Access the full text.
Sign up today, get DeepDyve free for 14 days.
Loading next page...
/lp/the-company-of-biologists/wnt-signaling-in-development-and-tissue-homeostasis-8jqNTyh483
References
References for this paper are not available at this time. We will be adding them shortly, thank you for your patience.
- Publisher
- The Company of Biologists
- Copyright
- © 2021 The Company of Biologists. All rights reserved.
- ISSN
- 0950-1991
- eISSN
- 0950-1991
- DOI
- 10.1242/dev.146589
- Publisher site
- See Article on Publisher Site
Abstract
© 2018. Published by The Company of Biologists Ltd | Development (2018) 145, dev146589. doi:10.1242/dev.146589 DEVELOPMENT AT A GLANCE Zachary Steinhart and Stephane Angers* ABSTRACT Introduction Wnt proteins are secreted growth factors that regulate the The Wnt-β-catenin signaling pathway is an evolutionarily conserved proliferation and differentiation of stem and progenitor cells, cell-cell communication system that is important for stem cell renewal, both during embryonic development and during adult tissue cell proliferation and cell differentiation both during embryogenesis homeostasis in multicellular animals (Logan and Nusse, 2004). and during adult tissue homeostasis. Genetic or epigenetic events The Drosophila Wnt protein Wingless (Wg) and the core members leading to hypo- or hyper-activation of the Wnt-β-catenin signaling of the intracellular signaling pathway it regulates were originally cascade have also been associated with human diseases such as identified and characterized in flies through genetic screens and cancer. Understanding how this pathway functions is thus integral for phenotypic analyses of embryonic morphogenesis defects developing therapies to treat diseases or for regenerative medicine (Nüsslein-Volhard and Wieschaus, 1980; `Sharma and Chopra, approaches. Here, and in the accompanying poster, we provide an 1976). The discovery that Wg was homologous to the mouse Wnt1 overview of Wnt-β-catenin signaling and briefly highlight its key proto-oncogene (Rijsewijk et al., 1987) supported the notion that functions during development and adult tissue homeostasis. Wnt1 and possibly other vertebrate Wnt homologs could have KEY WORDS: Wnt protein, Wnt signaling, Epigenetics important roles during normal vertebrate development, and that Wnt signaling activity might be dysregulated in cancer. A vast number of integrative genetic, biochemical and ’omic-based University of Toronto, 144 College Street, Toronto, ON M5S 3M2, Canada. approaches have since refined our understanding of how Wnt ligands are produced and secreted, how cells recognize and *Author for correspondence (stephane.angers@utoronto.ca) integrate Wnt signals to yield various cellular and physiological S.A., 0000-0001-7241-9044 responses, and how Wnt signals are modulated, terminated or DEVELOPMENT DEVELOPMENT AT A GLANCE Development (2018) 145, dev146589. doi:10.1242/dev.146589 amplified depending on spatiotemporal contexts. This work has proteins are seven-transmembrane receptors, of which there are 10 provided a foundation to recognize and study the pervasive roles of homologs in humans, which all contain a conserved 120 amino Wnt signaling during development and tissue homeostasis, as well acid extracellular cysteine-rich-domain (CRD) serving as the as to understand the frequent defects associated with this pathway obligate binding interface for Wnt (Janda et al., 2012; Povelones in human diseases such as cancer (Nusse and Clevers, 2017). and Nusse, 2005). Structural studies have revealed that Wnt Multiple functionally divergent Wnt-based signaling pathways proteins resemble the general structure of a hand, with the thumb have been identified to date. The best characterized of these is the and index fingers pinching the extracellular CRD of Frizzled. The Wnt-β-catenin pathway, which is often referred to as the ‘canonical’ Wnt palmitoleic acid moiety acts as a major binding determinant, Wnt pathway. This pathway culminates in the regulation of context- inserting itself in a hydrophobic crevice within the CRD specific β-catenin-dependent gene expression programs that direct (Janda et al., 2012). LRP5/6 Wnt co-receptors, which are stem and progenitor cell renewal, proliferation and differentiation. single transmembrane domain proteins, contain four extracellular By contrast, the non-canonical pathways operate independently of β-propeller domains that are involved in Wnt binding (Chen et al., β-catenin and have been described to impinge on small GTPases of 2011) and five PPPSP phosphorylation motifs within the the Rho family to control cell polarity and cell movement, or to act intracellular region (Tamai et al., 2004). 