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n2:pmcid: PMC0
bibo:doi: 10.1083%2Fjcb.201604119
n5:contains: _:vb56983390 _:vb56983343 _:vb56983351 _:vb56983306

Subject Item: _:vb56983306
rdf:type: n5:Section
dc:title: introduction
n5:contains: _:vb56983308 _:vb56983309 _:vb56983310 _:vb56983311 _:vb56983307 _:vb56983324 _:vb56983325 _:vb56983326 _:vb56983327 _:vb56983320 _:vb56983321 _:vb56983322 _:vb56983323 _:vb56983316 _:vb56983317 _:vb56983318 _:vb56983319 _:vb56983312 _:vb56983313 _:vb56983314 _:vb56983315 _:vb56983340 _:vb56983341 _:vb56983342 _:vb56983336 _:vb56983337 _:vb56983338 _:vb56983339 _:vb56983332 _:vb56983333 _:vb56983334 _:vb56983335 _:vb56983328 _:vb56983329 _:vb56983330 _:vb56983331

Subject Item: _:vb56983307
rdf:type: n2:Context
rdf:value: Intestinal stem cells (ISCs), which are crucial for physiological tissue homeostasis and regeneration after injury, are thought to play a critical role in this process (Potten, >>2004<<; Ch’ang et al., 2005).
n2:mentions: n3:14731078

Subject Item: _:vb56983308
rdf:type: n2:Context
rdf:value: Intestinal stem cells (ISCs), which are crucial for physiological tissue homeostasis and regeneration after injury, are thought to play a critical role in this process (Potten, 2004; Ch’ang et al., >>2005<<).
n2:mentions: n3:15864314

Subject Item: _:vb56983309
rdf:type: n2:Context
rdf:value: CBCs are characterized by high activity of the canonical Wnt pathway, and activity of the Wnt target gene Lgr5 is commonly used for their identification and prospective isolation (Cheng and Leblond, >>1974<<; Barker et al., 2007).
n2:mentions: n3:4440635

Subject Item: _:vb56983310
rdf:type: n2:Context
rdf:value: CBCs are characterized by high activity of the canonical Wnt pathway, and activity of the Wnt target gene Lgr5 is commonly used for their identification and prospective isolation (Cheng and Leblond, 1974; Barker et al., >>2007<<). Although CBCs are widely believed to maintain the daily proliferative burden of the high-turnover epithelium, they are sensitive to DNA damage–causing agents such as high-dose γ-irradiation (γ-IR), and several independent studies have
n2:mentions: n3:17934449

Subject Item: _:vb56983311
rdf:type: n2:Context
rdf:value: burden of the high-turnover epithelium, they are sensitive to DNA damage–causing agents such as high-dose γ-irradiation (γ-IR), and several independent studies have demonstrated that CBCs are largely ablated after γ-IR (Hua et al., >>2012<<; Yan et al., 2012; Metcalfe et al., 2014; Asfaha et al., 2015). Recently, Tao et al. (2015) showed that high Wnt pathway activity and basal crypt positioning sensitize CBCs to DNA damage, leading to their preferential depletion.
n2:mentions: n3:22841781

Subject Item: _:vb56983312
rdf:type: n2:Context
rdf:value: epithelium, they are sensitive to DNA damage–causing agents such as high-dose γ-irradiation (γ-IR), and several independent studies have demonstrated that CBCs are largely ablated after γ-IR (Hua et al., 2012; Yan et al., >>2012<<; Metcalfe et al., 2014; Asfaha et al., 2015). Recently, Tao et al. (2015) showed that high Wnt pathway activity and basal crypt positioning sensitize CBCs to DNA damage, leading to their preferential depletion.
n2:mentions: n3:22190486

Subject Item: _:vb56983313
rdf:type: n2:Context
rdf:value: they are sensitive to DNA damage–causing agents such as high-dose γ-irradiation (γ-IR), and several independent studies have demonstrated that CBCs are largely ablated after γ-IR (Hua et al., 2012; Yan et al., 2012; Metcalfe et al., >>2014<<; Asfaha et al., 2015). Recently, Tao et al. (2015) showed that high Wnt pathway activity and basal crypt positioning sensitize CBCs to DNA damage, leading to their preferential depletion.
n2:mentions: n3:24332836

Subject Item: _:vb56983314
rdf:type: n2:Context
rdf:value: to DNA damage–causing agents such as high-dose γ-irradiation (γ-IR), and several independent studies have demonstrated that CBCs are largely ablated after γ-IR (Hua et al., 2012; Yan et al., 2012; Metcalfe et al., 2014; Asfaha et al., >>2015<<). Recently, Tao et al. (2015) showed that high Wnt pathway activity and basal crypt positioning sensitize CBCs to DNA damage, leading to their preferential depletion.
n2:mentions: n3:26046762

Subject Item: _:vb56983315
rdf:type: n2:Context
rdf:value: Recently, Tao et al. (>>2015<<) showed that high Wnt pathway activity and basal crypt positioning sensitize CBCs to DNA damage, leading to their preferential depletion.
n2:mentions: n3:25609789

Subject Item: _:vb56983316
rdf:type: n2:Context
rdf:value: after radiation injury, although the timing of diphtheria toxin administration makes it difficult to dissect the contribution of radioresistant versus de novo–generated Lgr5+ cells to the regenerative process (Metcalfe et al., >>2014<<).
n2:mentions: n3:24332836

Subject Item: _:vb56983317
rdf:type: n2:Context
rdf:value: At least some of these reserve ISCs can be marked by CreER reporter genes targeted to the endogenous Bmi1 and Hopx loci (Sangiorgi and Capecchi, >>2008<<; Takeda et al., 2011; Yan et al., 2012; Li et al., 2014); however, recent evidence suggests that more differentiated cells may also act as facultative stem cells upon ablation of CBCs (Tetteh et al., 2016).
n2:mentions: n3:18536716

Subject Item: _:vb56983318
rdf:type: n2:Context
rdf:value: At least some of these reserve ISCs can be marked by CreER reporter genes targeted to the endogenous Bmi1 and Hopx loci (Sangiorgi and Capecchi, 2008; Takeda et al., >>2011<<; Yan et al., 2012; Li et al., 2014); however, recent evidence suggests that more differentiated cells may also act as facultative stem cells upon ablation of CBCs (Tetteh et al., 2016).
n2:mentions: n3:22075725

