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expressed in the adult epithelial progenitor/stem cells concomitantly with
their appearance ( Hasebe et al., 2008; Ishizuya-Oka et al., 2001 ). Shh is gen-
erally known to bind to a 12-transmembrane receptor, Patched (Ptc) ( Fuse
et al., 1999; Marigo, Davey, Zuo, Cunningham, & Tabin, 1996 ) and relieve
Ptc-mediated inhibition of the activity of Smoothened (Smo), a second
multipass membrane protein. This leads to the activation of the transcription
factors Glis, which finally regulate Shh target genes ( Ruiz i Altaba, 1999;
Sasaki, Nishizaki, Hui, Nakafuku, & Kondoh, 1999; Villavicencio,
Walterhouse, & Iannaccone, 2000 ). In the X. laevis intestine, the expression
of all of the Shh pathway components examined, namely, Ptc1, Smo, and
Gli1-3, has been shown to be upregulated by TH, although only Gli2, such
as Shh, is considered to be a TH direct response gene ( Hasebe, Kajita, Fu,
Shi, & Ishizuya-Oka, 2012 ). In contrast to the epithelium-specific expres-
sion of Shh, their expression is specific for mesenchymal tissues as in the
mammalian intestine ( Kolterud et al., 2009 ). In addition, our organ culture
study has shown that overexpression of Shh upregulates the expression of
Ptc1, Smo, and all Glis even in the absence of TH. These expression profiles
indicate that Shh by itself upregulates the expression of its pathway compo-
nents and other target genes in a paracrine manner.
To investigate possible roles of Shh in larval-to-adult intestinal remo-
deling, we previously performed culture experiments using the X. laevis
tadpole intestine ( Ishizuya-Oka, Hasebe, Shimizu, Suzuki, & Ueda, 2006;
Ishizuya-Oka et al., 2001 ). Exogenous Shh protein added to the TH-
containing culture medium promoted cell proliferation in the connective
tissue and muscles. In addition, Shh upregulated the expression of bone mor-
phogenetic protein (BMP) 4 only in the connective tissue just as Shh
upregulates themesenchyme-specific expression of BMP4 in the avian embry-
onicgut ( Roberts, Smith,Goff,&Tabin, 1998; Sukegawa et al., 2000 ). Further,
prolonged addition of exogenous Shh to the medium until day 7, when the
level of endogenous Shh expression becomes much lower, caused anomalies
of the adult epithelial structure. The epithelium often failed to form a lumen
as reported in the Shh-treated X. laevis embryonic gut ( Zhang, Rosenthal,
de Sauvage, & Shivdasani, 2001 ). This suggests that downregulation of the
Shh expression is necessary for normal differentiation of the intestinal epithe-
lium, although the action of Shh on the epithelium is indirect.
In contrast to Shh, exogenous BMP4 protein added to the culture medium
suppressed cell proliferation in the connective tissue and caused precocious dif-
ferentiation of the adult epithelium expressing IFABP in the X. laevis intestine
( Ishizuya-Oka et al., 2006 ). It should be noted that addition of excessive
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