Llgl1 Connects Cell Polarity with Cell-Cell Adhesion in Embryonic Neural Stem Cells

Publication date: Available online 25 May 2017
Source:Developmental Cell
Author(s): Yves Jossin, Minhui Lee, Olga Klezovitch, Elif Kon, Alexia Cossard, Wen-Hui Lien, Tania E. Fernandez, Jonathan A. Cooper, Valera Vasioukhin
Malformations of the cerebral cortex (MCCs) are devastating developmental disorders. We report here that mice with embryonic neural stem-cell-specific deletion of Llgl1 (Nestin-Cre/Llgl1^fl/fl), a mammalian ortholog of the Drosophila cell polarity gene lgl, exhibit MCCs resembling severe periventricular heterotopia (PH). Immunohistochemical analyses and live cortical imaging of PH formation revealed that disruption of apical junctional complexes (AJCs) was responsible for PH in Nestin-Cre/Llgl1^fl/fl brains. While it is well known that cell polarity proteins govern the formation of AJCs, the exact mechanisms remain unclear. We show that LLGL1 directly binds to and promotes internalization of N-cadherin, and N-cadherin/LLGL1 interaction is inhibited by atypical protein kinase C-mediated phosphorylation of LLGL1, restricting the accumulation of AJCs to the basolateral-apical boundary. Disruption of the N-cadherin-LLGL1 interaction during cortical development in vivo is sufficient for PH. These findings reveal a mechanism responsible for the physical and functional connection between cell polarity and cell-cell adhesion machineries in mammalian cells.

Teaser

The mechanisms responsible for developmental malformations of the cerebral cortex are not well understood. Jossin, Lee, Klezovitch et al. show that ablation of cell polarity protein LLGL1 during cortical development causes disruption of cell-cell adhesion structures and results in neuronal heterotopia. LLGL1 binds to cell adhesion protein N-cadherin and regulates its cellular localization.


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