Evolutionary biology: fly eyes get the whole picture.
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Animals↗
Biomedical subjects
Kevin Moses
Publications and source records attributed to Kevin Moses.
The Drosophila ramshackle gene encodes a chromatin-associated protein required for cell morphology in the developing eye.
We have identified ramshackle (ram) as a dominant suppressor of hedgehog loss-of-function in the developing Drosophila eye. We have characterized the gene and it encodes a double bromodomain protein with eight WD40 repeats. The Ram protein is localized predominantly to polytene chromosome interbands and is required for the transcription of some genes. ram is an essential gene and null mutants die during larval life. In the developing retina, ram mutant cells have morphological defects including disrupted apical junctions, disorganized actin cytoskeletons and mislocalized nuclei, which are followed by delays in cell-cycle transitions and the expression of differentiation markers. ram is a conserved gene: its vertebrate homolog (WDR9), which lies in Down's Syndrome Critical region 2 (DCR2) is also known to be associated with Brahma-Related-Gene 1 (BRG1).
Alleles↗
Characterization of Drosophila mini-me, a gene required for cell proliferation and survival.
In the developing Drosophila eye, the morphogenetic furrow is a developmental organizing center for patterning and cell proliferation. The furrow acts both to limit eye size and to coordinate the number of cells to the number of facets. Here we report the molecular and functional characterization of Drosophila mini-me (mnm), a potential regulator of cell proliferation and survival in the developing eye. We first identified mnm as a dominant modifier of hedgehog loss-of-function in the developing eye. We report that mnm encodes a conserved protein with zinc knuckle and RING finger domains. We show that mnm is dispensable for patterning of the eye disc, but required in the eye for normal cell proliferation and survival. We also show that mnm null mutant cells exhibit altered cell cycle profiles and contain excess nucleic acid. Moreover, mnm overexpression can induce cells to proliferate and incorporate BrdU. Thus, our data implicate mnm as a regulator of mitotic progression during the proliferative phase of eye development, possibly through the control of nucleic acid metabolism.
Amino Acid Sequence↗
smoothened and thickveins regulate Moleskin/Importin 7-mediated MAP kinase signaling in the developing Drosophila eye.
The Drosophila Mitogen Activated Protein Kinase (MAPK) Rolled is a key regulator of developmental signaling, relaying information from the cytoplasm into the nucleus. Cytoplasmic MEK phosphorylates MAPK (pMAPK), which then dimerizes and translocates to the nucleus where it regulates transcription factors. In cell culture, MAPK nuclear translocation directly follows phosphorylation, but in developing tissues pMAPK can be held in the cytoplasm for extended periods (hours). Here, we show that Moleskin antigen (Drosophila Importin 7/Msk), a MAPK transport factor, is sequestered apically at a time when lateral inhibition is required for patterning in the developing eye. We suggest that this apical restriction of Msk limits MAPK nuclear translocation and blocks Ras pathway nuclear signaling. Ectopic expression of Msk overcomes this block and disrupts patterning. Additionally, the MAPK cytoplasmic hold is genetically dependent on the presence of Decapentaplegic (Dpp) and Hedgehog receptors.
Animals↗
Smoothened, thickveins and the genetic control of cell cycle and cell fate in the developing Drosophila eye.
The Hedgehog and Decapentaplegic pathways have several well-characterized functions in the developing Drosophila compound eye, including initiation and progression of the morphogenetic furrow. Other functions involve control of cell cycle and cell survival as well as cell type specification. Here we have used the mosaic clone analysis of null mutations of the smoothened and thickveins genes (which encode the receptors for these two signals) both alone and in combination, to study cell cycle and cell fate in the developing eye. We conclude that both pathways have several, but differing roles in furrow induction and cell fate and survival, but that neither directly affects cell type specification.
Animals↗
MAP kinase subcellular localization controls both pattern and proliferation in the developing Drosophila wing.
Mitogen-activated protein kinases (MAPKs) phosphorylate target proteins in both the cytoplasm and nucleus, and a strong correlation exists between the subcellular localization of MAPK and resulting cellular responses. It was thought that MAPK phosphorylation was always followed by rapid nuclear translocation. However, we and others have found that MAPK phosphorylation is not always sufficient for nuclear translocation in vivo. In the developing Drosophila wing, MAPK-mediated signaling is required both for patterning and for cell proliferation, although the mechanism of this differential control is not fully understood. Here, we show that phosphorylated MAPK (pMAPK) is held in the cytoplasm in differentiating larval and pupal wing vein cells, and we show that this cytoplasmic hold is required for vein cell fate. At the same time, we show that MAPK does move into the nucleus of other wing cells where it promotes cell proliferation. We propose a novel Ras pathway bifurcation in Drosophila and our results suggest a mechanism by which MAPK phosphorylation can signal two different cellular outcomes (differentiation versus proliferation) based on the subcellular localization of MAPK.
Animals↗
Genetic and biochemical analysis of the role of Egfr in the morphogenetic furrow of the developing Drosophila eye.
