genetic basis for their control of cell shape and morphology. ..

..We propose to continue to study a group of planar polarity effector genes to understand how they function at the cellular level and the molecular genetic basis for their control of cell shape and morphology. ..

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