Biomedical subjects

Andrew Tomlinson

Publications and source records attributed to Andrew Tomlinson.

9 recordsLinked to original sources

PubMed2007

Dorsal-ventral midline signaling in the developing Drosophila eye.

Boundaries between different cell types play key roles in many developmental patterning processes. They can be established by various mechanisms, and signaling between the different cell types can occur in a number of ways. One mechanism of crossboundary signaling is controlled by the Notch (N)-modifying protein Fringe (Fng). At the Drosophila wing dorsal-ventral (D-V) border, the mechanism by which an Fng(+)-Fng(-) interface controls local N activation has been well characterized. A similar N-activating Fng(+)-Fng(-) interface has also been described at the D-V border of the fly eye, but the mechanisms that establish and regulate it are different from those in the wing. Here we describe the ventral role of the Sloppy-paired (Slp) transcription factor, and its interactions with dorsally expressed Iroquois (Iro) transcription factors in the regulation of signaling about the Fng(+)-Fng(-) interface in the developing eye. The two transcription factors are mutually repressive and initially abut at the D-V midline. However, N signaling at the interface downregulates Slp expression, and a gap opens between the two expression domains in which Serrate (Ser, an N ligand) is upregulated.

Animals↗

PubMed2006

Multiple roles of a trimeric G protein in Drosophila cell polarization.

Polarization of the cellular cytoskeleton underlies many cellular processes including axon growth cone guidance, chemotaxis and yeast mating. Planar cell polarity (PCP) is a similar phenomenon in which cells in an epithelium become uniformly polarized to generate a field of aligned structures such as the hair cells of the cochlea. In Drosophila PCP is under the hierarchical control of Frizzled (Fz)-a serpentine receptor (that also functions in the Wnt signaling pathway). Serpentine receptors are routinely transduced by trimeric G-proteins, but until recently the general consensus was that Fzs were not G-protein linked. In Drosophila a G-protein (Galpha(o)) has now been identified that functions in both the Wnt and PCP pathways. Here we review the cell polarity phenotypes of Galpha(o) mutants and discuss the evidence that it plays multifarious roles in PCP and the organization of the cytoskeleton.

Actins↗

PubMed2006

Organization of the peripheral fly eye: the roles of Snail family transcription factors in peripheral retinal apoptosis.

The periphery of the fly eye contains a number of concentrically arranged cellular specializations that are induced by Wingless (Wg) signaling from the surrounding head capsule (HC). One of these is the pigment rim (PR), which is a thick layer of pigment cells that lies directly adjacent to the HC and completely circumscribes the rest of the retina. Many of the cells of the PR are derived from presumptive pigment cells that previously surrounded peripheral ommatidia that subsequently died. Here, we describe the Wg-elicited expression of Snail family transcription factors in the eye periphery that directs the ommatidial death and subsequent PR formation. These transcription factors are expressed only in a subset of the ommatidial cells not including the photoreceptors. Yet, the photoreceptors die and, thus, a non-autonomous death signal is released from the Snail-family-expressing cells that direct the death of the photoreceptors. In addition, Wg also elicits a similar peripheral expression of Notum, an enzyme that limits the extent of Wg signaling. Furthermore, we describe a later requirement for Snail family proteins in the 2 degrees and 3 degrees pigment cells throughout the main body of the eye.

Animals↗

PubMed2006

Dual roles for the trimeric G protein Go in asymmetric cell division in Drosophila.

During asymmetric division, a cell polarizes and differentially distributes components to its opposite ends. The subsequent division differentially segregates the two component pools to the daughters, which thereby inherit different developmental directives. In Drosophila sensory organ precursor cells, the localization of Numb protein to the cell's anterior cortex is a key patterning event and is achieved by the combined action of many proteins, including Pins, which itself is localized anteriorly. Here, a role is described for the trimeric G protein Go in the anterior localization of Numb and daughter cell fate specification. Go is shown to interact with Pins. In addition to a role in recruiting Numb to an asymmetric location in the cell's cortex, Go transduces a signal from the Frizzled receptor that directs the position in which the complex forms. Thus, Go likely integrates the signaling that directs the formation of the complex with the signaling that directs where the complex forms.

Animals↗

PubMed2006

Twinstar, the Drosophila homolog of cofilin/ADF, is required for planar cell polarity patterning.