Subject Item: _:vb56983319
rdf:type: n2:Context
rdf:value: At least some of these reserve ISCs can be marked by CreER reporter genes targeted to the endogenous Bmi1 and Hopx loci (Sangiorgi and Capecchi, 2008; Takeda et al., 2011; Yan et al., >>2012<<; Li et al., 2014); however, recent evidence suggests that more differentiated cells may also act as facultative stem cells upon ablation of CBCs (Tetteh et al., 2016).
n2:mentions: n3:22190486

Subject Item: _:vb56983320
rdf:type: n2:Context
rdf:value: loci (Sangiorgi and Capecchi, 2008; Takeda et al., 2011; Yan et al., 2012; Li et al., 2014); however, recent evidence suggests that more differentiated cells may also act as facultative stem cells upon ablation of CBCs (Tetteh et al., >>2016<<). Despite the lack of consensus on the precise populations contributing to regeneration after injury, clear evidence demonstrates that under basal conditions in the absence of injury, Bmi1-/Hopx-CreER–marked reserve ISCs give rise to CBCs.
n2:mentions: n3:26831517

Subject Item: _:vb56983321
rdf:type: n2:Context
rdf:value: alleles mark a largely overlapping population of Wnt− reserve ISCs that give rise to active, Wnthigh Lgr5+ CBCs upon division, and consequently all functional cell types of the epithelium over long periods of time (Takeda et al., >>2011<<; Tian et al., 2011; Yan et al., 2012; Li et al., 2014).
n2:mentions: n3:22075725

Subject Item: _:vb56983322
rdf:type: n2:Context
rdf:value: largely overlapping population of Wnt− reserve ISCs that give rise to active, Wnthigh Lgr5+ CBCs upon division, and consequently all functional cell types of the epithelium over long periods of time (Takeda et al., 2011; Tian et al., >>2011<<; Yan et al., 2012; Li et al., 2014). Unlike Lgr5+ CBCs, the population of reserve ISCs is largely quiescent (in G0 and metabolically inactive) rather than activated (metabolically active and within the cell cycle; Li et al., 2016).
n2:mentions: n3:21927002

Subject Item: _:vb56983323
rdf:type: n2:Context
rdf:value: population of Wnt− reserve ISCs that give rise to active, Wnthigh Lgr5+ CBCs upon division, and consequently all functional cell types of the epithelium over long periods of time (Takeda et al., 2011; Tian et al., 2011; Yan et al., >>2012<<; Li et al., 2014). Unlike Lgr5+ CBCs, the population of reserve ISCs is largely quiescent (in G0 and metabolically inactive) rather than activated (metabolically active and within the cell cycle; Li et al., 2016).
n2:mentions: n3:22190486

Subject Item: _:vb56983324
rdf:type: n2:Context
rdf:value: Unlike Lgr5+ CBCs, the population of reserve ISCs is largely quiescent (in G0 and metabolically inactive) rather than activated (metabolically active and within the cell cycle; Li et al., >>2016<<). It has been postulated that the low metabolic activity of quiescent stem cells discourages genetic lesions induced by reactive oxygen species (Pazhanisamy, 2009). However, knowledge of the molecular mechanisms governing their
n2:mentions: n3:27237597

Subject Item: _:vb56983325
rdf:type: n2:Context
rdf:value: It has been postulated that the low metabolic activity of quiescent stem cells discourages genetic lesions induced by reactive oxygen species (Pazhanisamy, >>2009<<). However, knowledge of the molecular mechanisms governing their radioresistance and subsequent exit from the quiescent state in response to γ-IR injury is lacking.
n2:mentions: n3:20139050

Subject Item: _:vb56983326
rdf:type: n2:Context
rdf:value: Musashi (Msi) RNA-binding proteins are expressed in the stem cell compartments of several tissues including the brain, intestine, and blood and are up-regulated in cancers arising from these tissues (Park et al., >>2014<<; Li et al., 2015; Wang et al., 2015).
n2:mentions: n3:24395885

Subject Item: _:vb56983327
rdf:type: n2:Context
rdf:value: Musashi (Msi) RNA-binding proteins are expressed in the stem cell compartments of several tissues including the brain, intestine, and blood and are up-regulated in cancers arising from these tissues (Park et al., 2014; Li et al., >>2015<<; Wang et al., 2015).
n2:mentions: n3:26673327

Subject Item: _:vb56983328
rdf:type: n2:Context
rdf:value: RNA-binding proteins are expressed in the stem cell compartments of several tissues including the brain, intestine, and blood and are up-regulated in cancers arising from these tissues (Park et al., 2014; Li et al., 2015; Wang et al., >>2015<<). Msi proteins act primarily as translational regulators binding to messenger RNAs, and known target transcripts are involved in the regulation of cell cycle progression, metabolism, and stem cell self-renewal (Park et al., 2014; Li et al.
n2:mentions: n3:25774828

Subject Item: _:vb56983329
rdf:type: n2:Context
rdf:value: Msi proteins act primarily as translational regulators binding to messenger RNAs, and known target transcripts are involved in the regulation of cell cycle progression, metabolism, and stem cell self-renewal (Park et al., >>2014<<; Li et al., 2015; Wang et al., 2015).
n2:mentions: n3:24395885

Subject Item: _:vb56983330
rdf:type: n2:Context
rdf:value: proteins act primarily as translational regulators binding to messenger RNAs, and known target transcripts are involved in the regulation of cell cycle progression, metabolism, and stem cell self-renewal (Park et al., 2014; Li et al., >>2015<<; Wang et al., 2015). In the hematopoietic system, Msi2 is an important modulator of long-term hematopoietic stem cell (LT-HSC) proliferation and self-renewal (Hope et al., 2010; Ito et al., 2010; Kharas et al., 2010; Park et al., 2014).
n2:mentions: n3:26673327

