Molecular Biology of the Cell by Bruce Alberts, Alexander Johnson, Julian Lewis, David Morgan, Martin Raff, Keith Roberts, Peter Walter by by Bruce Alberts, Alexander Johnson, Julian Lewis, David Morg

1224 Chapter 22: Stem Cells and Tissue Renewal
Lgr5-
expressing
cell
day 1
day 2
Wnt
Paneth cell
Paneth cell
day 5
day 8
EphB expressed
in plasma membrane
EphBexpressing
cell
EphrinBexpressing
cell
(A)
(B)
250 µm
(C)
EphrinB expressed in
plasma membrane
Figure 22–8 Genesis of a minigut from a single Lgr5-expressing cell cultured in a cell-free
matrix. (A,B) The founder cell first divides to form a small vesicle. At random, one or more of the
cells in this vesicle differentiates as a Paneth cell (blue). This cell maintains Lgr5 expression (yellow)
in its immediate neighbors, which persist as stem cells that generate the full range of intestinal cell
types. (C ) Schematic diagram of the
MBoC6
key organizing
n22.105/22.08
signals. The Paneth cells organize crypts by
producing a Wnt signal that acts on neighboring cells and keeps them proliferating in the stemcell
state. A repulsive interaction based on ephrin–Eph binding causes the crypt cell types (which
express EphB, induced by Wnt) to segregate from the nondividing differentiated villus cell types
(which express EphrinB). Both ephrin and Eph are cell-surface proteins attached to the plasma
membrane; in many tissues, two cells that contain a different member of this pair repel each other
when they touch (see Figure 21–49). (Adapted from T. Sato and H. Clevers, Science 340:1190–
1194, 2013. With permission from AAAS.)
Ephrin–Eph Signaling Drives Segregation of the Different Gut Cell
Types
The remarkable self-organizing behavior of the cultured organoids suggests that
some interaction among the different epithelial cells drives them to segregate
from one another. The ephrin–Eph signaling pathway (discussed in Chapter 15)
appears to be responsible. The cells that live in the crypts express EphB receptor
proteins, while absorptive, goblet, and enteroendocrine cells, as they begin to differentiate,
switch off expression of this receptor and instead switch on expression
of its ligands, cell-surface proteins of the EphrinB family (Figure 22–8C). In various
other tissues, cells expressing Eph proteins are repelled by contacts with cells
expressing ephrins on their surface (see Figures 21–49 and 21–79). It seems that
the same is true in the gut lining, and that this mechanism serves to keep the cells
segregated and in their proper places. In EphB knockout mutants, the populations
become mixed, so that, for example, Paneth cells wander out onto the villi.
Notch Signaling Controls Gut Cell Diversification and Helps
Maintain the Stem-Cell State
If a single type of stem cell generates all the differentiated cell types in the gut
lining, what causes the progeny of this stem cell to diversify? Notch signaling has
this role in many other systems, where it mediates lateral inhibition—a competitive
interaction that drives neighboring cells toward different fates (see Figure
15–58 and Figure 21–35). All the essential components of the Notch pathway
are expressed in the crypts; it seems that Wnt signaling maintains them there. If
Notch signaling is abruptly blocked, within a few days all the cells in the crypts
differentiate as goblet cells, and absorptive cells cease to be produced; conversely,
if Notch signaling is artificially activated in all the cells, absorptive cells continue