Developing tissues require cells to undergo intricate processes to shift into appropriate niches. This requires a functional connection between adhesion-mediating events at the cell surface and a ...cytoskeletal reorganization to permit directed movement. A small number of proteins are proposed to link these processes. Here, we identify one candidate, Cindr, the sole Drosophila melanogaster member of the CD2AP/CIN85 family (this family has been previously implicated in a variety of processes). Using D. melanogaster retina, we demonstrate that Cindr links cell surface junctions (E-cadherin) and adhesion (Roughest) with multiple components of the actin cytoskeleton. Reducing cindr activity leads to defects in local cell movement and, consequently, tissue patterning and cell death. Cindr activity is required for normal localization of Drosophila E-cadherin and Roughest, and we show additional physical and functional links to multiple components of the actin cytoskeleton, including the actin-capping proteins capping protein alpha and capping protein beta. Together, these data demonstrate that Cindr is involved in dynamic cell rearrangement in an emerging epithelium.
Correct cellular patterning is central to tissue morphogenesis, but the role of epithelial junctions in this process is not well-understood. The
Drosophila pupal eye provides a sensitive and ...accessible model for testing the role of junction-associated proteins in cells that undergo dynamic and coordinated movements during development. Mutations in
polychaetoid (
pyd), the
Drosophila homologue of Zonula Occludens-1, are characterized by two phenotypes visible in the adult fly: increased sensory bristle number and the formation of a rough eye produced by poorly arranged ommatidia. We found that Pyd was localized to the adherens junction in cells of the developing pupal retina. Reducing Pyd function in the pupal eye resulted in mis-patterning of the interommatidial cells and a failure to consistently switch cone cell contacts from an anterior–posterior to an equatorial–polar orientation. Levels of Roughest, DE-Cadherin and several other adherens junction-associated proteins were increased at the membrane when Pyd protein was reduced. Further, both over-expression and mutations in several junction-associated proteins greatly enhanced the patterning defects caused by reduction of Pyd. Our results suggest that Pyd modulates adherens junction strength and Roughest-mediated preferential cell adhesion.
To better translate basic research findings into the clinic, we are moving away from the traditional one-gene-one-phenotype model towards the discovery of complex mechanisms. In this Editorial, the ...new Editor-in-Chief and Senior Editors of Disease Models & Mechanisms (DMM) discuss the role that the journal will play in this transition. DMM will continue to provide a platform for studies that bridge basic and applied science, and, by demanding the rigorous assessment of animal models of disease, will help drive the establishment of robust standards of preclinical testing for drug development.
Abstract
Cancer's complexity is a key difficulty in identifying useful therapeutics. In place of simplifying the disease, I will describe our use of Drosophila to develop complex, multigenic cancer ...models that directly reflect current human tumor sequencing data. These include colorectal, pancreatic, and thyroid tumor models. Further, I will discuss our approach– in collaboration with Kevan Shokat's laboratory– that combines fly genetics with medicinal chemistry to develop novel drugs through "rational polypharmacology," emphasizing a balance of "targets" and "anti-targets" that are designed to optimize therapeutic index.
Citation Format: Ross L. Cagan. Embracing complexity: A drosophila approach to cancer therapeutics. abstract. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr SY16-02. doi:10.1158/1538-7445.AM2013-SY16-02
For the cell biologist, identifying changes in gene expression using DNA microarrays is just the start of a long journey from tissue to cell. We discuss how chip users can first filter noise ...(false-positives) from daunting microarray datasets. Combining laser capture microdissection with real-time polymerase chain reaction and reverse transcription is a helpful follow-up step that allows expression of selected genes to be quantified using sensitive new in situ hybridization and immunohistochemical methods based on tyramide signal amplification.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
The p38 mitogen‐activated protein kinase (MAPK) cascade is an evolutionarily conserved signalling mechanism involved in processes as diverse as apoptosis, cell fate determination, immune function and ...stress response. Aberrant p38 signalling has been implicated in many human diseases, including heart disease, cancer, arthritis and neurodegenerative diseases. To further understand the role of p38 in these processes, we generated a Drosophila strain that is null for the D‐p38a gene. Mutants are homozygous viable and show no observable developmental defects. However, flies lacking D‐p38a are susceptible to some environmental stresses, including heat shock, oxidative stress and starvation. These phenotypes only partially overlap those caused by mutations in D‐MEKK1 and dTAK1, suggesting that the D‐p38a gene is required to mediate some, but not all, of the functions ascribed to p38 signalling.
The apoptotic machinery is utilized for a wide variety of tasks during development. Recent work has uncovered a new, non-apoptotic role for these factors during the individualization process of ...maturing spermatids.
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