Subject Item: _:vb56983331
rdf:type: n2:Context
rdf:value: as translational regulators binding to messenger RNAs, and known target transcripts are involved in the regulation of cell cycle progression, metabolism, and stem cell self-renewal (Park et al., 2014; Li et al., 2015; Wang et al., >>2015<<). In the hematopoietic system, Msi2 is an important modulator of long-term hematopoietic stem cell (LT-HSC) proliferation and self-renewal (Hope et al., 2010; Ito et al., 2010; Kharas et al., 2010; Park et al., 2014).
n2:mentions: n3:25774828

Subject Item: _:vb56983332
rdf:type: n2:Context
rdf:value: In the hematopoietic system, Msi2 is an important modulator of long-term hematopoietic stem cell (LT-HSC) proliferation and self-renewal (Hope et al., >>2010<<; Ito et al., 2010; Kharas et al., 2010; Park et al., 2014).
n2:mentions: n3:20621054

Subject Item: _:vb56983333
rdf:type: n2:Context
rdf:value: In the hematopoietic system, Msi2 is an important modulator of long-term hematopoietic stem cell (LT-HSC) proliferation and self-renewal (Hope et al., 2010; Ito et al., >>2010<<; Kharas et al., 2010; Park et al., 2014).
n2:mentions: n3:20639863

Subject Item: _:vb56983334
rdf:type: n2:Context
rdf:value: In the hematopoietic system, Msi2 is an important modulator of long-term hematopoietic stem cell (LT-HSC) proliferation and self-renewal (Hope et al., 2010; Ito et al., 2010; Kharas et al., >>2010<<; Park et al., 2014).
n2:mentions: n3:20616797

Subject Item: _:vb56983335
rdf:type: n2:Context
rdf:value: In the hematopoietic system, Msi2 is an important modulator of long-term hematopoietic stem cell (LT-HSC) proliferation and self-renewal (Hope et al., 2010; Ito et al., 2010; Kharas et al., 2010; Park et al., >>2014<<). Ectopic induction of Msi2 increases LT-HSC numbers, which is associated with a reduction in stem cell quiescence and a concomitant increase in the percentage of actively cycling LT-HSCs (Kharas et al., 2010). Conversely, Msi2 deletion
n2:mentions: n3:24395885

Subject Item: _:vb56983336
rdf:type: n2:Context
rdf:value: Ectopic induction of Msi2 increases LT-HSC numbers, which is associated with a reduction in stem cell quiescence and a concomitant increase in the percentage of actively cycling LT-HSCs (Kharas et al., >>2010<<). Conversely, Msi2 deletion results in loss of engraftment potential of LT-HSCs in transplantation assays, demonstrating the importance of Msi2 in this largely dormant stem cell population (Park et al., 2014).
n2:mentions: n3:20616797

Subject Item: _:vb56983337
rdf:type: n2:Context
rdf:value: Conversely, Msi2 deletion results in loss of engraftment potential of LT-HSCs in transplantation assays, demonstrating the importance of Msi2 in this largely dormant stem cell population (Park et al., >>2014<<).
n2:mentions: n3:24395885

Subject Item: _:vb56983338
rdf:type: n2:Context
rdf:value: In the intestinal epithelium, Msi proteins are expressed throughout the crypt, including in the active CBC stem cell compartment (Itzkovitz et al., >>2011<<; Li et al., 2014, 2015; Wang et al., 2015).
n2:mentions: n3:22119784

Subject Item: _:vb56983339
rdf:type: n2:Context
rdf:value: In the intestinal epithelium, Msi proteins are expressed throughout the crypt, including in the active CBC stem cell compartment (Itzkovitz et al., 2011; Li et al., 2014, >>2015<<; Wang et al., 2015).
n2:mentions: n3:26673327

Subject Item: _:vb56983340
rdf:type: n2:Context
rdf:value: In the intestinal epithelium, Msi proteins are expressed throughout the crypt, including in the active CBC stem cell compartment (Itzkovitz et al., 2011; Li et al., 2014, 2015; Wang et al., >>2015<<). We have previously established that Msi proteins are obligate and functionally redundant intestinal oncoproteins that drive epithelial transformation in large part through inhibition of intestinal tumor suppressors including Pten,
n2:mentions: n3:25774828

Subject Item: _:vb56983341
rdf:type: n2:Context
rdf:value: and functionally redundant intestinal oncoproteins that drive epithelial transformation in large part through inhibition of intestinal tumor suppressors including Pten, resulting in downstream mTORC1 complex activation (Li et al., >>2015<<; Wang et al., 2015); however, their role in intestinal homeostasis, regeneration, and stem cell self-renewal in vivo is entirely unknown.
n2:mentions: n3:26673327

Subject Item: _:vb56983342
rdf:type: n2:Context
rdf:value: redundant intestinal oncoproteins that drive epithelial transformation in large part through inhibition of intestinal tumor suppressors including Pten, resulting in downstream mTORC1 complex activation (Li et al., 2015; Wang et al., >>2015<<); however, their role in intestinal homeostasis, regeneration, and stem cell self-renewal in vivo is entirely unknown.
n2:mentions: n3:25774828

Subject Item: _:vb56983343
rdf:type: n5:Section
dc:title: materials and methods
n5:contains: _:vb56983344 _:vb56983345 _:vb56983346 _:vb56983347 _:vb56983348 _:vb56983349 _:vb56983350

Subject Item: _:vb56983344
rdf:type: n2:Context
rdf:value: Generation of the TRE-Msi1 doxycycline-inducible mouse model and Msi1 and Msi2 conditional alleles was previously described (Li et al., >>2015<<; Park et al., 2015). They were crossed with mice harboring tamoxifen-inducible Cre recombinases (Villin-, Hopx-, Bmi1-, and Lgr5-CreER mice) for conditional deletion of floxed alleles or activation of fluorescent reporter (el Marjou et al.
n2:mentions: n3:26673327

Subject Item: _:vb56983345
rdf:type: n2:Context
rdf:value: Generation of the TRE-Msi1 doxycycline-inducible mouse model and Msi1 and Msi2 conditional alleles was previously described (Li et al., 2015; Park et al., >>2015<<). They were crossed with mice harboring tamoxifen-inducible Cre recombinases (Villin-, Hopx-, Bmi1-, and Lgr5-CreER mice) for conditional deletion of floxed alleles or activation of fluorescent reporter (el Marjou et al., 2004; Barker et
n2:mentions: n3:25664853

