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A wingless flight.

Yu X - PLoS Biol. (2003)

View Article: PubMed Central - PubMed

Affiliation: Department of Psychiatry and Behavioral Sciences at Stanford University Medical Center in Palo Alto, California, USA. yuxiang@stanford.edu

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The Wnt/Wingless (Wg) pathway is an evolutionarily conserved signaling pathway that plays important roles in normal development and cancer, from worms and flies to mice and humans... Two papers, identifying the first components of this pathway, initiated the active research field of Wnt/Wg signal transduction and profoundly influenced my scientific career... To investigate the relationship among these genes, the two groups exploited genetic epistasis, a manipulation in which two mutations with different phenotypes are combined in a single organism: if the genes are components of the same signaling pathway, the double mutant would resemble mutation in the more downstream component... By combining pairs of mutations with opposite phenotypes and observing the resulting effect, the investigators ordered the genes in a single signaling pathway: porc is required for secretion of Wg, while zw3 acts downstream of dsh and upstream of arm to transduce the Wg signal in the recipient cell... My summer project thus began at the cutting edge of research on a novel signaling pathway... I was to repeat the epistasis experiments using the dsh, zw3, and arm mutants and observe the effects of these mutations in the midgut, especially on reporters containing the WRS... With a lot of beginner's luck, I found that dsh, zw3, and arm transduce the Wg signal in the midgut, just as in the epidermis, and that they act through the 12 bases in the Ubx promoter that Mariann's group identified as the WRS... The LEF/TCF proteins were first cloned as enhancer-binding factors in T cells, but they were poor transcriptional activators until their interaction with β-catenin was identified... Together, LEF/TCF and β-catenin function as potent transcriptional activators... Mutations that allow β-catenin to accumulate in the absence of Wnt signaling, such as truncations in the adenomatous polyposis coli (APC) protein and stabilizing mutations in β-catenin, can lead to cancer... During my postdoctoral work, I have identified β-catenin, in its cell adhesion function as part of the cadherin/catenin complex, as an important mediator of dendritic morphogenesis... It is very exciting to have identified a new function for my favorite molecule in a model system for which relatively little is known about the function of Wnt/ β-catenin signaling... I hope to be able to start my own research group in the near future to work on the role of Wnt/ β-catenin signaling in dendritic development and neural circuit formation.

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A Simplified Version of Wnt/Wg SignalingIn the absence of the Wnt ligand, Arm/ β-catenin (β) is phosphorylated by a complex of Axin, APC, and Zw3/GSK3 β and rapidly degraded. Upon Wnt (W) signaling through the Frizzled receptor and Dsh, this complex is inhibited: as a consequence, β-catenin accumulates and binds to LEF/TCF proteins to stimulate transcription of Wnt target genes.
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pbio.0000049-g001: A Simplified Version of Wnt/Wg SignalingIn the absence of the Wnt ligand, Arm/ β-catenin (β) is phosphorylated by a complex of Axin, APC, and Zw3/GSK3 β and rapidly degraded. Upon Wnt (W) signaling through the Frizzled receptor and Dsh, this complex is inhibited: as a consequence, β-catenin accumulates and binds to LEF/TCF proteins to stimulate transcription of Wnt target genes.

Mentions: In 1994 two groups, led by Norbert Perrimon and Roel Nusse, identified the first components of the Wg signaling pathway (Noordermeer et al. 1994; Siegfried et al. 1994) in the fruitfly Drosophila melanogaster. Embryos lacking the segment polarity gene wingless (wg) are completely covered with small pointed ridges (denticles) on their undersurface (ventral cuticle), in contrast to wild-type embryos, which have an alternating pattern of naked cuticle and denticle belts (Cadigan and Nusse 1997). Similar phenotypes were observed in a number of other mutations, including dishevelled (dsh), porcupine (porc), and armadillo (arm), while mutation in zeste-white 3 (zw3) or overexpression of Wg resulted in the opposite phenotype, i.e., an entirely naked cuticle. To investigate the relationship among these genes, the two groups exploited genetic epistasis, a manipulation in which two mutations with different phenotypes are combined in a single organism: if the genes are components of the same signaling pathway, the double mutant would resemble mutation in the more downstream component. By combining pairs of mutations with opposite phenotypes and observing the resulting effect, the investigators ordered the genes in a single signaling pathway: porc is required for secretion of Wg, while zw3 acts downstream of dsh and upstream of arm to transduce the Wg signal in the recipient cell. Thus, the first four components of the Wnt signaling pathway were identified (see Figure 1).


A wingless flight.

