Drosophila RET contains an active tyrosine kinase and elicits neurotrophic activities in mammalian cells
TL;DR: Initial biochemical and functional characterization of the dRET protein in cell culture systems indicate significant conservation between the biological effects elicited by the human and Drosophila RET kinases, and suggest functions for dRET in neuronal differentiation in the fly.
About: This article is published in FEBS Letters.The article was published on 2005-07-04 and is currently open access. It has received 32 citations till now. The article focuses on the topics: Glial cell line-derived neurotrophic factor & Tyrosine phosphorylation.
Citations
More filters
TL;DR: It is shown that RTK genes respond transcriptionally to insecticides by a mode-of-action independent way, raising the possibilities that insecticides may exert their sublethal effects through affecting the expression ofRTK genes.
Abstract: Sublethal effects of insecticides on insects have been widely documented. However, the underlining mechanisms remain largely unclear. Insecticides may be as ligands and disruptors to affect the expression and function of tyrosine kinase receptors (RTKs). Based on the transcriptome and the genomic data of Leptinotarsa decemlineata , 15 novel RTK members were identified and annotated in the present paper. These RTKs showed distinct 1:1 orthology relationships with Tribolium castaneum ones, suggesting functional conservation of RTKs in insects. The expression responses of the 16 RTKs to sublethal exposure to two juvenile hormone analogs (methoprene and pyriproxyfen) and three γ-aminobutyric acid receptor blockers (fipronil, butene-fipronil and endosulfan) were determined. Each of the 5 insecticides changed the expression levels of a specific subset of RTK genes, demonstrating that RTK genes respond transcriptionally to insecticides by a mode-of-action independent way. Our results raise the possibilities that insecticides may exert their sublethal effects through affecting the expression of RTK genes.
3 citations
DOI•
01 Jan 2017
TL;DR: .........................................................................
Abstract: ......................................................................................................................................... ii Lay Summary ............................................................................................................................... iv Preface .............................................................................................................................................v Table of
2 citations
Cites background from "Drosophila RET contains an active t..."
...Overexpression, rearrangement or point mutations of Ret are known to activate oncogenic signaling in both human and flies (Abrescia et al., 2005; Read et al., 2005)....
[...]
01 Jan 2016
TL;DR: In this chapter, interesting features of T-cadherin, RET, calsyntenins, and 7D- cadherins that have been discovered in the past 20 years are reviewed.
Abstract: In addition to the various cadherins described in previous chapters, there are several atypical cadherins that have unique structures and functions. Because of their great diversity, some cadherins have unexpected roles beyond cell–cell adhesion. In this chapter, we review interesting features of T-cadherin, RET, calsyntenins, and 7D-cadherins that have been discovered in the past 20 years.
2 citations
TL;DR: The Drosophila models facilitate studying the role of each component of the bidirectional signaling between pre- and postsynaptic neurons in the development of the key diagnostic NDD symptom—a defective memory formation resulted from synaptic atrophy.
Abstract: Molecular mechanisms of the synapse and dendrite integrity maintenance and their disruption in psychiatric and neurodegenerative diseases (NDD) are being studied intensively to identify target genes for therapeutic activities. It is suggested that synapse is a tripartite system in which glia, alongside with well-studied pre- and postsynaptic neurons, represents a third, poorly studied partner in synaptic transmission involved in a positive feedback loop between the other two partners. It is the glia cell-derived neurotrophic factor (GDNF) and the transmembrane proteins, neuregulins, that mediate bidirectional coupling between presynaptic neurons and their postsynaptic targets. Neuregulins are structurally related to the epidermal growth factor and have a cytoplasmic domain that interacts with intracellular LIM kinase 1 (LIMK1), the key enzyme of actin remodeling. Since neurons and axons that do not receive a sufficient GDNF supply are at risk of degeneration and synapse elimination, GDNF became a central target factor in human NDD therapy. The delivery of GDNF-producing stem cells to the nidus of neurodegeneration by transplantation surgery is an efficient tool for NDD treatment. A new approach is proposed based on the use of the Drosophila heat shock (hs) promoter that responds to the mammalian body temperature and ensures constant expression of the human GDNF gene. The Drosophila models facilitate studying the role of each component of the bidirectional signaling between pre- and postsynaptic neurons in the development of the key diagnostic NDD symptom—a defective memory formation resulted from synaptic atrophy. To assess the efficiency of memory formation depending on the level of GDNF and LIMK1 brain expression, we used the Drosophila strains simulating different nervous system disorders: GDNF, the transgenic flies that carry the human GDNF gene under hs-promoter, l(1)ts403, the mutants with disruption of heat shock proteins (HSPs) mRNA nuclear trafficking, and agn
ts3
carrying a mutation in LIMK1 gene. We investigated at the behavioral (learning/memory) level the functional connections between GDNF, LIMK1 and HSP signaling transductions that might offer promising targets for complex approaches to NDD treatment.
