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Development. 2015 Jun 15;142(12):2147-62. doi: 10.1242/dev.121046. Epub 2015 May 26.

Rab8a vesicles regulate Wnt ligand delivery and Paneth cell maturation at the intestinal stem cell niche.

Author information

1
Department of Biological Sciences, Rutgers University, Newark, NJ 07102, USA.
2
Department of Genetics, Human Genetics Institute of New Jersey, Rutgers University, Piscataway, NJ 08854, USA.
3
Department of Biomedical Genetics, Center for Oral Biology, James P. Wilmot Cancer Center, Stem Cell and Regenerative Medicine Institute, University of Rochester Medical Center, Rochester, NY 14642, USA.
4
Department of Cell Biology, Graduate School of Medicine, Osaka University 2-2, Yamadaoka, Suita, Osaka 565-0871, Japan.
5
Department of Genetics, Human Genetics Institute of New Jersey, Rutgers University, Piscataway, NJ 08854, USA Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08901, USA.
6
Department of Biological Sciences, Rutgers University, Newark, NJ 07102, USA Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08901, USA ngao@andromeda.rutgers.edu.

Abstract

Communication between stem and niche supporting cells maintains the homeostasis of adult tissues. Wnt signaling is a crucial regulator of the stem cell niche, but the mechanism that governs Wnt ligand delivery in this compartment has not been fully investigated. We identified that Wnt secretion is partly dependent on Rab8a-mediated anterograde transport of Gpr177 (wntless), a Wnt-specific transmembrane transporter. Gpr177 binds to Rab8a, depletion of which compromises Gpr177 traffic, thereby weakening the secretion of multiple Wnts. Analyses of generic Wnt/β-catenin targets in Rab8a knockout mouse intestinal crypts indicate reduced signaling activities; maturation of Paneth cells - a Wnt-dependent cell type - is severely affected. Rab8a knockout crypts show an expansion of Lgr5(+) and Hopx(+) cells in vivo. However, in vitro, the knockout enteroids exhibit significantly weakened growth that can be partly restored by exogenous Wnts or Gsk3β inhibitors. Immunogold labeling and surface protein isolation identified decreased plasma membrane localization of Gpr177 in Rab8a knockout Paneth cells and fibroblasts. Upon stimulation by exogenous Wnts, Rab8a-deficient cells show ligand-induced Lrp6 phosphorylation and transcriptional reporter activation. Rab8a thus controls Wnt delivery in producing cells and is crucial for Paneth cell maturation. Our data highlight the profound tissue plasticity that occurs in response to stress induced by depletion of a stem cell niche signal.

KEYWORDS:

Gpr177; Intestinal stem cell; Paneth cell; Rab8a; Wnt secretion; Wntless

PMID:
26015543
PMCID:
PMC4483769
DOI:
10.1242/dev.121046
[Indexed for MEDLINE]
Free PMC Article

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