Planar cell polarity (PCP) is a level of tissue organization in which cells adopt a uniform orientation within the plane of an epithelium. The process of tissue polarization is likely to be initiated by an extracellular gradient. Thus, determining how cells decode and convert this graded information into subcellular asymmetries is key to determining how cells direct the reorganization of the cytoskeleton to produce uniformly oriented structures. Twinstar (Tsr), the Drosophila homolog of Cofilin/ADF (actin depolymerization factor), is a component of the cytoskeleton that regulates actin dynamics. We show here that various alleles of tsr produce PCP defects in the wing, eye and several other epithelia. In wings mutant for tsr, Frizzled (Fz) and Flamingo (Fmi) proteins do not properly localize to the proximodistal boundaries of cells. The correct asymmetric localization of these proteins instructs the actin cytoskeleton to produce one actin-rich wing hair at the distal-most vertex of each cell. These results argue that actin remodeling is not only required in the manufacture of wing hairs, but also in the PCP read-out that directs where a wing hair will be secreted.

Actin Depolymerizing Factors↗

PubMed2005

Trimeric G protein-dependent frizzled signaling in Drosophila.

Frizzled (Fz) proteins are serpentine receptors that transduce critical cellular signals during development. Serpentine receptors usually signal to downstream effectors through an associated trimeric G protein complex. However, clear evidence for the role of trimeric G protein complexes for the Fz family of receptors has hitherto been lacking. Here, we show roles for the Galpha(o) subunit (Go) in mediating the two distinct pathways transduced by Fz receptors in Drosophila: the Wnt and planar polarity pathways. Go is required for transduction of both pathways, and epistasis experiments suggest that it is an immediate transducer of Fz. While overexpression effects of the wild-type form are receptor dependent, the activated form (Go-GTP) can signal when the receptor is removed. Thus, Go is likely part of a trimeric G protein complex that directly transduces Fz signals from the membrane to downstream components.

Animals↗

PubMed2004

Drosophila Smoothened phosphorylation sites essential for Hedgehog signal transduction.

The Hedgehog (Hh) signalling pathway is crucial for animal development and is aberrantly activated in several types of cancer. In Drosophila melanogaster, Hh signalling regulates target gene expression through the transcription factor Cubitus interruptus (Ci). Together, Protein Kinase A, Casein Kinase 1 and Glycogen Synthase Kinase 3 silence the pathway in the absence of ligand by phosphorylating Ci at a defined cluster of sites, thereby promoting its proteolytic conversion to a transcriptional repressor (Ci-75). In the presence of Hh, Ci-155 is no longer converted to Ci-75 and its ability to activate transcription is potentiated. All Hh responses require the seven transmembrane domain protein Smoothened, which itself becomes hyperphosphorylated during Hh signalling. Here we show that a cluster of protein kinase A and protein kinase A-primed casein kinase 1 phosphorylation sites in Smoothened, similarly distributed to those regulating Ci, are essential for Smoothened to transduce a Hh signal and for normal regulation of Smoothened protein levels.

Amino Acid Sequence↗

PubMed2004

Evidence that the cysteine-rich domain of Drosophila Frizzled family receptors is dispensable for transducing Wingless.

Members of the Frizzled family of serpentine transmembrane receptors are required to transduce Wingless/Int (Wnt) signals and contain in their N-terminal regions a conserved Wnt-binding cysteine-rich domain (CRD). Each CRD has specific affinities for particular Wnts, and it is generally believed that signal transduction depends on the strength of this interaction. Here, we report in vivo evidence that the CRD is dispensable for Frizzled family receptors to transduce Wingless (Wg), the primary Wnt signal in Drosophila. Thus, we infer that signal transduction does not require binding of Wg to the CRD, but instead depends on interactions between Wg and other portions of the receptor, or other proteins of the receptor complex.

Animals↗

PubMed2003

Patterning the peripheral retina of the fly: decoding a gradient.

The peripheral regions of the fly eye show a number of specializations. First, immediately interior to the circumscribing head capsule and completely encircling the rest of the eye lies a thick band of pigment cells (pigment rim; PR). Second, in the dorsal periphery of the eye directly interior to the PR lie the dorsal rim (DR) ommatidia that are specialized polarized light detectors. The equivalent position in the ventral eye is occupied by standard ommatidia. Third, ommatidia characteristically project mechanosensory hairs above their lenses, but in the most peripheral rows (including the DR) the ommatidia are bald. Wingless secreted from the head capsule appears to organize all these peripheral specializations. Higher Wg levels induce PR, intermediate levels induce DR, and lower levels induce baldness. The predisposition of dorsal cells to generate DR ommatidia appears to be endowed by the exclusive dorsal expression of Iroquois genes.

Animals↗