![]() SOX9 is also involved in the development of the neural crest ( Spokony et al., 2002) and of the spinal cord glial cells ( Stolt et al., 2003). SOX9 function is best known for its essential roles in chondrogenesis ( Foster et al., 1994 Wagner et al., 1994 Wright et al., 1995 Bi et al., 1999, 2001) and the development of the male gonad ( Foster et al., 1994 Wagner et al., 1994 Kent et al., 1996 Südbeck et al., 1996). This unexpectedly led to the identification of SOX9. Here, we screened the intestine epithelium for expressed SOX genes to investigate the possibility of a functional link with the related Tcf factors. Similarly to TCFs, SOX proteins have been widely implicated in the establishment of cell multipotency ( Avilion et al., 2003 Kim et al., 2003), cell commitment ( Mori-Akiyama et al., 2003 Stolt et al., 2003), and differentiation ( Kamachi et al., 2000 Stolt et al., 2002). The TCF/LEF transcription factors share a common high mobility group DNA binding domain with the SOX transcription factors. However, evidence for such branch-determining factors, each mediating part of the Wnt response downstream of the TCF/LEF transcription factors, is presently lacking. The diversity of cellular processes involving Wnt signals suggests branching of the pathway to permit specific cell responses. Moreover, targeted mutations of APC or β-catenin are sufficient to initiate tumorigenesis in the mouse ( Fodde et al., 1994 Shibata et al., 1997 Harada et al., 1999), highlighting the importance of the Wnt pathway in the development of cancer. ![]() Such mutations result in stabilization of β-catenin, which then continuously interacts with TCF4, leading to constitutive activation of target genes ( Korinek et al., 1997). Finally, mutations in components of the Wnt pathway, including the tumor suppressor APC and the multifunctional β-catenin protein, are found in the vast majority of colon cancers ( Morin et al., 1997). In addition, Wnt signals control the differentiation of the secretory cell lineage of the epithelium, because overexpression of the Wnt-pathway inhibitor Dickkopf1 blocks differentiation of the Paneth, goblet, and enteroendocrine cell types ( Pinto et al., 2003). The Wnt pathway also regulates the expression of the Eph/Ephrin surface molecules, responsible for the ordered positioning of epithelial cells along the crypt-villus axis ( Batlle et al., 2002). Consistent with this, no proliferation can be detected, and all epithelial cells appear differentiated, in the intestine of mice null for TCF4, the main Wnt pathway transcription factor in the intestinal epithelium ( Korinek et al., 1998). In the intestine, the Wnt signaling pathway has been implicated in the regulation of the proliferation/differentiation balance ( van de Wetering et al., 2002). Interaction with β-catenin activates the TCF/LEF transcription factors, resulting in transcription of target genes ( Brantjes et al., 2002). Upon binding of a secreted Wnt molecule to its corresponding Frizzled receptor, the canonical Wnt pathway is activated, resulting in the stabilization and accumulation of β-catenin in the nucleus. ![]() ![]() ![]() In the small intestine, a fourth cell type, the Paneth cells, migrates downward and settles at the bottom of the crypts as terminally differentiated cells ( Potten and Moeffler, 1990 Stappenbeck et al., 1998).Įxtracellular signals, including Wnt molecules, are required for this organization of the intestine epithelium. Multipotent stem cells, located near the bottom of the crypts, generate new cells which migrate to the villus while differentiating into enterocyte, goblet, and enteroendocrine cells. This epithelium consists of a proliferative compartment, the crypt of Lieberkühn, and a differentiated, functional compartment, consisting of the villus in the small intestine and the luminal surface in the colon. Proliferation, differentiation, and migration of cells must be coordinately regulated to maintain the integrity of the continuously renewing intestine epithelium. ![]()
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