A key event in patterning the developing Drosophila compound eye is the progressive restriction of the transcription factor Atonal in the morphogenetic furrow. The Atonal pattern evolves from expression in all cells to an over-dispersed pattern of single founder cells (the future R8 photoreceptors). This restriction involves Notch-mediated lateral inhibition. However, there have been inconsistent data on a similar proposed role for the Egf receptor (Egfr). Experiments using a conditional Egfr mutation (Egfr(tsla)) suggested that Egfr does not regulate Atonal restriction, whereas experiments using Egfr-null mosaic Minute+ clones suggested that it does. Here, we have re-examined both approaches. We report that the lesion in Egfr(tsla) is a serine to phenylalanine change in a conserved extracellular ligand-binding domain. We show by biochemical and genetic approaches that the Egfr(tsla) protein is rapidly and completely inactivated upon shift to the non-permissive temperature. We also find that on temperature shift the protein moves from the cell surface into the cell. Finally, we report a flaw in the Egfr-null mosaic Minute+ clone approach. Thus, we demonstrate that Egfr does not play a role in the initial specification or spacing of ommatidial founder cells.
Animals↗
Pointed regulates an eye-specific transcriptional enhancer in the Drosophila hedgehog gene, which is required for the movement of the morphogenetic furrow.
Drosophila development depends on stable boundaries between cellular territories, such as the embryonic parasegment boundaries and the compartment boundaries in the imaginal discs. Patterning in the compound eye is fundamentally different: the boundary is not stable, but moves (the morphogenetic furrow). Paradoxically, Hedgehog signaling is essential to both: Hedgehog is expressed in the posterior compartments in the embryo and in imaginal discs, and posterior to the morphogenetic furrow in the eye. Therefore, uniquely in the eye, cells receiving a Hedgehog signal will eventually produce the same protein. We report that the mechanism that underlies this difference is the special regulation of hedgehog (hh) transcription through the dual regulation of an eye specific enhancer. We show that this enhancer requires the Egfr/Ras pathway transcription factor Pointed. Recently, others have shown that this same enhancer also requires the eye determining transcription factor Sine oculis (So). We discuss these data in terms of a model for a combinatorial code of furrow movement.
Animals↗
Slingshot cofilin phosphatase localization is regulated by receptor tyrosine kinases and regulates cytoskeletal structure in the developing Drosophila eye.
Animal development requires that positional information act on the genome to control cell fate and cell shape. The primary determinant of animal cell shape is the cytoskeleton and thus the mechanisms by which extracellular signals influence the cytoskeleton are crucial for morphogenesis. In the developing Drosophila compound eye, localized polymerization of actin functions to constrict the apical surface of epithelial cells, both at the morphogenetic furrow and later to maintain the coherence of the nascent ommatidia. As elsewhere, actin polymerization in the developing eye is regulated by ADF/cofilin ('Twinstar', or 'Tsr' in Drosophila), which is activated by Slingshot (Ssh), a cofilin phosphatase. Here we show that Ssh does act in the developing eye to limit actin polymerization in the assembling ommatidia, but not in the morphogenetic furrow. While Ssh does control cell shape, surprisingly there are no direct or immediate consequences for cell type. Ssh protein becomes apically concentrated in cells that express elevated levels of the Sevenless (Sev) receptor-tyrosine kinase (RTK), even those which receive no ligand. We interpret this as a non-signal driven, RTK-dependent localization of Ssh to allow for locally increased actin filament turnover. We suggest that there are two modes of actin remodeling in the developing eye: a non-RTK, non-Ssh mediated mechanism in the morphogenetic furrow, and an RTK and Ssh-dependent mode during ommatidial assembly.
Actin Depolymerizing Factors↗
Fragile X protein functions with lgl and the par complex in flies and mice.
Fragile X syndrome, the most common form of inherited mental retardation, is caused by loss of function for the Fragile X Mental Retardation 1 gene (FMR1). FMR1 protein (FMRP) has specific mRNA targets and is thought to be involved in their transport to subsynaptic sites as well as translation regulation. We report a saturating genetic screen of the Drosophila autosomal genome to identify functional partners of dFmr1. We recovered 19 mutations in the tumor suppressor lethal (2) giant larvae (dlgl) gene and 90 mutations at other loci. dlgl encodes a cytoskeletal protein involved in cellular polarity and cytoplasmic transport and is regulated by the PAR complex through phosphorylation. We provide direct evidence for a Fmrp/Lgl/mRNA complex, which functions in neural development in flies and is developmentally regulated in mice. Our data suggest that Lgl may regulate Fmrp/mRNA sorting, transport, and anchoring via the PAR complex.
Alcohol Oxidoreductases↗
Biochemical and genetic interaction between the fragile X mental retardation protein and the microRNA pathway.
Fragile X syndrome is caused by a loss of expression of the fragile X mental retardation protein (FMRP). FMRP is a selective RNA-binding protein which forms a messenger ribonucleoprotein (mRNP) complex that associates with polyribosomes. Recently, mRNA ligands associated with FMRP have been identified. However, the mechanism by which FMRP regulates the translation of its mRNA ligands remains unclear. MicroRNAs are small noncoding RNAs involved in translational control. Here we show that in vivo mammalian FMRP interacts with microRNAs and the components of the microRNA pathways including Dicer and the mammalian ortholog of Argonaute 1 (AGO1). Using two different Drosophila melanogaster models, we show that AGO1 is critical for FMRP function in neural development and synaptogenesis. Our results suggest that FMRP may regulate neuronal translation via microRNAs and links microRNAs with human disease.
