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    • We therefore favor the final possibility that

    2018-10-22

    We therefore favor the final possibility: that a cell type that evaded Cre-mediated Porcn deletion is a sufficient source of essential, intestine-active Wnts. That cell is unlikely to reside in the epithelium, where Villin-Cre mice drove efficient Cre expression, leaving no intact Porcn DNA in isolated epithelial cells. By contrast, although Myh11-expressing smooth-muscle mct2 inhibitor or SEMF are not a required physiologic Wnt source, gut mesenchyme contains diverse additional cell types, including endothelium, nonmuscle fibroblasts, leukocytes, lymphocytes, and neurons (Powell et al., 2011). Endothelial and neuronal contributions cannot readily be assessed in mice because their deficiencies are lethal early (Dumont et al., 1994; Enomoto et al., 1998), and intestinal functions seem intact in Rag2-null mice (Shinkai et al., 1992), indicating that lymphocytes either provide no essential Wnts or act redundantly with other cells. This extent of specificity or redundancy in intestinal Wnt source(s) challenges the prevailing view and reveals unanticipated complexity in control of intestinal self-renewal.
    Experimental Procedures
    Acknowledgments We thank Sylvie Robine for Villin mice. This work was supported by National Institute of Health grants R01DK081113 and R01DK082889 to R.A.S. and a National Science Foundation Graduate Research Fellowship to A.K.S.R.
    Introduction Stem cells are critical for tissue homeostasis and regeneration in adult tissues (Simons and Clevers, 2011; Weissman, 2000). The overall decline in tissue regenerative potential with age is accompanied by an age-dependent reduction of adult stem cell functions (Rando, 2006; Rossi et al., 2005; Sharpless and DePinho, 2007). This leads to the hypothesis that stem cell aging may be responsible for age-associated tissue function deterioration and age-related degenerative diseases (Balducci and Ershler, 2005; Bell and Van Zant, 2004; Krtolica, 2005; Van Zant and Liang, 2003). Therefore, understanding the underlying mechanisms that control adult stem cell behavior will provide a platform for therapeutic applications in age-related diseases. The Drosophila adult midgut is an excellent system for studying stem cell biology. Mammalian and fly intestines show marked similarities (Casali and Batlle, 2009; Stainier, 2005; Wang and Hou, 2010). Previous studies demonstrated that fly adult midgut is maintained by ISCs (Micchelli and Perrimon, 2006; Ohlstein and Spradling, 2006). ISCs self-renew and produce enteroblasts (EBs), which will differentiate into either enterocytes (ECs) or enteroendocrine cells (ee) by differential Notch signaling (Micchelli and Perrimon, 2006; Ohlstein and Spradling, 2006; Ohlstein and Spradling, 2007). It has been shown that midgut homeostasis is lost in aged flies, and Jun N-terminal kinase (JNK) signaling contributes to tissue homeostasis loss (Biteau et al., 2008; Choi et al., 2008). However, which endogenous stimuli result in JNK signaling activation in the aging gut and how JNK signaling is regulated remain unexplored. The Hedgehog (Hh) signaling pathway is evolutionarily conserved in regulating tissue growth and patterning (Ingham et al., 2011; Jiang and Hui, 2008). Aberrant Hh signaling activation causes numerous diseases (Barakat et al., 2010; Taipale and Beachy, 2001). Once released, Hh binds to Patched (Ptc) and alleviates its inhibitory effect on Smoothened (Smo). Smo recruits the Cubitus interruptus (Ci) complex and induces target gene expression (Lum and Beachy, 2004). Ci is polyubiquitinated and degraded in the lysosome, mediated by Debra (Dbr) (Dai et al., 2003). Previous studies have shown that Hh signaling provides a negative feedback signal in regulating the colonic stem cell niche (Büller et al., 2012; Yeung et al., 2011). It was reported that Hh signaling regulates the behavior of ovarian somatic stem cells and hindgut stem cells in fly (Forbes et al., 1996a, 1996b; King et al., 2001; Takashima et al., 2008). However, the function of Hh signaling in adult midgut homeostasis is unclear.