2 citations
03 Nov 2016
TL;DR: The conserved receptor tyrosine kinase (RTK) Ret (re-arranged during transfection) has been identified as an important regulator of C4da neuron dendrite development and patterning, providing novel insight into the Ret signaling pathway required for C4 da neuron dendsrite development, including the identification of mav as a potential ligand.
Abstract: The development of a functional nervous system requires correct neuronal specification to allow proper sensory information processing and communication within the neuronal network. In particular, neuronal dendrite development is highly complex and therefore strictly regulated by a variety of substrate and tissue interaction. Neurons establish subtype specific, often highly stereotyped branching patterns to cover their receptive field. Cell type specific functional complexity correlates with the morphological complexity characterized by the dendritic shape, arborization and size (Ramon y Cajal S, 1911). However, due to this complexity, mechanistic and molecular insight into dendrite development is still limited.
The Drosophila melanogaster larval peripheral nervous system (PNS) is a powerful genetic model for the analysis of dendrite development and function. Within the larval PNS, the well characterized dendritic arborization (da) neurons provide an excellent system to study dendrite development in vivo. C4da neurons feature class specific highly complex dendritic fields tiling the entire larval body wall. In this study, the conserved receptor tyrosine kinase (RTK) Ret (re-arranged during transfection) has been identified as an important regulator of C4da neuron dendrite development and patterning. A newly generated Ret knock-out (Retko) allele revealed strong C4da neuron dendrite growth and adhesion defects. This phenotype could be fully rescued by C4da neuron specific expression of transgenic Ret in Retko animals. Subsequent structure-function analysis of Ret revealed that the extra- and intracellular domain are both required for C4da dendrite development indicating that Ret transduces extracellular signals into the cell. Surprisingly, Ret tyrosine kinase activity is dispensable for Ret function in dendrite development, as expression of kinase-inactive Ret showed complete rescue activity. These results provide evidence that Ret is cell-autonomously required for C4da neuron dendrite patterning independently of its kinase activity. Furthermore, Retko animals displayed behavioural defects linked to C4da neuron function.
A candidate screen for Ret ligands identified the TGFβ ligand maverick (mav) as a potential interactor mediating Ret function in C4da neuron development. Mav is likely expressed and secreted by epithelial cells and analysis of mav function by generation of a mav knock-out allele (mavko) confirmed a role for mav in Ret dependent C4da neuron development. Moreover, mav likely acts as a permissive guidance signal required for C4da neuron dendrite patterning. Additionally, overexpression of mav and Ret is sufficient to induce dendrite growth in heterologous neurons suggesting that mav/Ret signaling is able to transduce growth signals. Overall, the data provide evidence that Ret and mav are acting in same signaling pathway in C4da neuron development, potentially as a novel receptor-ligand protein complex.
Analysis of the underlying signaling pathway indicated that canonical TGFβ signaling is not involved in Ret and mav function. Instead, genome wide microarray profiling of Retko C4da neurons identified RanBPM as a potential mediator of Ret intracellular signaling. Further analysis showed that RanBPM is expressed in C4da neurons and its loss-of-function displays Ret-like phenotypes in C4da neurons. In addition, a functional genetic link between RanBPM and Ret in C4da neurons development could be identified suggesting that RanBPM is a novel component of the Ret signaling pathway.
This work provides novel insight into the Ret signaling pathway required for C4da neuron dendrite development, including the identification of mav as a potential ligand. Based on the high degree of conservation of Ret, these findings suggest potentially conserved functions in dendrite development of vertebrates.
1 citations
Cites background from "Drosophila RET contains an active t..."
...However so far, Ret has not been shown to be involved in cell adhesion by homophilic interactions (Abrescia et al., 2005)....
[...]
...This result confirmed the conserved functionality of the Ret tyrosine kinase activity and downstream signaling between human and Drosophila and its function in neuronal differentiation (Abrescia et al., 2005)....
[...]
...Rather, extracellular cadherin-like domains suggest a role for Ret in adhesion, although Drosophila Ret is unable of homophilic binding in vitro (Abrescia et al., 2005)....
[...]
References
More filters
TL;DR: The protein kinase complement of the human genome is catalogued using public and proprietary genomic, complementary DNA, and expressed sequence tag sequences to provide a starting point for comprehensive analysis of protein phosphorylation in normal and disease states and a detailed view of the current state of human genome analysis through a focus on one large gene family.
Abstract: We have catalogued the protein kinase complement of the human genome (the "kinome") using public and proprietary genomic, complementary DNA, and expressed sequence tag (EST) sequences. This provides a starting point for comprehensive analysis of protein phosphorylation in normal and disease states, as well as a detailed view of the current state of human genome analysis through a focus on one large gene family. We identify 518 putative protein kinase genes, of which 71 have not previously been reported or described as kinases, and we extend or correct the protein sequences of 56 more kinases. New genes include members of well-studied families as well as previously unidentified families, some of which are conserved in model organisms. Classification and comparison with model organism kinomes identified orthologous groups and highlighted expansions specific to human and other lineages. We also identified 106 protein kinase pseudogenes. Chromosomal mapping revealed several small clusters of kinase genes and revealed that 244 kinases map to disease loci or cancer amplicons.
