Delta1 Expression, Cell Cycle Exit, and Commitment to a Specific Secretory Fate Coincide within a Few Hours in the Mouse Intestinal Stem Cell System

Abstract

The stem cells of the small intestine are multipotent: they give rise, via transit-amplifying cell divisions, to large numbers of columnar absorptive cells mixed with much smaller numbers of three different classes of secretory cells - mucus-secreting goblet cells, hormone-secreting enteroendocrine cells, and bactericide-secreting Paneth cells. Notch signaling is known to control commitment to a secretory fate, but why are the secretory cells such a small fraction of the population, and how does the diversity of secretory cell types arise? Using the mouse as our model organism, we find that secretory cells, and only secretory cells, pass through a phase of strong expression of the Notch ligand Delta1 (Dll1). Onset of this Dll1 expression coincides with a block to further cell division and is followed in much less than a cell cycle time by expression of Neurog3 – a marker of enteroendocrine fate – or Gfi1 – a marker of goblet or Paneth cell fate. By conditional knock-out of Dll1, we confirm that Delta-Notch signaling controls secretory commitment through lateral inhibition. We infer that cells stop dividing as they become committed to a secretory fate, while their neighbors continue dividing, explaining the final excess of absorptive over secretory cells. Our data rule out schemes in which cells first become committed to be secretory, and then diversify through subsequent cell divisions. A simple mathematical model shows how, instead, Notch signaling may simultaneously govern the commitment to be secretory and the choice between alternative modes of secretory differentiation.

ADAM10 Regulates Notch Function in Intestinal Stem Cells of Mice

“…Notch plays an essential role in crypt cell proliferation 5,29 but it is only recently that lineage tracing and Notch inhibition studies have demonstrated that active Notch signaling is present 2–4,33 and required for maintenance of ISCs 7,34 . Notch inhibition led to reduced proliferation, loss of the stem cell marker, Olfm4, and apoptosis of CBCs, indicating that active Notch signaling is required for survival of Lgr5 + CBCs.…”

Functional linc-POU3F3 is overexpressed and contributes to tumorigenesis in glioma

“…Moreover, as it was demonstrated that the POU3F3 gene could interact with DLL1 and Sox2 promoters, activating their transcription (Catena et al, 2004;Castro et al, 2006), POU3F3 is involved into regulating cell proliferation via cell-cycle (G1) arrest and apoptosis through its influence on DLL1 and Sox2 (Otsubo et al, 2008;Stamataki et al, 2011). Meanwhile, since DLL1 acts as a Notch ligand, the influence of DLL1 expression by linc-POU3F3 also affect the Notch signaling, which regulates multiple cellular processes, including differentiation, proliferation, and cell fate decisions, and required for organogenesis and tissue homeostasis (Artavanis-Tsakonas et al, 1999).…”

Plasticity within stem cell hierarchies in mammalian epithelia

“…Within crypts, the Notch ligand Dll1 is expressed by secretory cell progenitors at cell positions just above the stem cell zone, which are immediate descendants of Lgr5+ cells [32,33]. Lineage tracing using a Dll1-GFP-IRESCreERT2 allele has shown that, during homeostasis, these cells generate small, short lived clones that comprise goblet cells, Paneth cells, tuft cells, and enteroendocrine cells.…”