Subject Item: _:vb56983346
rdf:type: n2:Context
rdf:value: They were crossed with mice harboring tamoxifen-inducible Cre recombinases (Villin-, Hopx-, Bmi1-, and Lgr5-CreER mice) for conditional deletion of floxed alleles or activation of fluorescent reporter (el Marjou et al., >>2004<<; Barker et al., 2007; Sangiorgi and Capecchi, 2008; Takeda et al., 2011).
n2:mentions: n3:15282745

Subject Item: _:vb56983347
rdf:type: n2:Context
rdf:value: crossed with mice harboring tamoxifen-inducible Cre recombinases (Villin-, Hopx-, Bmi1-, and Lgr5-CreER mice) for conditional deletion of floxed alleles or activation of fluorescent reporter (el Marjou et al., 2004; Barker et al., >>2007<<; Sangiorgi and Capecchi, 2008; Takeda et al., 2011).
n2:mentions: n3:17934449

Subject Item: _:vb56983348
rdf:type: n2:Context
rdf:value: tamoxifen-inducible Cre recombinases (Villin-, Hopx-, Bmi1-, and Lgr5-CreER mice) for conditional deletion of floxed alleles or activation of fluorescent reporter (el Marjou et al., 2004; Barker et al., 2007; Sangiorgi and Capecchi, >>2008<<; Takeda et al., 2011).
n2:mentions: n3:18536716

Subject Item: _:vb56983349
rdf:type: n2:Context
rdf:value: Cre recombinases (Villin-, Hopx-, Bmi1-, and Lgr5-CreER mice) for conditional deletion of floxed alleles or activation of fluorescent reporter (el Marjou et al., 2004; Barker et al., 2007; Sangiorgi and Capecchi, 2008; Takeda et al., >>2011<<).
n2:mentions: n3:22075725

Subject Item: _:vb56983350
rdf:type: n2:Context
rdf:value: Intestinal epithelial cells were isolated as described previously (Sato et al., >>2009<<), with modifications. Small intestine was dissected out of mice of the appropriate genotype, opened longitudinally, and washed twice with cold PBS.
n2:mentions: n3:19329995

Subject Item: _:vb56983351
rdf:type: n5:Section
dc:title: results
n5:contains: _:vb56983352 _:vb56983353 _:vb56983354 _:vb56983355 _:vb56983356 _:vb56983357 _:vb56983358 _:vb56983359 _:vb56983384 _:vb56983385 _:vb56983386 _:vb56983387 _:vb56983388 _:vb56983389 _:vb56983376 _:vb56983377 _:vb56983378 _:vb56983379 _:vb56983380 _:vb56983381 _:vb56983382 _:vb56983383 _:vb56983368 _:vb56983369 _:vb56983370 _:vb56983371 _:vb56983372 _:vb56983373 _:vb56983374 _:vb56983375 _:vb56983360 _:vb56983361 _:vb56983362 _:vb56983363 _:vb56983364 _:vb56983365 _:vb56983366 _:vb56983367

Subject Item: _:vb56983352
rdf:type: n2:Context
rdf:value: 1 A; Li et al., >>2015<<). To unequivocally test the functional contribution of Msi proteins to intestinal homeostasis and stem cell self-renewal, we intercrossed Msi1 and Msi2 conditional knockout alleles previously generated in our laboratory (Katz et al.,
n2:mentions: n3:26673327

Subject Item: _:vb56983353
rdf:type: n2:Context
rdf:value: To unequivocally test the functional contribution of Msi proteins to intestinal homeostasis and stem cell self-renewal, we intercrossed Msi1 and Msi2 conditional knockout alleles previously generated in our laboratory (Katz et al., >>2014<<; Park et al., 2014; Li et al., 2015; Wang et al., 2015) with mice harboring a Villin-CreER transgene that drives robust, inducible recombination throughout all epithelial cells in the small intestine and colon (el Marjou et al., 2004; Li
n2:mentions: n3:25380226

Subject Item: _:vb56983354
rdf:type: n2:Context
rdf:value: test the functional contribution of Msi proteins to intestinal homeostasis and stem cell self-renewal, we intercrossed Msi1 and Msi2 conditional knockout alleles previously generated in our laboratory (Katz et al., 2014; Park et al., >>2014<<; Li et al., 2015; Wang et al., 2015) with mice harboring a Villin-CreER transgene that drives robust, inducible recombination throughout all epithelial cells in the small intestine and colon (el Marjou et al., 2004; Li et al., 2015).
n2:mentions: n3:24395885

Subject Item: _:vb56983355
rdf:type: n2:Context
rdf:value: contribution of Msi proteins to intestinal homeostasis and stem cell self-renewal, we intercrossed Msi1 and Msi2 conditional knockout alleles previously generated in our laboratory (Katz et al., 2014; Park et al., 2014; Li et al., >>2015<<; Wang et al., 2015) with mice harboring a Villin-CreER transgene that drives robust, inducible recombination throughout all epithelial cells in the small intestine and colon (el Marjou et al., 2004; Li et al., 2015).
n2:mentions: n3:26673327

Subject Item: _:vb56983356
rdf:type: n2:Context
rdf:value: Msi proteins to intestinal homeostasis and stem cell self-renewal, we intercrossed Msi1 and Msi2 conditional knockout alleles previously generated in our laboratory (Katz et al., 2014; Park et al., 2014; Li et al., 2015; Wang et al., >>2015<<) with mice harboring a Villin-CreER transgene that drives robust, inducible recombination throughout all epithelial cells in the small intestine and colon (el Marjou et al., 2004; Li et al., 2015).
n2:mentions: n3:25774828

Subject Item: _:vb56983357
rdf:type: n2:Context
rdf:value: 2014; Park et al., 2014; Li et al., 2015; Wang et al., 2015) with mice harboring a Villin-CreER transgene that drives robust, inducible recombination throughout all epithelial cells in the small intestine and colon (el Marjou et al., >>2004<<; Li et al., 2015).
n2:mentions: n3:15282745

