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Epithelial Cell Proliferation in the Developing Zebrafish Intestine Is Epithelial cell proliferation in the developing zebrafish intestine is regulated by the Wnt pathway and microbial signaling via Myd88 Sarah E. Cheesman, James T. Neal, Erika Mittge, Barbara M. Seredick, and Karen Guillemin1 Institute of Molecular Biology, University of Oregon, Eugene, OR 97403 Edited by Jeffrey I. Gordon, Washington University School of Medicine, St. Louis, MO, and approved September 2, 2010 (received for review February 8, 2010) Rates of cell proliferation in the vertebrate intestinal epithelium are zygosity of the WT Apc gene results in adenoma formation (8). These modulated by intrinsic signaling pathways and extrinsic cues. Here, animals display a similar phenotype to human patients with familial we report that epithelial cell proliferation in the developing zebra- adenomatous polyposis coli, who develop thousands of colonic pol- fish intestine is stimulated both by the presence of the resident yps as a result of clonal loss of APC function. Conversely, when Wnt microbiota and by activation of Wnt signaling. We find that the re- signaling is attenuated in transgenic adult mice overexpressing the sponse to microbial proliferation-promoting signals requires Myd88 Wnt receptor inhibitor Dkk-1 (9, 10) or in neonates lacking Tcf4 but not TNF receptor, implicating host innate immune pathways but (7, 11), the small intestine is depleted of proliferating cells that nor- not inflammation in the establishment of homeostasis in the mally replenish the intestinal epithelium. developing intestinal epithelium. We show that loss of axin1, a com- Similar analyses in zebrafish have shown that Wnt signaling ponent of the β-catenin destruction complex, results in greater than regulates cell proliferation in the adult zebrafish intestine; however WT levels of intestinal epithelial cell proliferation. Compared with its function in the larval intestine during the period of establish- conventionally reared axin1 mutants, germ-free axin1 mutants ment of the gut microbiota has not been determined (12). mrc exhibit decreased intestinal epithelial cell proliferation, whereas Zebrafish heterozygous for the apc mutation, which contains a monoassociation with the resident intestinal bacterium Aeromonas premature stop codon in the apc gene, spontaneously develop in- mrc/mrc veronii results in elevated epithelial cell proliferation. Disruption of testinal neoplasia as adults (13), but apc homozygotes β-catenin signaling by deletion of the β-catenin coactivator tcf4 par- die before 96 h postfertilization (hpf), before maturation of the tially decreases the proliferation-promoting capacity of A. veronii. larval gut, which begins to function in nutrient uptake at 5 d post- We show that numbers of intestinal epithelial cells with cytoplasmic fertilization (dpf) (14, 15). Conversely, zebrafish homozygous for exl β-catenin are reduced in the absence of the microbiota in both the null mutation tcf4 exhibit a loss of proliferative compart- WT and axin1 mutants and elevated in animals’ monoassociated ments within the intestinal epithelium, but this defect is only A. veronii. Collectively, these data demonstrate that resident intes- reported to be apparent in young adult zebrafish at 5 wk of age tinal bacteria enhance the stability of β-catenin in intestinal epithe- (16). An earlier role for tcf4 in the intestine is suggested by the mrc/mrc lial cells and promote cell proliferation in the developing vertebrate finding that removal of tcf4 in the apc mutant rescues ex- intestine. pression of the intestinal marker ifabp at 72 hpf but not the early larval lethality (17). Collectively, these results demonstrate that axin1 | β-catenin | germ-free | intestinal epithelial cell | microbiota appropriate levels of Wnt signaling are crucial for the maintenance of intestinal epithelial renewal in the adult intestine, but they do he vertebrate intestinal epithelium is one of the most rapidly not explain how intestinal epithelial renewal rates are established Trenewing tissues in the body. Perturbation of normal tissue during larval development. This is a crucial period in zebrafish homeostasis attributable to genetic lesions or environmental development, analogous to the postnatal period in mammals, insults, such as infection with bacterial pathogens, can lead to when the digestive tract is first colonized by microbes that influence hyperproliferative diseases of the intestinal tract (1). The regula- the organ’s maturation (18). tion of intestinal epithelial cell proliferation has been studied ex- One mechanism by which animals perceive the presence of tensively in the context of colorectal cancer (CRC), which has microbes is through the innate immune Toll-like receptor (TLR) revealed canonical Wnt