2+ via heterotrimeric G proteins to control Ca signaling (Angers and The binding of a Wnt ligand to the FZD-LRP5/6 complex first Moon, 2009). Here, and in the accompanying poster, we discuss the results in recruitment of the cytoplasmic protein Dishevelled key features of the canonical Wnt-β-catenin pathway and briefly (Klingensmith et al., 1994; Krasnow et al., 1995), putatively via highlight its roles in development, stem cells and adult tissue direct interaction with Frizzled (Cong et al., 2004; Tauriello et al., homeostasis. 2012), and of Axin-GSK3 complexes via the interaction of Axin with Dishevelled. GSK3 (Tamai et al., 2004) and the Wnt signal recognition and pathway initiation Cdk14(PFTK1)-Cyclin Y mitotic kinase complex (Davidson The Wnt-β-catenin signaling pathway centers around the post- et al., 2009) then phosphorylate PPPSP motifs within the translational control of β-catenin protein abundance. In the absence intracellular region of LRP5/6, thereby priming them for further of Wnt proteins, cytoplasmic levels of β-catenin are kept low phosphorylation by the membrane-anchored kinase casein kinase 1 through ubiquitin-dependent proteasomal degradation, a process γ (Davidson et al., 2005; Zeng et al., 2005). The phosphorylated governed by a molecular machine called the β-catenin destruction C-terminal tail of LRP5/6 was thought to represent a high-affinity complex (Stamos and Weis, 2012). The destruction complex is binding site for Axin, thereby leading to the titration of active composed of the scaffolding proteins Axin (Behrens, 1998; Hart destruction complex molecules and to β-catenin stabilization. et al., 1998) and APC (Munemitsu et al., 1995; Rubinfeld et al., However, this model mostly relied on yeast two-hybrid 1993), and the kinases CK1α (Amit et al., 2002; Liu et al., 2002; experiments that identified Axin clones using the LRP5 tail as a Rubinfeld et al., 1996) and GSK3α/β (Amit et al., 2002; Liu et al., bait (Mao et al., 2001); subsequent biochemical (Cselenyi et al., 2002; Rubinfeld et al., 1996). The destruction complex functions 2008; Piao et al., 2008) and structural experiments (Stamos et al., by catalyzing the serine/threonine phosphorylation of a highly 2014) have demonstrated that phospho-LRP5/6 blocks β-catenin conserved phospho-degron at the N terminus of β-catenin degradation directly by inhibiting GSK3 activity. Whether Axin (Winston et al., 1999), which earmarks β-catenin for recruitment interacts with the phosphorylated LRP5/6 intracellular tail indirectly β-TRCP to the SCF E3-ubiquitin ligase (Hart et al., 1999) and ensuing through GSK3, or whether direct binding of Axin is needed, proteasome-mediated degradation (Hart et al., 1999). Simply put, remains to be determined. in the absence of Wnt proteins, neo-synthesized β-catenin is The subsequent accumulation of β-catenin leads to its constitutively targeted for proteolysis, and Wnts function by translocation to the nucleus, where it acts as a transcriptional co- inhibiting this degradation. activator by binding to and modulating the activity of the Tcf/Lef Wnts are proteins of ∼40 kDa that are post-translationally family of DNA-binding proteins (Behrens et al., 1996; Molenaar modified through palmitoylation and glycosylation. The human et al., 1996; van de Wetering et al., 1997) that otherwise repress genome encodes 19 Wnt proteins (Nusse, 2001), all of which are Wnt-responsive enhancers through their physical interaction with secreted through a conserved secretory pathway. Wnt proteins Groucho/Tle family of co-repressors (Cavallo et al., 1998; Roose are translated in the endoplasmic reticulum (ER), where they are et al., 1998). How this transcriptional switch functions at the palmitoylated by the ER-bound o-acyl-transferase