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Human Molecular Genetics Advance Access originally published online on June 21, 2007
Human Molecular Genetics 2007 16(16):1993-2003; doi:10.1093/hmg/ddm147
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© The Author 2007. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

MPP1 links the Usher protein network and the Crumbs protein complex in the retina

Ilse Gosens1,4, Erwin van Wijk1,2,4, Ferry F.J. Kersten1,2,4, Elmar Krieger3,4, Bert van der Zwaag5, Tina Märker6, Stef J.F. Letteboer1, Simone Dusseljee1, Theo Peters2, Henk A. Spierenburg5, Ingrid M. Punte1, Uwe Wolfrum6, Frans P.M. Cremers1,4, Hannie Kremer2,{dagger} and Ronald Roepman1,4,*,{dagger}

1 Department of Human Genetics, 2 Department of Otorhinolaryngology, 3 Center for Molecular and Biomolecular Informatics, 4 Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Geert Grooteplein Zuid 10, PO Box 9101, 6500 HB, Nijmegen, The Netherlands, 5 Department of Pharmacology and Anatomy, Rudolf Magnus Institute of Neuroscience, University Medical Centre Utrecht, Utrecht, The Netherlands and 6 Department of Cell and Matrix Biology, Institute of Zoology, Johannes Gutenberg University of Mainz, Mainz, Germany

* To whom correspondence should be addressed. Tel: +31 24 3610487; Fax: +31 24 3668752; Email: r.roepman{at}antrg.umcn.nl

Received March 15, 2007; Revised June 10, 2007; Accepted June 10, 2007

The highly ordered distribution of neurons is an essential feature of a functional mammalian retina. Disruptions in the apico-basal polarity complexes at the outer limiting membrane (OLM) of the retina are associated with retinal patterning defects in vertebrates. We have analyzed the binding repertoire of MPP5/Pals1, a key member of the apico-basal Crumbs polarity complex, that has functionally conserved counterparts in zebrafish (nagie oko) and Drosophila (Stardust). We show that MPP5 interacts with its MAGUK family member MPP1/p55 at the OLM. Mechanistically, this interaction involves heterodimerization of both MAGUK modules in a directional fashion. MPP1 expression in the retina throughout development resembles the expression of whirlin, a multi-PDZ scaffold protein and an important organizer in the Usher protein network. We demonstrate that both proteins interact strongly by both a classical PDZ domain-to-PDZ binding motif (PBM) mechanism, and a mechanism involving internal epitopes. MPP1 and whirlin colocalize in the retina at the OLM, at the outer synaptic layer and at the basal bodies and the ciliary axoneme. In view of the known roles of the Crumbs and Usher protein networks, our findings suggest a novel link of the core developmental processes of actin polymerization and establishment/maintenance of apico-basal cell polarity through MPP1. These processes, essential in neural development and patterning of the retina, may be disrupted in eye disorders that are associated with defects in these protein networks.

{dagger} The authors wish it to be known that, in their opinion, the last two authors should be regarded as joint senior authors of this paper.


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