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J Neurosci. 2015 Mar 25;35(12):4983-98. doi: 10.1523/JNEUROSCI.4130-14.2015.

The Wnt adaptor protein ATP6AP2 regulates multiple stages of adult hippocampal neurogenesis.

Author information

1
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.
2
Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, California 92037.
3
Institute of Anatomy and Cell Biology, Universitätsmedizin Greifswald, 17487 Greifswald, Germany.
4
Institute of Physiology, University of Greifswald, 17495 Karlsburg, Germany, and.

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.

KEYWORDS:

ATP6AP2; CELSR1-3; PCP signaling; Wnt signaling; adult neurogenesis

PMID:
25810528
PMCID:
PMC4389597
DOI:
10.1523/JNEUROSCI.4130-14.2015
[Indexed for MEDLINE]
Free PMC Article

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