porcupine molecular level was recently clarified with the identification of (van den Heuvel et al., 1993; Willert et al., 2003). This is an the E3 ubiquitin ligase UBR5 as a required component of the essential step in Wnt protein secretion (Herr and Basler, 2012) and Wnt-dependent response (Flack et al., 2017). UBR5 functions introduces a modification that is required for Wnt activity (Janda through the Wnt- and ubiquitin-mediated inactivation of Groucho/ et al., 2012; Proffitt and Virshup, 2012; Willert et al., 2003). Tle, thereby leading to de-repression and activation of β-catenin Following their palmitoylation Wnt protein interact with the target genes in a context-dependent manner. Wnt-β-catenin target multipass transmembrane escort protein GPR177, the vertebrate genes vary depending on cell lineage/type (Nakamura et al., 2016), homolog of Drosophila Wingless/Evi/Sprinter, which mediates but common targets include genes that function in positive- and endosome trafficking to the plasma membrane and the release of negative-feedback regulation of the pathway, genes involved in Wnt proteins into the extracellular space (Bänziger et al., 2006; cell-cycle progression and genes involved in stem cell function. Bartscherer et al., 2006; Goodman et al., 2006). The cell-surface receptor for Wnts that is responsible for Wnt signal restriction and termination transducing signals through the β-catenin pathway consists of a Multiple mechanisms exist to restrict and/or terminate Wnt heterodimer between a Frizzled family member (Bhanot et al., signaling at the ligand, receptor, intracellular and nuclear levels. 1996; MacDonald and He, 2012; Yang-Snyder et al., 1996) and At the ligand level, the extracellular enzymes Tiki and Notum one of the Wnt co-receptors LRP5 or LRP6 (LRP5/6) (Pinson function as a protease and a carboxylesterase to cleave the N et al., 2000; Tamai et al., 2000; Wehrli et al., 2000). Frizzled terminus of Wnts (Zhang et al., 2012) or remove their palmitoleate DEVELOPMENT DEVELOPMENT AT A GLANCE Development (2018) 145, dev146589. doi:10.1242/dev.146589 moiety (Kakugawa et al., 2015; Zhang et al., 2015), respectively. R-spondin to the LGR4/5/6-RNF43/ZNRF3 complex leads to Additionally, Wnt ligands are inhibited through direct interaction endocytosis of the complex and therefore blocks the ability of with secreted proteins that prevent their interaction with the receptor RNF43 and ZNRF3 to downregulate Frizzled at the cell surface, complex, such as Wnt inhibitory factor (WIF) (Hsieh et al., 1999), hence leading to a sensitized Wnt signaling state (Hao et al., 2012). or secreted frizzled related proteins (sFRPs) (Hsieh et al., 1999; Interestingly, R-spondin may also have roles that are independent of Leyns et al., 1997; Rattner et al., 1997; Wang et al., 1997), which LGR proteins as RSPO2 and RSPO3 were found to have remaining share homology with the Frizzled CRD. activities in LGR4/5/6 triple-knockout cells (Lebensohn and Several negative-feedback loops exist to terminate or dampen Rohatgi, 2018). In this case, R-spondin activity is instead Wnt signals at the receptor level. Dickkopf-1 (Dkk1) (Glinka et al., mediated by ZNRF3/RNF43 and heparan sulfate proteoglycans. 1998) is a Wnt-β-catenin target gene (González-Sancho et al., 2005) Interestingly, a recent study revealed that Wnt and R-spondin and functions by binding to LRP5/6 in competition with Wnts have non-overlapping roles during stem cell homeostasis (Yan et al., (Bafico et al., 2001; Semënov et al., 2001). Rnf43 and Znrf3 are 2017). This study indicated that, whereas R-spondin overexpression recently characterized Wnt-β-catenin target genes that encode is sufficient to expand the Lgr5 stem cell population in the transmembrane E3-ubiquitin-ligases (Hao et al., 2012; Koo et al., intestine, increasing Wnt ligand levels is ineffective. This highlights 2012) involved in ubiquitin-dependent Frizzled endocytosis and a unique role for R-spondin in providing the high levels of Wnt proteasomal degradation, thereby reducing receptor levels at the signaling activity required to drive stem cell proliferation and self- plasma membrane. renewal. These results led the authors to propose a model in which In the