Subject Item: _:vb56983358
rdf:type: n2:Context
rdf:value: 2014; Li et al., 2015; Wang et al., 2015) with mice harboring a Villin-CreER transgene that drives robust, inducible recombination throughout all epithelial cells in the small intestine and colon (el Marjou et al., 2004; Li et al., >>2015<<). Ablation of either Msi1 or Msi2 individually throughout the intestinal epithelium and colon had no effect on tissue homeostasis, proliferation, or differentiation (not depicted), consistent with published studies demonstrating their
n2:mentions: n3:26673327

Subject Item: _:vb56983359
rdf:type: n2:Context
rdf:value: throughout the intestinal epithelium and colon had no effect on tissue homeostasis, proliferation, or differentiation (not depicted), consistent with published studies demonstrating their functional redundancy (Sakakibara et al., >>2002<<; Li et al., 2015).
n2:mentions: n3:12407178

Subject Item: _:vb56983360
rdf:type: n2:Context
rdf:value: intestinal epithelium and colon had no effect on tissue homeostasis, proliferation, or differentiation (not depicted), consistent with published studies demonstrating their functional redundancy (Sakakibara et al., 2002; Li et al., >>2015<<).
n2:mentions: n3:26673327

Subject Item: _:vb56983361
rdf:type: n2:Context
rdf:value: findings demonstrate that Msi does not support activity of the canonical Wnt pathway and are in contrast to in vitro studies and in vivo gain-of-function assays suggesting that Msi potentiates activity of this pathway (Rezza et al., >>2010<<; Spears and Neufeld, 2011; Cambuli et al., 2015).
n2:mentions: n3:20826465

Subject Item: _:vb56983362
rdf:type: n2:Context
rdf:value: Msi does not support activity of the canonical Wnt pathway and are in contrast to in vitro studies and in vivo gain-of-function assays suggesting that Msi potentiates activity of this pathway (Rezza et al., 2010; Spears and Neufeld, >>2011<<; Cambuli et al., 2015).
n2:mentions: n3:21199875

Subject Item: _:vb56983363
rdf:type: n2:Context
rdf:value: activity of the canonical Wnt pathway and are in contrast to in vitro studies and in vivo gain-of-function assays suggesting that Msi potentiates activity of this pathway (Rezza et al., 2010; Spears and Neufeld, 2011; Cambuli et al., >>2015<<).
n2:mentions: n3:26303183

Subject Item: _:vb56983364
rdf:type: n2:Context
rdf:value: Ultimately, we tested the effects of Msi loss on the activity of CBCs marked by an Lgr5-eGFP-CreER reporter allele (Barker et al., >>2007<<). Msi loss had no effect on the frequency or proliferation of CBCs (Fig. S2, F and G).
n2:mentions: n3:17934449

Subject Item: _:vb56983365
rdf:type: n2:Context
rdf:value: Given prior findings demonstrating that Msi1/2 activity potentiates the activity of the mTORC1 complex in colorectal cancer (Li et al., >>2015<<; Wang et al., 2015), and that mTORC1 is similarly dispensable for intestinal homeostasis but is required for epithelial regeneration in response to injury (Ashton et al., 2010; Faller et al., 2015), we next sought to determine how Msi
n2:mentions: n3:26673327

Subject Item: _:vb56983366
rdf:type: n2:Context
rdf:value: Given prior findings demonstrating that Msi1/2 activity potentiates the activity of the mTORC1 complex in colorectal cancer (Li et al., 2015; Wang et al., >>2015<<), and that mTORC1 is similarly dispensable for intestinal homeostasis but is required for epithelial regeneration in response to injury (Ashton et al., 2010; Faller et al., 2015), we next sought to determine how Msi loss affects
n2:mentions: n3:25774828

Subject Item: _:vb56983367
rdf:type: n2:Context
rdf:value: of the mTORC1 complex in colorectal cancer (Li et al., 2015; Wang et al., 2015), and that mTORC1 is similarly dispensable for intestinal homeostasis but is required for epithelial regeneration in response to injury (Ashton et al., >>2010<<; Faller et al., 2015), we next sought to determine how Msi loss affects intestinal regeneration in response to radiation injury.
n2:mentions: n3:20708588

Subject Item: _:vb56983368
rdf:type: n2:Context
rdf:value: in colorectal cancer (Li et al., 2015; Wang et al., 2015), and that mTORC1 is similarly dispensable for intestinal homeostasis but is required for epithelial regeneration in response to injury (Ashton et al., 2010; Faller et al., >>2015<<), we next sought to determine how Msi loss affects intestinal regeneration in response to radiation injury.
n2:mentions: n3:25383520

Subject Item: _:vb56983369
rdf:type: n2:Context
rdf:value: or control Msi1flx/flx::Msi2flx/flx mice were treated with five daily doses of tamoxifen and subjected to 12 Gy of ionizing γ-IR 1 wk later to ablate proliferative cells including CBCs (Tian et al., >>2011<<; Tao et al., 2015). In this context, intestinal regeneration (quantified by the number of clonal regenerative crypt foci per unit length 72 h after injury) was severely compromised in the absence of Msi activity (Fig.
n2:mentions: n3:21927002

Subject Item: _:vb56983370
rdf:type: n2:Context
rdf:value: or control Msi1flx/flx::Msi2flx/flx mice were treated with five daily doses of tamoxifen and subjected to 12 Gy of ionizing γ-IR 1 wk later to ablate proliferative cells including CBCs (Tian et al., 2011; Tao et al., >>2015<<). In this context, intestinal regeneration (quantified by the number of clonal regenerative crypt foci per unit length 72 h after injury) was severely compromised in the absence of Msi activity (Fig.
n2:mentions: n3:25609789

Subject Item: _:vb56983371
rdf:type: n2:Context
rdf:value: epithelium in response to such high-dose γ-IR resides in a population of reserve intestinal ISCs that are marked, at least in part, by Hopx-CreER or Bmi1-CreER alleles (and possibly by other proxy reporter alleles; Montgomery et al., >>2011<<; Takeda et al., 2011; Yan et al., 2012; Metcalfe et al., 2014; Asfaha et al., 2015).
n2:mentions: n3:21173232

