Wnt signaling specifies and patterns intestinal endoderm

Brigham and Women's Hospital and Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA.
Mechanisms of development (Impact Factor: 2.44). 08/2011; 128(7-10):387-400. DOI: 10.1016/j.mod.2011.07.005
Source: PubMed


Wnt signaling has been implicated in many developmental processes, but its role in early endoderm development is not well understood. Wnt signaling is active in posterior endoderm as early as E7.5. Genetic and chemical activation show that the Wnt pathway acts directly on endoderm to induce the intestinal master regulator Cdx2, shifting global gene away from anterior endoderm and toward a posterior, intestinal program. In a mouse embryonic stem cell differentiation platform that yields pure populations of definitive endoderm, Wnt signaling induces intestinal gene expression in all cells. We have identified a set of genes specific to the anterior small intestine, posterior small intestine, and large intestine during early development, and show that Wnt, through Cdx2, activates large intestinal gene expression at high doses and small intestinal gene expression at lower doses. These findings shed light on the mechanism of embryonic intestinal induction and provide a method to manipulate intestinal development from embryonic stem cells.

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    • "After gastrulation, the primitive gut of most animals seems a tube with no apparent differentiation at the morphological level. However, several distinct or partially overlapping transcription factor and signaling molecule expression territories can be detected along the whole length of the archenteron (Jacobs et al., 2012; Lengyel and Iwaki, 2002; McGhee, 2007; Sherwood et al., 2011; van den Brink, 2007; Zorn and Wells, 2009). The interaction between molecular regulators leads, eventually, to the establishment of fine boundaries of gene expression subdividing the gut into distinct domains, precursors of the different digestive organs. "
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    ABSTRACT: The anteroposterior patterning of the embryonic gut represents one of the most intriguing biological processes in development. A dynamic control of gene transcription regulation and cell movement is perfectly orchestrated to shape a functional gut in distinct specialized parts. Two ParaHox genes, Xlox and Cdx, play key roles in vertebrate and sea urchin gut patterning through molecular mechanisms that are still mostly unclear. Here, we have combined functional analysis methodologies with high-resolution imaging and RNA-seq to investigate Xlox and Cdx regulation and function. We reveal part of the regulatory machinery responsible for the onset of Xlox and Cdx transcription, uncover a Wnt10 signal that mediates Xlox repression in the intestinal cells, and provide evidence of Xlox- and Cdx-mediated control of stomach and intestine differentiation, respectively. Our findings offer a novel mechanistic explanation of how the control of transcription is linked to cell differentiation and morphogenesis for the development of a perfectly organized biological system such as the sea urchin larval gut.
    Development 05/2014; 141(12). DOI:10.1242/dev.105775 · 6.46 Impact Factor
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    • "In most animals, gastrulation results in the formation of a tube (the archenteron) with no apparent morphological differentiation. However, even in the absence of overt morphological differences, several distinct or partially overlapping expression territories of signaling molecules and transcription factors can be detected along the axis of the archenteron (Jacobs et al., 2012; Lengyel and Iwaki, 2002; McGhee, 2007; Sherwood et al., 2011; van den Brink, 2007; Zorn and Wells, 2009). Interaction between these types of regulatory molecules leads to the establishment of molecularly distinct domains that are defined by precise boundaries of gene expression, indicating the precursors of various digestive organs. "
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    ABSTRACT: The development of the endoderm is a multistage process. From the initial specification of the endodermal domain in the embryo to the final regionalization of the gut, there are multiple stages that require the involvement of complex gene regulatory networks. In one concrete case, the sea urchin embryo, some of these stages and their genetic control are (relatively) well understood. Several studies have underscored the relevance of individual transcription factor activities in the process, but very few have focused the attention on gene interactions within specific gene regulatory networks (GRNs). Sea urchins offer an ideal system to study the different factors involved in the morphogenesis of the gut. Here we review the knowledge gained over the last ten years on the process and its regulation, from the early specification of endodermal lineages to the late events linked to the patterning of functional domains in the gut. A lesson of remarkable importance has been learnt from comparison of the mechanisms involved in gut formation in different bilaterian animals; some of these genetic mechanisms are particularly well conserved. Patterning the gut seems to involve common molecular players and shared interactions, whether we look at mammals or echinoderms. This astounding degree of conservation reveals some key aspects of deep homology that are most probably shared by all bilaterian guts. © 2013 Wiley Periodicals, Inc.
    genesis 03/2014; 52(3). DOI:10.1002/dvg.22738 · 2.02 Impact Factor
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    • "Further differences between nodal and activin-generated DE could be due their differential ability to synergize with Wnt signaling to promote anterior endoderm fate, as has been shown in fish and frogs (Ho et al., 1999; Zorn et al., 1999), and in ESCs (Sumi et al., 2008). Manipulation of the posterior regulatory network has been the focus of efforts to direct the intestinal differentiation of mouse and human PSC-derived DE (Ameri et al., 2009; Cao et al., 2010; McCracken et al., 2011; Ogaki et al., 2013; Sherwood et al., 2011; Spence et al., 2011b; Ueda et al., 2010). Activation of the Wnt pathway in DE cultures derived from mouse ESCs directs a posterior fate, as demonstrated by Cdx2 expression. "
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    ABSTRACT: With the high prevalence of gastrointestinal disorders, there is great interest in establishing in vitro models of human intestinal disease and in developing drug-screening platforms that more accurately represent the complex physiology of the intestine. We will review how recent advances in developmental and stem cell biology have made it possible to generate complex, three-dimensional, human intestinal tissues in vitro through directed differentiation of human pluripotent stem cells. These are currently being used to study human development, genetic forms of disease, intestinal pathogens, metabolic disease and cancer.
    Development 02/2014; 141(4):752-60. DOI:10.1242/dev.097386 · 6.46 Impact Factor
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