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Regulation of Lethal giant larvae by Dishevelled
Gretchen L Dollar1, Ursula Weber, Marek Mlodzik
1Department of Molecular, Cell and Developmental Biology, Box 1020, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, New York 10029, USA.
Abstract:
The establishment of polarity in many cell types depends on Lgl, the tumour suppressor product of lethal giant larvae, which is involved in basolateral protein targeting. The conserved complex of Par3, Par6 and atypical protein kinase C phosphorylates and inactivates Lgl at the apical surface; however, the signalling mechanisms that coordinate cell polarization in development are not well defined. Here we show that a vertebrate homologue of Lgl associates with Dishevelled, an essential mediator of Wnt signalling, and that Dishevelled regulates the localization of Lgl in Xenopus ectoderm and Drosophila follicular epithelium. We show that both Lgl and Dsh are required for normal apical-basal polarity of Xenopus ectodermal cells. In addition, we show that the Wnt receptor Frizzled 8, but not Frizzled 7, causes Lgl to dissociate from the cortex with the concomitant loss of its activity in vivo. These findings suggest a molecular basis for the regulation of cell polarity by Frizzled and Dishevelled.
Insights
Lethal giant larvae (Lgl) protein localization and activity, crucial for cell polarity, are regulated by Dishevelled (Dsh) and Wnt signaling. This reveals a molecular mechanism controlling cell polarization during development.
Area of Science:
- Cell biology
- Developmental biology
- Molecular signaling
Background:
- Cell polarity is fundamental for tissue development and function.
- Lethal giant larvae (Lgl) protein is a key regulator of cell polarity and basolateral protein targeting.
- The precise signaling pathways governing cell polarization remain incompletely understood.
Purpose of the Study:
- To investigate the role of Dishevelled (Dsh) in regulating Lgl localization and cell polarity.
- To elucidate the involvement of Wnt signaling pathways in the control of Lgl activity.
- To define the molecular mechanisms underlying Wnt-mediated regulation of cell polarity.
Main Methods:
- Investigated the association between Lgl and Dishevelled (Dsh) in Xenopus ectoderm and Drosophila follicular epithelium.
- Utilized Xenopus and Drosophila models to study the functional requirement of Lgl and Dsh in establishing apical-basal polarity.
- Examined the effect of Wnt receptor Frizzled 8 activation on Lgl localization and activity in vivo.
Main Results:
- Demonstrated that a vertebrate Lgl homolog associates with Dishevelled (Dsh).
- Showed that Dsh regulates the localization of Lgl in both Xenopus ectoderm and Drosophila follicular epithelium.
- Confirmed that both Lgl and Dsh are essential for normal apical-basal polarity in Xenopus ectodermal cells.
- Found that activation of Frizzled 8, but not Frizzled 7, leads to Lgl dissociation from the cortex and loss of its activity.
Conclusions:
- Dishevelled (Dsh) plays a critical role in regulating the localization and activity of Lethal giant larvae (Lgl) protein.
- Wnt signaling, specifically through Frizzled 8, directly impacts Lgl function, providing a molecular link between Wnt pathways and cell polarity.
- These findings offer a novel molecular framework for understanding how Frizzled and Dishevelled coordinate cell polarity during development.
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