cytoplasm, the best-studied negative feedback for β-catenin Wnt ligands act as priming factors, enabling expression of the levels involves Axin2. Both Axin1 and Axin2 are functionally R-spondin receptors LGR5 and RNF43/ZNRF3. Within this model, equivalent proteins (Chia and Costantini, 2005) but, in contrast to primed cells exposed to R-spondin would be competent to its paralog Axin1, which is expressed constitutively, Axin2 is a produce the high Wnt-β-catenin signaling response and activate Wnt target gene (Jho et al., 2002; Lustig et al., 2002). Given that transcriptional programs required for cell proliferation and self- Axin proteins are thought to be limiting components of the renewal. On the other hand, cells further away from the source of β-catenin destruction complex (Lee et al., 2003), the rise in Axin R-spondin (the stem cell niche) have higher levels of functional levels in response to Wnt signaling leads to increased destruction RNF43/ZNRF3 at their surface and, as a result, gradually express complex formation and β-catenin degradation, thereby providing decreasing amounts of Frizzled receptors, which is translated into a mechanism for negative feedback (Goentoro and Kirschner, decreased levels of Wnt-β-catenin signaling. 2009). The Wnt target gene Nkd1 also provides negative feedback in the cytoplasm but the exact mechanism by which it functions Wnt signaling in early vertebrate embryonic development remains unclear. NKD1 was first suspected to bind to and inhibit Cell-cell communication is integral during the embryonic Dishevelled (Rousset et al., 2001); however, other findings have development of multicellular organisms, acting to coordinate stem shown that it interacts directly with β-catenin and prevents its cell self-renewal, cell fate decisions, cell migration and the nuclear import (Van Raay et al., 2011). Finally, the 81 amino organization of cells into tissues. The Wnt-β-catenin signaling acid protein inhibitor of β-catenin and T cell factor (ICAT) was pathway is one of the evolutionary conserved communication found to directly interact with and inhibit β-catenin in the nucleus, systems that regulates embryonic development. It involves Wnt acting to inhibit the posteriorizing activity of Wnt-β-catenin ligands that are released by Wnt-producing cells and that act over signaling in a spatiotemporal manner in the nervous system (Satoh various ranges to influence neighboring Wnt-responsive cells. et al., 2004). Wnt-β-catenin signaling is instrumental for defining the dorsoventral and anteroposterior body axes in multiple animal Wnt signal amplification species (Genikhovich and Technau, 2017; Niehrs, 2010). For A number of recent studies have revealed a mechanism involving example, following Xenopus egg fertilization, cortical rotation leads the cell surface protein LGR5 and secreted R-spondin proteins that to dorsal translocation of maternal determinants that are important provides a way of augmenting signaling through the Wnt pathway. for β-catenin signaling activation, which in turn leads to Lgr5, which is among the best-characterized target genes of the specification of the Spemann organizer (Moon and Kimelman, Wnt-β-catenin signaling pathway, is an established stem cell 1998) – an essential embryonic inducer of dorsoventral patterning. marker (Barker et al., 2007). As such, Lgr5 reporter mice have Accordingly, the injection of Wnt mRNA or other factors that proven valuable for the identification, isolation and functional activate β-catenin signaling into future ventral blastomeres characterization of tissue stem cells (Barker et al., 2007). However, notoriously leads to duplication of the dorsal axis and results in the precise role of LGR5 and its homologs LGR4/LGR6 remained two-headed frog embryos (McMahon and Moon, 1989). Whether controversial until the discovery that they function as receptors for Wnt ligands themselves were involved in dorsal axis induction in four R-spondin secreted proteins, RSPO1-RSPO4 (Carmon et al., Xenopus remained controversial for a long time, but Wnt-11 was 2011; de Lau et al., 2011; Glinka et al., 2011). It was further eventually identified as the ligand implicated in this context revealed that R-spondins do not