Animals↗
Growth and specification: fly Pax6 homologs eyegone and eyeless have distinct functions.
Development requires not only the correct specification of organs and cell types in the right places (pattern), but also the control of their size and shape (growth). Many signaling pathways control both pattern and growth and how these two are distinguished has been something of a mystery. In the fly eye, a Pax6 homolog (eyeless) controls eye specification together with several other genes. Now Dominguez et al.1 show that Notch signaling controls eye growth through a second Pax6 protein (Eyegone). In mice and humans the single Pax6 gene appears to encode both specification and growth controlling proteins through alternative mRNA splicing.
Alternative Splicing↗
Born again at the synapse: a new function for the anaphase promoting complex/cyclosome.
Currently, perhaps the most significant biological problem is to understand the mechanisms of learning and memory, and many of the answers will come from molecular explanations of synaptic plasticity. Two new papers have established a surprising connection: the Anaphase Promoting Complex/Cyclosome (APC/C) has a second function in controlling local protein stability at synapses, and hence in the control of behavior .
Anaphase-Promoting Complex-Cyclosome↗
Cell-cycle regulation and cell-type specification in the developing Drosophila compound eye.
During nervous system development stem cell daughters must exit the proliferative cycle to adopt specific neural and glial fates and they must do so in the correct positions. Cell proliferation in the central nervous system occurs in neuroepithelia such as the neural retina and the ventricular zones. As cells are assigned specific fates they migrate out of the plane of the epithelium to form higher layers. Recent evidence from the Drosophila compound eye suggests that a novel mode of Ras pathway regulation may be crucial in both cell-cycle exit and neural patterning: "MAP Kinase cytoplasmic hold".
Animals↗
RNA-mediated neurodegeneration caused by the fragile X premutation rCGG repeats in Drosophila.
Fragile X syndrome carriers have FMR1 alleles, called premutations, with an intermediate number of 5' untranslated CGG repeats between patients (>200 repeats) and normal individuals (<60 repeats). A novel neurodegenerative disease has recently been appreciated in some premutation carriers. As no neurodegeneration is seen in fragile X patients, who do not express FMR1, we hypothesize that lengthened rCGG repeats of the premutation transcript may lead to neurodegeneration. Here, using Drosophila melanogaster, we show that 90 rCGG repeats alone are sufficient to cause neurodegeneration. This phenotype is neuron specific and rCGG repeat dosage sensitive. Although devoid of mutant protein, this neurodegeneration exhibits neuronal inclusion bodies that are Hsp70 and ubiquitin positive. Overexpression of Hsp70 could suppress the neurodegeneration. These results demonstrate that neurodegenerative phenotype associated with fragile X premutation is indeed caused by the lengthened rCGG repeats and provide the first in vivo experimental demonstration of RNA-mediated neurodegeneration.
Animals↗
Looking up: regional patterning in the fly eye.
The Drosophila compound eye includes a dorsal domain specialized for the detection of the plane of polarized light. Two new papers show that this domain is controlled by graded Wingless signals acting through the homeodomain transcription factor Homothorax.
Animals↗
Nuclear translocation of activated MAP kinase is developmentally regulated in the developing Drosophila eye.
In proneural groups of cells in the morphogenetic furrow of the developing Drosophila eye phosphorylated mitogen activated protein kinase (MAPK) antigen is held in the cytoplasm for hours. We have developed a reagent to detect nuclear MAPK non-antigenically and report our use of this reagent to confirm that MAPK nuclear translocation is regulated by a second mechanism in addition to phosphorylation. This "cytoplasmic hold" of activated MAPK has not been observed in cell culture systems. We also show that MAPK cytoplasmic hold has an essential function in vivo: if it is overcome, developmental patterning in the furrow is disrupted.
Active Transport, Cell Nucleus↗
Retinal development in Drosophila: specifying the first neuron.
In vertebrates, a proneural basic helix-loop-helix transcription factor (Ath5, Atonal homolog 5) plays a crucial role in the specification of the first retinal neuron: the retinal ganglion cell (RGC). Math5 homozygous null mutant mice lack RGCs and have no optic nerve. Furthermore, the expression of the Ath5 protein is regulated to give a non-random dispersed pattern of RGCs. In Drosophila, retinal histogenesis is precisely coordinated and is associated with a progressive wave called the morphogenetic furrow. In the furrow, single precisely spaced cells are specified to become the first retinal neural cell type: the R8 photoreceptor cell. This Drosophila founder cell specification is coincident with and dependant upon the expression of the fly Ath5 ortholog: Atonal. Indeed, in both taxa, the process of founder cell specification may be viewed as the regulation of Atonal expression. It is now clear that, in flies, this regulation depends on the action of inductive and inhibitory signals. This review concentrates on the signaling mechanisms that produce this precise pattern of founder cells.
Animals↗