signaling as a key regulator of cell division signaling pathway (19). TLRs were initially studied for their role in and differentiation (2). Another contributing factor to rates of perceiving pathogens and activating host protective inflammatory intestinal epithelial cell proliferation is the associated microbial responses. However, there is growing evidence for the critical role community, as indicated by the paucity of proliferating cells in the that TLR signaling plays in host perception of indigenous benefi- intestines of germ-free (GF) rodents and zebrafish (3–5). How- cial microbes (20), which typically do not elicit a strong in- ever, the mechanisms underlying microbiota-induced cell pro- flammatory response. Myd88 functions as a key adaptor protein liferation are poorly understood. downstream of the majority of TLRs; when perturbed, it interferes Evidence for the role of Wnt signaling in intestinal homeostasis comes from mutations that perturb this genetic pathway. Canonical Wnt signaling is modulated by the levels of β-catenin protein; when This paper results from the Arthur M. Sackler Colloquium of the National Academy of abundant, β-catenin protein accumulates in the cytoplasm and Sciences, "Microbes and Health," held November 2–3, 2009, at the Arnold and Mabel Beckman Center of the National Academies of Sciences and Engineering in Irvine, CA. translocates into the nucleus, where it interacts with coactivators, The complete program and audio files of most presentations are available on the NAS such as the intestine-specific transcription factor Tcf4, to turn on Web site at http://www.nasonline.org/SACKLER_Microbes_and_Health. c-myc transcription of proproliferative target genes, including and Author contributions: S.E.C., J.T.N., and K.G. designed research; S.E.C., J.T.N., E.M., and sox9 (6, 7). In the absence of endogenous Wnt ligands, β-catenin B.M.S. performed research; S.E.C., J.T.N., E.M., B.M.S., and K.G. analyzed data; and S.E.C. levels are kept low by the activity of the cytoplasmic destruction and K.G. wrote the paper. complex, composed of Apc, Axin, and GSK-3, which target β-catenin The authors declare no conflict of interest. for destruction by the proteosome. Constitutive activation of Wnt This article is a PNAS Direct Submission. signaling, such as in the case of genetic loss of the β-catenin de- 1To whom correspondence should be addressed. E-mail: [email protected]. struction complex, results in unchecked intestinal cell proliferation. Min/+ This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. This is seen in Apc mutant mice in which clonal loss of hetero- 1073/pnas.1000072107/-/DCSupplemental. 4570–4577 | PNAS | March 15, 2011 | vol. 108 | suppl. 1 www.pnas.org/cgi/doi/10.1073/pnas.1000072107 Downloaded by guest on September 25, 2021 with TLR signaling in mammals. The zebrafish genome has du- A. veronii. Finally, we show that GF larvae have reduced numbers plicated tlr genes but only a single copy of myd88 (21, 22). We and of intestinal epithelial cells with cytoplasmic β-catenin and that others have shown that Myd88 functions in zebrafish to modulate A. veronii monoassociation is sufficient to promote the accumu- innate immune responses to microbes and microbial-associated lation of cytoplasmic β-catenin in the intestinal epithelium, dem- molecular patterns (MAMPs), such as LPS (23–25). Notably, LPS onstrating that resident intestinal bacteria enhance Wnt pathway sensing in zebrafish differs mechanistically from that in mammals activity and elevate rates of epithelial renewal in the developing and does not involve a Tlr4–MD2 complex (26). vertebrate intestine. Possible combinatorial effects of microbial and Wnt signaling on intestinal epithelial homeostasis are suggested by the observation Results Min/+ that Apc mice develop 50% fewer small intestinal adenomas Zebrafish Intestinal Epithelial Cell Proliferation Is Stimulated by the when reared GF than when reared under conventional conditions Microbiota. To investigate the influence of microbes on zebrafish Min/+ (27). Similarly, deletion of Myd88 in Apc mice results in fewer intestinal cell proliferation, we exposed larvae to the nucleotide Min/+ adenomas than in Apc controls (28). We set out to investigate analogues BrdU and 5-ethynyl-2′-deoxyuridine (EdU) and quan- how the microbiota and Wnt signaling affect proliferation of the tified S-phase nuclei in 30 serial sections in the intestinal bulb (Fig. developing vertebrate intestinal epithelium. We used a gnotobiotic 1 A and B). The absolute numbers of labeled cells varied with the zebrafish model, which allowed us to manipulate readily both the different nucleotide analogues and even between trials, but the presence and composition of the microbiota and the genetic relative levels of cell proliferation between
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