7,486 citations
"Drosophila RET contains an active t..." refers background in this paper
...actually correspond to pseudogenes and do not encode enzimatically active kinases [14]....
[...]
...structural motifs which unequivocally identify RET as a unique receptor tyrosine kinase in those species [9,13,14]....
[...]
...Fbgn0011829) is an active tyrosine kinase [14], and may therefore exert functions similar to human RET (herein hRET) with regards to downstream signaling....
[...]
Mark Raymond Adams1, Susan E. Celniker2, Robert A. Holt1, Cheryl A. Evans1 +191 more•Institutions (23)
TL;DR: The nucleotide sequence of nearly all of the approximately 120-megabase euchromatic portion of the Drosophila genome is determined using a whole-genome shotgun sequencing strategy supported by extensive clone-based sequence and a high-quality bacterial artificial chromosome physical map.
Abstract: The fly Drosophila melanogaster is one of the most intensively studied organisms in biology and serves as a model system for the investigation of many developmental and cellular processes common to higher eukaryotes, including humans. We have determined the nucleotide sequence of nearly all of the approximately 120-megabase euchromatic portion of the Drosophila genome using a whole-genome shotgun sequencing strategy supported by extensive clone-based sequence and a high-quality bacterial artificial chromosome physical map. Efforts are under way to close the remaining gaps; however, the sequence is of sufficient accuracy and contiguity to be declared substantially complete and to support an initial analysis of genome structure and preliminary gene annotation and interpretation. The genome encodes approximately 13,600 genes, somewhat fewer than the smaller Caenorhabditis elegans genome, but with comparable functional diversity.
6,180 citations
"Drosophila RET contains an active t..." refers background in this paper
...tified in the Drosophila genome [17,18,29,30], which could be taken to imply that cognate dRET ligands might be ‘‘nonneurotrophic’’ signaling factors....
[...]
TL;DR: It is shown that mice homozygous for a targeted mutation in c-ret develop to term, but die soon after birth, showing renal agenesis or severe dysgenesis, and lacking enteric neurons throughout the digestive tract, indicating an essential component of a signalling pathway required for renal organogenesis and enteric neurogenesis.
Abstract: Receptor tyrosine kinases (RTKs) are cell-surface molecules that transduce signals for cell growth and differentiation. The RTK encoded by the c-ret proto-oncogene is rearranged and constitutively activated in a large proportion of thyroid papillary carcinomas, and germ-line point mutations in c-ret seem to be responsible for the dominantly inherited cancer syndromes multiple endocrine neoplasia (MEN) types 2A and B. The gene is expressed in the developing central and peripheral nervous systems (sensory, autonomic and enteric ganglia) and the excretory system (Wolffian duct and ureteric bud epithelium) of mice, indicating that it may play a role in normal development. Here we show that mice homozygous for a targeted mutation in c-ret develop to term, but die soon after birth, showing renal agenesis or severe dysgenesis, and lacking enteric neurons throughout the digestive tract. Ret is thus an essential component of a signalling pathway required for renal organogenesis and enteric neurogenesis.
1,580 citations
Howard Hughes Medical Institute1, Celera Corporation2, University of California, Berkeley3, Harvard University4, University of Pennsylvania5, Wellcome Trust6, Stanford University7, Fred Hutchinson Cancer Research Center8, National Institutes of Health9, Lawrence Berkeley National Laboratory10, University of Leeds11, University of California, San Diego12, California Institute of Technology13, Massachusetts Institute of Technology14, BC Cancer Research Centre15, University of Maryland, Baltimore16, Centre national de la recherche scientifique17, University of California, San Francisco18, Columbia University19, Baylor College of Medicine20
TL;DR: The fly has orthologs to 177 of the 289 human disease genes examined and provides the foundation for rapid analysis of some of the basic processes involved in human disease.
Abstract: A comparative analysis of the genomes of Drosophila melanogaster, Caenorhabditis elegans, and Saccharomyces cerevisiae-and the proteins they are predicted to encode-was undertaken in the context of cellular, developmental, and evolutionary processes. The nonredundant protein sets of flies and worms are similar in size and are only twice that of yeast, but different gene families are expanded in each genome, and the multidomain proteins and signaling pathways of the fly and worm are far more complex than those of yeast. The fly has orthologs to 177 of the 289 human disease genes examined and provides the foundation for rapid analysis of some of the basic processes involved in human disease.
1,563 citations
TL;DR: In this paper, the expression cloning and characterization of GDNFR-α, a novel glycosylphosphatidylinositol-linked cell surface receptor for glial cell line-derived neurotrophic factor (GDNF), was reported.
1,164 citations