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First published online 15 July 2008
doi: 10.1242/jcs.033167

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Divergent polarization mechanisms during vertebrate epithelial development mediated by the Crumbs complex protein Nagie oko

Nana Bit-Avragim^1,2,*, Nicole Hellwig^1,*, Franziska Rudolph¹, Chantilly Munson³, Didier Y. S. Stainier³ and Salim Abdelilah-Seyfried^1,

¹ Max Delbrück Center (MDC) for Molecular Medicine, 13125 Berlin, Germany
² Department of Cardiology, The Charité University Medical School of Berlin, Campus Buch, Campus Virchow Clinics, 13353 Berlin, Germany
³ Department of Biochemistry and Biophysics and Programs in Developmental Biology, Genetics, and Human Genetics, Cardiovascular Research Institute, University of California, San Francisco, CA 94143-2711, USA

Author for correspondence (e-mail: salim{at}mdc-berlin.de)

Accepted 14 May 2008

The zebrafish MAGUK protein Nagie oko is a member of the evolutionarily conserved Crumbs protein complex and functions as a scaffolding protein involved in the stabilization of multi-protein assemblies at the tight junction. During zebrafish embryogenesis, mutations in nagie oko cause defects in both epithelial polarity and cardiac morphogenesis. We used deletion constructs of Nagie oko in functional rescue experiments to define domains essential for cell polarity, maintenance of epithelial integrity and cardiac morphogenesis. Inability of Nagie oko to interact with Crumbs proteins upon deletion of the PDZ domain recreates all aspects of the nagie oko mutant phenotype. Consistent with this observation, apical localization of Nagie oko within the myocardium and neural tube is dependent on Oko meduzy/Crumbs2a. Disruption of direct interactions with Patj or Lin-7, two other members of the Crumbs protein complex, via the bipartite L27 domains produces only partial nagie oko mutant phenotypes and does not impair correct junctional localization of the truncated Nagie oko deletion protein within myocardial cells. Similarly, loss of the evolutionarily conserved region 1 domain, which mediates binding to Par6, causes only a subset of the nagie oko mutant epithelial phenotypes. Finally, deletion of the C-terminus, including the entire guanylate kinase and the SH3 domains, renders the truncated Nagie oko protein inactive and recreates all features of the nagie oko mutant phenotype when tested in functional complementation assays. Our observations reveal a previously unknown diversity of alternative multi-protein assembly compositions of the Crumbs–Nagie-oko and Par6-aPKC protein complexes that are highly dependent on the developmental context.

Key words: Nagie oko, Cell polarity, Heart, Organogenesis, aPKC, Mpp5, Pals1, Lin-7, Crumbs, Par6

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