Subject Item: _:vb56983372
rdf:type: n2:Context
rdf:value: to such high-dose γ-IR resides in a population of reserve intestinal ISCs that are marked, at least in part, by Hopx-CreER or Bmi1-CreER alleles (and possibly by other proxy reporter alleles; Montgomery et al., 2011; Takeda et al., >>2011<<; Yan et al., 2012; Metcalfe et al., 2014; Asfaha et al., 2015).
n2:mentions: n3:22075725

Subject Item: _:vb56983373
rdf:type: n2:Context
rdf:value: γ-IR resides in a population of reserve intestinal ISCs that are marked, at least in part, by Hopx-CreER or Bmi1-CreER alleles (and possibly by other proxy reporter alleles; Montgomery et al., 2011; Takeda et al., 2011; Yan et al., >>2012<<; Metcalfe et al., 2014; Asfaha et al., 2015). Bmi1- or Hopx-CreER reporters are known to mark a largely overlapping population of rare reserve ISCs (although the Hopx-CreER population is more homogeneous; Li et al., 2014).
n2:mentions: n3:22190486

Subject Item: _:vb56983374
rdf:type: n2:Context
rdf:value: of reserve intestinal ISCs that are marked, at least in part, by Hopx-CreER or Bmi1-CreER alleles (and possibly by other proxy reporter alleles; Montgomery et al., 2011; Takeda et al., 2011; Yan et al., 2012; Metcalfe et al., >>2014<<; Asfaha et al., 2015). Bmi1- or Hopx-CreER reporters are known to mark a largely overlapping population of rare reserve ISCs (although the Hopx-CreER population is more homogeneous; Li et al., 2014).
n2:mentions: n3:24332836

Subject Item: _:vb56983375
rdf:type: n2:Context
rdf:value: ISCs that are marked, at least in part, by Hopx-CreER or Bmi1-CreER alleles (and possibly by other proxy reporter alleles; Montgomery et al., 2011; Takeda et al., 2011; Yan et al., 2012; Metcalfe et al., 2014; Asfaha et al., >>2015<<). Bmi1- or Hopx-CreER reporters are known to mark a largely overlapping population of rare reserve ISCs (although the Hopx-CreER population is more homogeneous; Li et al., 2014).
n2:mentions: n3:26046762

Subject Item: _:vb56983376
rdf:type: n2:Context
rdf:value: Lgr5-CreER had no significant effect on regeneration, although a modest, nonsignificant decrease in regeneration was observed, possibly reflecting the function of an Lgr5low cell previously described as radioresistant (Tao et al., >>2015<<). In contrast, Msi loss in rare Hopx-CreER reserve ISCs (making up less than 0.5% of the crypt epithelium; Takeda et al., 2011; Li et al., 2014) and some of their immediate progeny (as some reserve ISCs must divide during the time
n2:mentions: n3:25609789

Subject Item: _:vb56983377
rdf:type: n2:Context
rdf:value: In contrast, Msi loss in rare Hopx-CreER reserve ISCs (making up less than 0.5% of the crypt epithelium; Takeda et al., >>2011<<; Li et al., 2014) and some of their immediate progeny (as some reserve ISCs must divide during the time required for multiple tamoxifen injections before irradiation) resulted in failed epithelial regeneration to an extent
n2:mentions: n3:22075725

Subject Item: _:vb56983378
rdf:type: n2:Context
rdf:value: epithelial regeneration after injury, recent data also suggest that the more differentiated progeny of Lgr5+ CBCs can revert to the CBC state and reacquire stem cell activity after CBC ablation with diphtheria toxin (Tetteh et al., >>2016<<). Under basal, noninjury conditions, Hopx-/Bmi1-CreER ISCs are known to give rise to Lgr5+ CBCs upon division (Takeda et al., 2011; Tian et al., 2011; Li et al., 2014).
n2:mentions: n3:26831517

Subject Item: _:vb56983379
rdf:type: n2:Context
rdf:value: Under basal, noninjury conditions, Hopx-/Bmi1-CreER ISCs are known to give rise to Lgr5+ CBCs upon division (Takeda et al., >>2011<<; Tian et al., 2011; Li et al., 2014).
n2:mentions: n3:22075725

Subject Item: _:vb56983380
rdf:type: n2:Context
rdf:value: Under basal, noninjury conditions, Hopx-/Bmi1-CreER ISCs are known to give rise to Lgr5+ CBCs upon division (Takeda et al., 2011; Tian et al., >>2011<<; Li et al., 2014).
n2:mentions: n3:21927002

Subject Item: _:vb56983381
rdf:type: n2:Context
rdf:value: As predicted, in the resting state, reserve ISCs marked by Hopx-/Bmi-CreER::R26-Lox-Stop-Lox-tdTomato reporter activity 18 h after a single tamoxifen dose (Takeda et al., >>2011<<; Li et al., 2014) expressed low levels of Msi genes and existed in a Wntoff/low state, with little to no expression of canonical Wnt targets such as Lgr5, Ascl2, and Ccnd1, along with high levels of the cell cycle inhibitor Cdkn1a, in
n2:mentions: n3:22075725

Subject Item: _:vb56983382
rdf:type: n2:Context
rdf:value: Four days after initiation of lineage tracing (when about half of reserve ISCs have divided to form clusters of two or more daughter cells; Takeda et al., >>2011<<; Li et al., 2014), reserve ISC progeny began activating Msi genes and canonical Wnt target genes (Fig.
n2:mentions: n3:22075725

Subject Item: _:vb56983383
rdf:type: n2:Context
rdf:value: Recent findings that high Wnt pathway activity and cell cycling render CBCs susceptible to DNA damage (Tao et al., >>2015<<) support a model in which a more dormant pool of reserve stem cells remains resistant to injury to regenerate the epithelium after damage.
n2:mentions: n3:25609789

Subject Item: _:vb56983384
rdf:type: n2:Context
rdf:value: quiescence usually refers to cells with a dormant genome and low metabolic activity, reflected by low RNA levels in a diploid cell (G0), rather than simply the absence of cycling, which can also result from G1 arrest (Hüttmann et al., >>2001<<; Fukada et al., 2007). We first examined reserve ISC populations marked by Hopx-/Bmi1-CreER:
n2:mentions: n3:11532352

