Intact function of Lgr5 receptor-expressing intestinal stem cells in the absence of Paneth cells

Proc Natl Acad Sci U S A. 2012 Mar 6;109(10):3932-7. doi: 10.1073/pnas.1113890109. Epub 2012 Feb 21.


Lifelong self-renewal of the adult intestinal epithelium requires the activity of stem cells located in mucosal crypts. Lgr5 and Bmi1 are two molecular markers of crypt-cell populations that replenish all lineages over time and hence function as stem cells. Intestinal stem cells require Wnt signaling, but the understanding of their cellular niche is incomplete. Lgr5-expressing crypt base columnar cells (CBCs) reside deep in the crypt, mingled among mature Paneth cells that are well positioned for short-range signaling. Partial lineage ablation previously had implied that Paneth cells are nonessential constituents of the stem-cell niche, but recently their absence was reported to interfere with Lgr5(+) CBCs, resurrecting an appealing idea. However, previous mouse models failed to remove Paneth cells completely or permanently; defining the intestinal stem-cell niche requires clarity with respect to the Paneth cell role. We find that Lgr5(+) cells with stem-cell activity cluster in future crypts early in life, before Paneth cells develop. We also crossed conditional Atoh1(-/-) mice, which lack Paneth cells entirely, with Lgr5(GFP) mice to visualize Lgr5(+) CBCs and to track their stem-cell function. In the sustained absence of Paneth cells, Lgr5(+) CBCs occupied the full crypt base, proliferated briskly, and generated differentiated progeny over many months. Gene expression in fluorescence-sorted Lgr5(+) CBCs reflected intact Wnt signaling despite the loss of Paneth cells. Thus, Paneth cells are dispensable for survival, proliferation, and stem-cell activity of CBCs, and direct contact with Lgr5-nonexpressing cells is not essential for CBC function.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Cell Proliferation
  • Crosses, Genetic
  • Green Fluorescent Proteins / metabolism
  • Immunohistochemistry / methods
  • Intestinal Mucosa / metabolism
  • Intestines / cytology
  • Ki-67 Antigen / biosynthesis
  • Mice
  • Mice, Transgenic
  • Microfilament Proteins / metabolism
  • Paneth Cells / cytology*
  • Receptors, G-Protein-Coupled / genetics
  • Receptors, G-Protein-Coupled / metabolism*
  • Signal Transduction
  • Stem Cells / cytology*


  • Atoh1 protein, mouse
  • Basic Helix-Loop-Helix Transcription Factors
  • Ki-67 Antigen
  • Lgr5 protein, mouse
  • Microfilament Proteins
  • Receptors, G-Protein-Coupled
  • villin
  • Green Fluorescent Proteins