title: The Wnt adaptor protein ATP6AP2 regulates multiple stages of adult hippocampal neurogenesis.
abstract: In the mammalian hippocampus, canonical Wnt signals provided by the microenvironment regulate the differentiation of adult neural stem cells (NSCs) toward the neuronal lineage. Wnts are part of a complex and diverse set of signaling pathways and the role of Wnt/Planar cell polarity (PCP) signaling in adult neurogenesis remains unknown. Using in vitro assays on differentiating adult NSCs, we identified a transition of Wnt signaling responsiveness from Wnt/β-catenin to Wnt/PCP signaling. In mice, retroviral knockdown strategies against ATP6AP2, a recently discovered core protein involved in both signaling pathways, revealed that its dual role is critical for granule cell fate and morphogenesis. We were able to confirm its dual role in neurogenic Wnt signaling in vitro for both canonical Wnt signaling in proliferating adult NSCs and non-canonical Wnt signaling in differentiating neuroblasts. Although LRP6 appeared to be critical for granule cell fate determination, in vivo knockdown of PCP core proteins FZD3 and CELSR1-3 revealed severe maturational defects without changing the identity of newborn granule cells. Furthermore, we found that CELSR1-3 control distinctive aspects of PCP-mediated granule cell morphogenesis with CELSR1 regulating the direction of dendrite initiation sites and CELSR2/3 controlling radial migration and dendritic patterning. The data presented here characterize distinctive roles for Wnt/β-catenin signaling in granule cell fate determination and for Wnt/PCP signaling in controlling the morphological maturation of differentiating neuroblasts.
authors: Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, California 92037, Institute of Physiology, University of Greifswald, 17495 Karlsburg, Germany, and Institute of Anatomy and Cell Biology, Universitätsmedizin Greifswald, 17487 Greifswald, Germany sschafer@salk.edu.
authors: Simon T
authors: ST
authors: Schafer
authors: Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, California 92037.
authors: Jinju
authors: http://orcid.org/0000-0003-1844-2301
authors: J
authors: Han
authors: Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, California 92037.
authors: Monique
authors: http://orcid.org/0000-0003-1162-6781
authors: M
authors: Pena
authors: Institute of Anatomy and Cell Biology, Universitätsmedizin Greifswald, 17487 Greifswald, Germany.
authors: Oliver
authors: http://orcid.org/0000-0002-6265-9156
authors: O
authors: von Bohlen Und Halbach
authors: Institute of Physiology, University of Greifswald, 17495 Karlsburg, Germany, and.
authors: Jörg
authors: J
authors: Peters
authors: Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, California 92037.
authors: Fred H
authors: FH
authors: Gage
mesh_terms: D000818:Animals; D015820:Cadherins / Q000235:genetics / Q000502:physiology; D002454:Cell Differentiation / Q000502:physiology; D016764:Cell Polarity / Q000502:physiology; D002478:Cells, Cultured; D005260:Female; D051157:Frizzled Receptors / Q000235:genetics / Q000502:physiology; D018507:Gene Expression Regulation, Developmental / Q000235:genetics / Q000502:physiology*; D055785:Gene Knockdown Techniques; D006624:Hippocampus / Q000166:cytology* / Q000254:growth & development; D051379:Mice; D058953:Neural Stem Cells / Q000502:physiology; D055495:Neurogenesis / Q000235:genetics / Q000502:physiology*; D006180:Proton-Translocating ATPases / Q000235:genetics / Q000502:physiology*; D011956:Receptors, Cell Surface / Q000235:genetics / Q000502:physiology*; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D015854:Up-Regulation; D060449:Wnt Signaling Pathway / Q000235:genetics / Q000502:physiology; D051176:beta Catenin / Q000502:physiology; D000093342:Prorenin Receptor
chemical_list: D015820:Cadherins; D051157:Frizzled Receptors; D006180:Proton-Translocating ATPases; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D051176:beta Catenin; C583530:ATP6AP2 protein, mouse; D000093342:Prorenin Receptor; C117380:Celsr1 protein, mouse; C498478:Celsr2 protein, mouse; C444454:Celsr3 protein, mouse; C486339:Fzd3 protein, mouse
keywords: ATP6AP2; CELSR1-3; PCP signaling; Wnt signaling; adult neurogenesis