Biomedical Engineering Reference
In-Depth Information
membrane-bound Delta on adjacent cells results in cleavage of the Notch
intracellular domain by g-secretase. The intracellular domain translocates to
the nucleus where it directs transcriptional activity. Notch signaling in the
'Notch high' cell induces expression of Hes1, a transcriptional repressor. In
many models the expression of this transcriptional repressor is important for
the maintenance of the precursor cell/stem cell phenotype. This also seems to be
the case in intestinal precursor cells, as inhibition of the Notch signaling cascade
in mice by use of a g-secretase inhibitor results in halted crypt proliferation and
drives precursor cell descendants prematurely into the goblet cell lineage (van
Es et al., 2005b). Intestinal restricted expression of a constitutive active form of
the mouse Notch1 receptor in a mouse model results in an opposite phenotype,
with expansion of the stem cell/transit-amplifying cell pool and inhibition of cell
differentiation (Fre et al., 2005).
2.2.3 TGFb Family Signaling
The TGFb family of proteins includes the bone morphogenetic proteins
(BMPs) and Activins. Members of the TGFb family bind to a heterodimeric
complex of a type I and type II receptor, resulting in the phosphorylation and
subsequent activation of a receptor-regulated SMAD (SMAD2 and 3 for the
TGFb and Activin receptor complexes and SMAD1, 5, and 8 for the BMP
receptor complex). These activated SMADs then form a complex with the co-
SMAD SMAD4. The SMAD dimer translocates to the nucleus where it binds
specific DNA sequences and directly modulates transcription. TGFb1,
TGFb2, and TGFb3 are all expressed in the adult colon. TGFb1isexpressed
by the differentiated enterocytes (Oshima et al., 1997), TGFb2 by endocrine
cells, and TGFb3 by the cells at the base of the crypts (Dunker et al., 2002).
Mostly based on in vitro experiments in colon-cancer cell lines it is often
suggested that TGFb signaling acts as a negative regulator of cellular prolif-
eration in the colon. This is unlikely to be the major role in normal colonic
epithelium in vivo as the type II TGFb receptor is mainly expressed by the
differentiated epithelial cells (Oshima et al., 1997). Indeed, mice heterozygous
for either Tgfb2 or Tgfb3 display substantially reduced epithelial apoptosis
whereas precursor cell proliferation is unaffected (Dunker et al., 2002). This
corroborated earlier findings in Tgfb1
/
mice that do not display increased
proliferation either (Engle et al., 1999).
A variety of BMPs and their antagonists are expressed by epithelial and
stromal cells in the colon (Li et al., 2007). Inhibitors of BMP signaling seem to
predominate at the base of the crypt (Kosinski et al., 2007) resulting in a
situation that favors BMP signaling in the cells at the top of the crypt, consistent
with the expression of activated BMP-associated receptor SMADs in these cells
(Hardwick et al., 2004). Similar to the role of TGFb signaling in vivo, BMP
signaling therefore regulates apoptosis of differentiated epithelial cells in vivo
(Hardwick et al., 2004). In contrast to TGFb signaling, however, the BMP
pathway also seems to be a critical regulator of precursor cell behavior.
