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Chordin, anantagonist of BMP4 (
Piccolo, Sasai, Lu,&DeRobertis, 1996
), that
is, lack of endogenous BMP4, leads to the reduction in proliferation and the
total number of adult epithelial cells. This implies that a certain amount of
BMP4 is required to maintain stem cells in the small intestine as in the case
of mammalian embryonic stem cells and primordial germ cells (
Fujiwara,
Dunn, & Hogan, 2001; Qi et al., 2004; Ying, Nichols, Chambers, & Smith,
2003
). Since amajor type I receptor for BMP4, BMPR-1A is expressed in both
the connective tissue and adult progenitor/stem cells (
Ishizuya-Oka et al.,
2006
), it seems likely that the action of BMP4 on the adult epithelium is direct,
differently from the indirect action of Shh. Further, the
Xenopus
homolog of
Drosophila
Tolloid closely related to BMP1 (Tolloid/BMP1), which regulates
the activity of BMP4 by degrading Chordin in the early
X. laevis
embryos
(
Balemans & Van Hul, 2002; Blitz, Shimmi, Wunnenberg-Stapleton,
O'Connor, & Cho, 2000; Wardle, Welch, & Dale, 1999
), has also been iden-
tified as a TH response gene related BMP4 (
Shimizu, Ishizuya-Oka, Amano,
Yoshizato,&Ueda, 2002
). Its expression is specific for the connective tissue and
is considered to be directly upregulated by THduring intestinal remodeling. It
is thus highly possible that the activityof BMP4 is spatiotemporally regulatedby
Tolloid/BMP1 throughChordin. These
in vitro
findings implicate Shh/BMP4
pathway as a key signaling essential for establishment of the stem cell niche.
To clarify roles of Shh/BMP4 signaling in adult stem cell development more
precisely, next step should be directed toward gain- or loss-of-function studies
of this pathway
in vivo
, by using recent frog Tg technology (
Rankin, Hasebe,
Zorn, & Buchholz, 2009; Rankin, Zorn, & Buchholz, 2011
).
5.3. Other signaling pathways
In the adult mammalian intestine, there is a growing body of evidence that
canonical Wnt/
b
-catenin signaling pathway plays a central role in mainte-
nance or proliferation of adult stem cells and their descendants (
Medema &
Vermeulen, 2011; Sato et al., 2009
). Although roles of Wnt signaling path-
ways in the amphibian intestinal remodeling have not yet been examined,
their components including
b
-catenin, Frizzled2, Wnt5a, and Ror2 have
been identified as TH response genes in the
X. laevis
intestine (
Buchholz
et al., 2007
). In addition, among TH response genes, there are many Wnt tar-
gets such as CD44 andWnt regulators including R-spondin1, which amplifies
canonical Wnt responses in the presence of LGR5 (
Ootani et al., 2009
),
and secreted Frizzled-related protein 2, which is a so-called Wnt inhibitor
(
Bovolenta, Esteve, Ruiz, Cisneros, & Lopez-Rios, 2008
) but has been shown