Subject Item: _:vb56983385
rdf:type: n2:Context
rdf:value: to cells with a dormant genome and low metabolic activity, reflected by low RNA levels in a diploid cell (G0), rather than simply the absence of cycling, which can also result from G1 arrest (Hüttmann et al., 2001; Fukada et al., >>2007<<). We first examined reserve ISC populations marked by Hopx-/Bmi1-CreER::R26-Lox-Stop-Lox-tdTomato and found that the majority of these populations reside in G0 (Fig.
n2:mentions: n3:17600112

Subject Item: _:vb56983386
rdf:type: n2:Context
rdf:value: Interestingly, these findings are consistent with previous studies on the mTORC1 complex, inactivation of which similarly results in G1 arrest (Kalaitzidis et al., >>2012<<) as well as failure of the intestinal epithelium to regenerate in response to high dose γ-IR injury (Ashton et al., 2010; Faller et al., 2015).
n2:mentions: n3:22958934

Subject Item: _:vb56983387
rdf:type: n2:Context
rdf:value: previous studies on the mTORC1 complex, inactivation of which similarly results in G1 arrest (Kalaitzidis et al., 2012) as well as failure of the intestinal epithelium to regenerate in response to high dose γ-IR injury (Ashton et al., >>2010<<; Faller et al., 2015).
n2:mentions: n3:20708588

Subject Item: _:vb56983388
rdf:type: n2:Context
rdf:value: mTORC1 complex, inactivation of which similarly results in G1 arrest (Kalaitzidis et al., 2012) as well as failure of the intestinal epithelium to regenerate in response to high dose γ-IR injury (Ashton et al., 2010; Faller et al., >>2015<<).
n2:mentions: n3:25383520

Subject Item: _:vb56983389
rdf:type: n2:Context
rdf:value: To address this question, we used a mouse model in which a single copy of Msi1 is targeted into safe-haven chromatin and is under control of the doxycycline-inducible tetracycline-responsive element (TRE-Msi1; Li et al., >>2015<<). Administration of doxycycline to Hopx-/Bmi1-CreER::R26-Lox-Stop-Lox-tdTomato::TRE-Msi1 mice for as little as 36 h resulted in robust exit of reserve ISCs from G0 and subsequent entry into the cell cycle (Fig. 5 A). This ectopic Msi
n2:mentions: n3:26673327

Subject Item: _:vb56983390
rdf:type: n5:Section
dc:title: discussion
n5:contains: _:vb56983391 _:vb56983408 _:vb56983409 _:vb56983410 _:vb56983404 _:vb56983405 _:vb56983406 _:vb56983407 _:vb56983400 _:vb56983401 _:vb56983402 _:vb56983403 _:vb56983396 _:vb56983397 _:vb56983398 _:vb56983399 _:vb56983392 _:vb56983393 _:vb56983394 _:vb56983395

Subject Item: _:vb56983391
rdf:type: n2:Context
rdf:value: clear that several tissues in adult mammals, most notably the hematopoietic system, bifurcate their stem cell compartments into a slow-cycling, quiescent stem cell capable of giving rise to a cycling, active stem cell (Li and Clevers, >>2010<<). The benefit of such an organizational structure is the capacity to promote tissue regeneration after damage while maintaining the proliferative output necessary to keep up with the demands of high-turnover tissues using a relatively
n2:mentions: n3:20110496

Subject Item: _:vb56983392
rdf:type: n2:Context
rdf:value: that observed in the hematopoietic system, with a radioresistant, slow-cycling reserve ISC giving rise to an actively proliferating crypt base columnar cell, whose self-renewal is driven by high Wnt pathway activity (Li and Clevers, >>2010<<; Montgomery et al., 2011; Takeda et al., 2011; Tian et al., 2011; Li et al., 2014; Asfaha et al., 2015).
n2:mentions: n3:20110496

Subject Item: _:vb56983393
rdf:type: n2:Context
rdf:value: system, with a radioresistant, slow-cycling reserve ISC giving rise to an actively proliferating crypt base columnar cell, whose self-renewal is driven by high Wnt pathway activity (Li and Clevers, 2010; Montgomery et al., >>2011<<; Takeda et al., 2011; Tian et al., 2011; Li et al., 2014; Asfaha et al., 2015).
n2:mentions: n3:21173232

Subject Item: _:vb56983394
rdf:type: n2:Context
rdf:value: a radioresistant, slow-cycling reserve ISC giving rise to an actively proliferating crypt base columnar cell, whose self-renewal is driven by high Wnt pathway activity (Li and Clevers, 2010; Montgomery et al., 2011; Takeda et al., >>2011<<; Tian et al., 2011; Li et al., 2014; Asfaha et al., 2015).
n2:mentions: n3:22075725

Subject Item: _:vb56983395
rdf:type: n2:Context
rdf:value: slow-cycling reserve ISC giving rise to an actively proliferating crypt base columnar cell, whose self-renewal is driven by high Wnt pathway activity (Li and Clevers, 2010; Montgomery et al., 2011; Takeda et al., 2011; Tian et al., >>2011<<; Li et al., 2014; Asfaha et al., 2015).
n2:mentions: n3:21927002

Subject Item: _:vb56983396
rdf:type: n2:Context
rdf:value: to an actively proliferating crypt base columnar cell, whose self-renewal is driven by high Wnt pathway activity (Li and Clevers, 2010; Montgomery et al., 2011; Takeda et al., 2011; Tian et al., 2011; Li et al., 2014; Asfaha et al., >>2015<<). There has been considerable interest in gaining a better understanding of radioresistant intestinal cells that contribute to regeneration after damage by radiation/chemotherapy because of the relevance in the context of traditional
n2:mentions: n3:26046762

Subject Item: _:vb56983397
rdf:type: n2:Context
rdf:value: Recently, we have demonstrated that the Msi2 RNA-binding protein is capable of driving long-term hematopoietic stem cells out of quiescence and into the cell cycle (Kharas et al., >>2010<<). In the intestinal epithelium, Msi1 and Msi2 function redundantly by binding to several transcripts that encode known negative regulators of mTORC1, including Pten, Bmpr1a, and Lrig1, and aberrant Msi activation leads to Pten repression
n2:mentions: n3:20616797

