The Sokol Laboratory
The establishment of cell polarity
Current research
- Wnt signaling in development
- Establishment of cell polarity
- Early neural development
- Asymmetric division of neural stem / progenitor cells
Publications
Polarity is a fundamental cell property that is essential for cell functions and is required for cell maintenance and differentiation. How does polarity of the egg translate to polarized tissues in the developing embryo? In embryonic development, cell polarity is reflected in asymmetric division of progenitor cells and developmental fate decisions. The frog Xenopus laevis makes an important in vivo vertebrate system to study cell polarity in various developmental contexts (Figure 1). Using both frog and mouse embryos, we study biochemical mechanisms that generate cell and tissue polarity and would like to understand how communication between embryonic cells regulates polarized protein trafficking and cell polarity during early development.
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Figure 1. Basolateral distribution of GFP-Lgl in Xenopus embryonic ectoderm. Restricted localization of GFP-Lgl is not only an example of highly specific protein trafficking, but may be one of the key processes that are responsible for apical-basal polarity determination. |
The anterior and posterior poles of the C. elegans zygote are specified after fertilization by differential distribution of the PAR (par titioning defective) proteins to opposite regions of the zygote. PAR proteins influence asymmetric localization of cell fate determinants and mitotic spindle orientation not only in the C. elegans embryo, but have conserved functions in Drosophila and vertebrate embryos The apical Par protein complex, consisting of the PDZ-containing proteins Par-6 and Par-3 and atypical protein kinase C (aPKC), functions to control asymmetric divisions and establish cell polarity in a variety of cell types. Par-6 associates with aPKC and its substrate, the product of lethal giant larvae (Lgl). Activation of aPKC in this complex results in phosphorylation of Lgl and its dissociation from the cortex (Figure 2). Lgl is a WD domain-containing tumor suppressor that is essential for cell polarity determination and formation of adherens junctions in Drosophila . Lgl was shown to bind syntaxin 4, a component of the basolateral exocytic machinery, suggesting that Lgl controls cell polarity via directed exocytosis. Consistent with that view, the yeast homologues of Lgl Sro7 and Sro77, are required for polarized exocytosis. Together, these observations show that the Par complex regulates epithelial cell polarity through Lgl.
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Figure 2. Cell polarity is established by molecular interactions of the Par-6/aPKC complex and Lgl, leading to asymmetric localization of cell fate determinants in the opposing regions of the cell. |
Our work has shown that a vertebrate homologue of Lgl associates with Dishevelled, an essential mediator of Wnt signaling, and that Dishevelled regulates the localization of Lgl in Xenopus ectoderm and Drosophila follicular epithelium. We demonstrated that both Lgl and Dsh are required for normal apical-basal polarity of Xenopus ectodermal cells. Furthermore, we have shown that the Wnt receptor Frizzled 8, but not Frizzled 7, causes the dissociation of Lgl from the cortex and the concomitant loss of Lgl activity in vivo.
Our current studies are focused on the elucidation of the mechanism used by Lgl to control epithelial polarity. We are also carrying out the functional analysis of Frizzled and Lgl domains involved in this process.