Yu X - PLoS Biol. (2003)

A Simplified Version of Wnt/Wg SignalingIn the absence of the Wnt ligand, Arm/ β-catenin (β) is phosphorylated by a complex of Axin, APC, and Zw3/GSK3 β and rapidly degraded. Upon Wnt (W) signaling through the Frizzled receptor and Dsh, this complex is inhibited: as a consequence, β-catenin accumulates and binds to LEF/TCF proteins to stimulate transcription of Wnt target genes.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC300676&req=5

pbio.0000049-g001: A Simplified Version of Wnt/Wg SignalingIn the absence of the Wnt ligand, Arm/ β-catenin (β) is phosphorylated by a complex of Axin, APC, and Zw3/GSK3 β and rapidly degraded. Upon Wnt (W) signaling through the Frizzled receptor and Dsh, this complex is inhibited: as a consequence, β-catenin accumulates and binds to LEF/TCF proteins to stimulate transcription of Wnt target genes.
Mentions: In 1994 two groups, led by Norbert Perrimon and Roel Nusse, identified the first components of the Wg signaling pathway (Noordermeer et al. 1994; Siegfried et al. 1994) in the fruitfly Drosophila melanogaster. Embryos lacking the segment polarity gene wingless (wg) are completely covered with small pointed ridges (denticles) on their undersurface (ventral cuticle), in contrast to wild-type embryos, which have an alternating pattern of naked cuticle and denticle belts (Cadigan and Nusse 1997). Similar phenotypes were observed in a number of other mutations, including dishevelled (dsh), porcupine (porc), and armadillo (arm), while mutation in zeste-white 3 (zw3) or overexpression of Wg resulted in the opposite phenotype, i.e., an entirely naked cuticle. To investigate the relationship among these genes, the two groups exploited genetic epistasis, a manipulation in which two mutations with different phenotypes are combined in a single organism: if the genes are components of the same signaling pathway, the double mutant would resemble mutation in the more downstream component. By combining pairs of mutations with opposite phenotypes and observing the resulting effect, the investigators ordered the genes in a single signaling pathway: porc is required for secretion of Wg, while zw3 acts downstream of dsh and upstream of arm to transduce the Wg signal in the recipient cell. Thus, the first four components of the Wnt signaling pathway were identified (see Figure 1).

View Article: PubMed Central - PubMed

Affiliation: Department of Psychiatry and Behavioral Sciences at Stanford University Medical Center in Palo Alto, California, USA. yuxiang@stanford.edu

AUTOMATICALLY GENERATED EXCERPT
Please rate it.

The Wnt/Wingless (Wg) pathway is an evolutionarily conserved signaling pathway that plays important roles in normal development and cancer, from worms and flies to mice and humans... Two papers, identifying the first components of this pathway, initiated the active research field of Wnt/Wg signal transduction and profoundly influenced my scientific career... To investigate the relationship among these genes, the two groups exploited genetic epistasis, a manipulation in which two mutations with different phenotypes are combined in a single organism: if the genes are components of the same signaling pathway, the double mutant would resemble mutation in the more downstream component... By combining pairs of mutations with opposite phenotypes and observing the resulting effect, the investigators ordered the genes in a single signaling pathway: porc is required for secretion of Wg, while zw3 acts downstream of dsh and upstream of arm to transduce the Wg signal in the recipient cell... My summer project thus began at the cutting edge of research on a novel signaling pathway... I was to repeat the epistasis experiments using the dsh, zw3, and arm mutants and observe the effects of these mutations in the midgut, especially on reporters containing the WRS... With a lot of beginner's luck, I found that dsh, zw3, and arm transduce the Wg signal in the midgut, just as in the epidermis, and that they act through the 12 bases in the Ubx promoter that Mariann's group identified as the WRS... The LEF/TCF proteins were first cloned as enhancer-binding factors in T cells, but they were poor transcriptional activators until their interaction with β-catenin was identified... Together, LEF/TCF and β-catenin function as potent transcriptional activators... Mutations that allow β-catenin to accumulate in the absence of Wnt signaling, such as truncations in the adenomatous polyposis coli (APC) protein and stabilizing mutations in β-catenin, can lead to cancer... During my postdoctoral work, I have identified β-catenin, in its cell adhesion function as part of the cadherin/catenin complex, as an important mediator of dendritic morphogenesis... It is very exciting to have identified a new function for my favorite molecule in a model system for which relatively little is known about the function of Wnt/ β-catenin signaling... I hope to be able to start my own research group in the near future to work on the role of Wnt/ β-catenin signaling in dendritic development and neural circuit formation.

Show MeSH
Related in: MedlinePlus