Subject Item: _:vb56983398
rdf:type: n2:Context
rdf:value: redundantly by binding to several transcripts that encode known negative regulators of mTORC1, including Pten, Bmpr1a, and Lrig1, and aberrant Msi activation leads to Pten repression and induction of the AKT–mTORC1 axis (Li et al., >>2015<<; Wang et al., 2015).
n2:mentions: n3:26673327

Subject Item: _:vb56983399
rdf:type: n2:Context
rdf:value: to several transcripts that encode known negative regulators of mTORC1, including Pten, Bmpr1a, and Lrig1, and aberrant Msi activation leads to Pten repression and induction of the AKT–mTORC1 axis (Li et al., 2015; Wang et al., >>2015<<).
n2:mentions: n3:25774828

Subject Item: _:vb56983400
rdf:type: n2:Context
rdf:value: intestinal epithelium and colon, had no adverse effects on homeostasis, active CBC self-renewal, or Wnt pathway target gene expression, despite the high level of both Msi family members in the Wnthigh CBC stem cells (Potten et al., >>2003<<; Cambuli et al., 2013; Li et al., 2015; Wang et al., 2015).
n2:mentions: n3:12558601

Subject Item: _:vb56983401
rdf:type: n2:Context
rdf:value: and colon, had no adverse effects on homeostasis, active CBC self-renewal, or Wnt pathway target gene expression, despite the high level of both Msi family members in the Wnthigh CBC stem cells (Potten et al., 2003; Cambuli et al., >>2013<<; Li et al., 2015; Wang et al., 2015).
n2:mentions: n3:23712573

Subject Item: _:vb56983402
rdf:type: n2:Context
rdf:value: no adverse effects on homeostasis, active CBC self-renewal, or Wnt pathway target gene expression, despite the high level of both Msi family members in the Wnthigh CBC stem cells (Potten et al., 2003; Cambuli et al., 2013; Li et al., >>2015<<; Wang et al., 2015).
n2:mentions: n3:26673327

Subject Item: _:vb56983403
rdf:type: n2:Context
rdf:value: on homeostasis, active CBC self-renewal, or Wnt pathway target gene expression, despite the high level of both Msi family members in the Wnthigh CBC stem cells (Potten et al., 2003; Cambuli et al., 2013; Li et al., 2015; Wang et al., >>2015<<).
n2:mentions: n3:25774828

Subject Item: _:vb56983404
rdf:type: n2:Context
rdf:value: Reserve ISCs are often referred to as being quiescent or residing in G0, as this state is thought of as being protective to stem cells in unfavorable environments (Cheung and Rando, >>2013<<). Indeed, we observed that the majority of ISCs marked by Hopx-CreER or Bmi1-CreER reside in G0, whereas the remainder of the population cycles actively. We demonstrate that Msi activity controls the exit of reserve ISCs from the G0 state
n2:mentions: n3:23698583

Subject Item: _:vb56983405
rdf:type: n2:Context
rdf:value: Interestingly, the phenotype of Msi loss of function is reminiscent of inactivation of mTORC1: both result in failed intestinal regeneration after injury and in G1 cell cycle arrest (Ashton et al., >>2010<<; Kalaitzidis et al., 2012; Faller et al., 2015).
n2:mentions: n3:20708588

Subject Item: _:vb56983406
rdf:type: n2:Context
rdf:value: Interestingly, the phenotype of Msi loss of function is reminiscent of inactivation of mTORC1: both result in failed intestinal regeneration after injury and in G1 cell cycle arrest (Ashton et al., 2010; Kalaitzidis et al., >>2012<<; Faller et al., 2015).
n2:mentions: n3:22958934

Subject Item: _:vb56983407
rdf:type: n2:Context
rdf:value: the phenotype of Msi loss of function is reminiscent of inactivation of mTORC1: both result in failed intestinal regeneration after injury and in G1 cell cycle arrest (Ashton et al., 2010; Kalaitzidis et al., 2012; Faller et al., >>2015<<). We have previously established that in the context of colorectal cancer, mTORC1 is a functionally important target of Msi activity, and both mTORC1 and Msi are required for transformation of the epithelium downstream of APC loss.
n2:mentions: n3:25383520

Subject Item: _:vb56983408
rdf:type: n2:Context
rdf:value: marked with proxy reporter alleles driven by the mTert promoter (a population that likely overlaps with the Hopx-/Bmi1-CreER-marked population in the current study based on their functional and molecular similarities; Richmond et al., >>2015<<). These findings are entirely consistent with observations in hematopoietic and muscle tissues that the mTORC1 complex similarly governs stem cell quiescence (Kalaitzidis et al., 2012; Rodgers et al., 2014).
n2:mentions: n3:26686631

Subject Item: _:vb56983409
rdf:type: n2:Context
rdf:value: These findings are entirely consistent with observations in hematopoietic and muscle tissues that the mTORC1 complex similarly governs stem cell quiescence (Kalaitzidis et al., >>2012<<; Rodgers et al., 2014).
n2:mentions: n3:22958934

Subject Item: _:vb56983410
rdf:type: n2:Context
rdf:value: These findings are entirely consistent with observations in hematopoietic and muscle tissues that the mTORC1 complex similarly governs stem cell quiescence (Kalaitzidis et al., 2012; Rodgers et al., >>2014<<).
n2:mentions: n3:24870234

Subject Item: _:vb616264631
rdf:type: n2:RelevantBibliographicResource
n2:RelevantScore: 12
n2:hasRelevantPaperId: n3:21927002

Subject Item: _:vb616264632
rdf:type: n2:RelevantBibliographicResource
n2:RelevantScore: 11
n2:hasRelevantPaperId: n3:17934449

Subject Item: _:vb616264633
rdf:type: n2:RelevantBibliographicResource
n2:RelevantScore: 11
n2:hasRelevantPaperId: n3:22075725

Subject Item: _:vb616264634
rdf:type: n2:RelevantBibliographicResource
n2:RelevantScore: 10
n2:hasRelevantPaperId: n3:22190486

Subject Item: _:vb616264635
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