title: Atp6ap2/(pro)renin receptor interacts with Par3 as a cell polarity determinant required for laminar formation during retinal development in mice.
abstract: (Pro)renin receptor [(P)RR], also known as Atp6ap2, has attracted growing attention as a key molecule for tissue renin-angiotensin system (RAS). In addition to its role in tissue RAS activation, Atp6ap2/(P)RR was originally identified as an accessory subunit for vacuolar H(+)-ATPase (v-ATPase), which is a multisubunit proton pump involved in diverse and fundamental cellular physiology. In this study, to elucidate the physiological function of Atp6ap2/(P)RR during retinal development in mammals, we used Cre-LoxP system to generate photoreceptor-specific conditional knock-out (CKO) mice, and revealed a critical role of Atp6ap2/(P)RR in photoreceptor development. Deletion of photoreceptor Atp6ap2/(P)RR did not affect retinal cell differentiation, but led to laminar disorganization around the outer nuclear layer together with severe dysfunction of photoreceptor cells. In the CKO mice, cell adhesion and polarity molecules, some of which were colocalized with Atp6ap2/(P)RR at the apical edge of the wild-type developing retina, were substantially dispersed together with mislocalization of retinal progenitor cells apart from the apical surface. Among theses molecules, coimmunoprecipitation using retinal homogenates and ATP6AP2/(P)RR-transfected cells showed that Atp6ap2/(P)RR interacted with partitioning defective 3 homolog (PAR3) protein, which is known to function in the Par-atypical protein kinase C (aPKC) system. Furthermore, yeast two-hybrid assays demonstrated direct molecular interaction between ATP6AP2/(P)RR and PAR3. Our present data revealed the novel function of Atp6ap2/(P)RR required for laminar formation during retinal development. We propose that this cellular activity associated with the Par-aPKC system, in addition to the v-ATPase function and tissue RAS activation, is the third biological role of Atp6ap2/(P)RR.
authors.affiliation: Laboratory of Ocular Cell Biology and Visual Science, Department of Ophthalmology, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido 060-8638, Japan, Department of Ophthalmology, Keio University School of Medicine, Tokyo 160-8582, Japan, Laboratory for Molecular and Developmental Biology, Institute for Protein Research, Osaka University, and JST, CREST, Suita, Osaka, 565-0871, Japan, and Department of Endocrinology and Hypertension, Tokyo Women's Medical University, Tokyo 162-8666, Japan.
authors.forename: Atsuhiro
authors.initials: A
authors.lastname: Kanda
authors.forename: Kousuke
authors.initials: K
authors.lastname: Noda
authors.forename: Kenya
authors.initials: K
authors.lastname: Yuki
authors.forename: Yoko
authors.initials: Y
authors.lastname: Ozawa
authors.forename: Takahisa
authors.initials: T
authors.lastname: Furukawa
authors.forename: Atsuhiro
authors.initials: A
authors.lastname: Ichihara
authors.forename: Susumu
authors.initials: S
authors.lastname: Ishida
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D015153:Blotting, Western; D002448:Cell Adhesion / Q000502:physiology; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000502:physiology*; D002452:Cell Count; D018797:Cell Cycle Proteins; D016764:Cell Polarity / Q000502:physiology*; D004596:Electroretinography; D047468:Immunoprecipitation; D051379:Mice; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D016296:Mutagenesis / Q000502:physiology; D020419:Photoreceptor Cells, Vertebrate / Q000502:physiology; D010957:Plasmids / Q000235:genetics / Q000502:physiology; D016133:Polymerase Chain Reaction; D006180:Proton-Translocating ATPases / Q000235:genetics / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D012160:Retina / Q000254:growth & development*; D000093342:Prorenin Receptor
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D015815:Cell Adhesion Molecules; D018797:Cell Cycle Proteins; D006180:Proton-Translocating ATPases; D011956:Receptors, Cell Surface; C583530:ATP6AP2 protein, mouse; D000093342:Prorenin Receptor; C115084:Pard3 protein, mouse