possess signaling activity on their (Tao et al., 2005). At the onset of gastrulation, Wnt ligand- own (Janda et al., 2017) but rather amplify Wnt signaling activity, as dependent β-catenin signaling then activates a largely distinct they require the presence of Wnt ligands. A missing link in our transcriptional program that directs anteroposterior axis understanding of RSPO-LGR4/5/6 function came with the development. In this context, Wnt-β-catenin signaling is inhibited identification that the E3 ubiquitin ligases RNF43/ZNRF3 act as anteriorly, leading to the development of head structures, and co-receptors for RSPOs (Chen et al., 2013; Hao et al., 2012; Zebisch activated posteriorly to define tail formation (Green et al., 2015). et al., 2013). As mentioned above, Rnf43 and Znrf3 are themselves Paramount to these patterning events, the spatiotemporal regulation target genes of Wnt-β-catenin signaling, and when upregulated are of Wnt-β-catenin transcriptional programs is achieved through the part of a negative-feedback loop that downregulates cell-surface action of secreted antagonists, epigenetic regulation, the actions of levels of Frizzled-LRP5/6 complexes. Thus, the binding of different Tcf/Lef factors and signaling integration with other DEVELOPMENT DEVELOPMENT AT A GLANCE Development (2018) 145, dev146589. doi:10.1242/dev.146589 developmental pathways. Beyond these early roles in establishing the adult intestinal epithelium, which turns over fully every 4-5 days the embryonic body axes, Wnt-β-catenin signaling plays important and thereby requires balanced stem and progenitor cell self-renewal, roles during the morphogenesis of multiple tissues derived from the proliferation and differentiation (Clevers, 2013). The intestinal three germ layers. epithelium is composed of two compartments: the villi, which are responsible for the absorptive and secretion functions of the Wnt signaling in embryonic stem cells intestine; and the crypts of Lieberkühn, which are not exposed to The derivation of human embryonic stems cells (ESCs) and induced the intestinal lumen, and contain tissue stem cells and rapidly pluripotent stem cells (iPSCs) has provided a system for studying proliferating transit amplifying cells. Genetic studies have shown human embryonic development and human diseases, and a that the disruption of Tcf4 (Korinek et al., 1998) or β-catenin (Fevr framework for the production of large quantities of differentiated et al., 2007), or the overexpression of Dkk1 (Fevr et al., 2007; Pinto cells that can be transplanted for regenerative medicine or tissue et al., 2003), leads to robust loss of transit amplifying cells and crypt engineering applications. The directed differentiation of such structures, confirming the functional requirement of Wnt-β-catenin pluripotent stem cells (PSCs) into specialized cells in culture signaling in the intestinal epithelium. These genetic experiments are follows the same principles underlying embryonic development; as corroborated by the fact that APC loss-of-function mutations induce such, insights gained from developmental biology have guided adenoma formation (Morin, 1997) and occur in 80% of colorectal strategies for using growth factors and inhibitors of developmental cancers (Cancer Genome Atlas Network, 2012). Studies on the signaling pathways to maintain pluripotency or steer cell fate expression of Wnt target genes have identified a Wnt signaling towards the desired lineage with increasing efficiencies (Williams gradient, with highest expression in the base of the crypt, et al., 2012). particularly in the crypt base columnar cells (CBCs) (Kosinski Functional redundancy between Wnt-β-catenin signaling et al., 2007; Van der Flier et al., 2007). Wnts are bound to the plasma activation, leukemia inhibitory factor (LIF) signaling activation membrane of cells at the base of the crypt and are diluted with each and MAPK pathway inhibition is important for maintaining the cell division away from the base, thereby establishing a gradient naive pluripotent state in ESCs. Indeed, β-catenin KO ESCs (Farin et al., 2016). Underlying the CBCs at the bottom of crypts are maintain their pluripotency when cultured with LIF but rapidly exit myoepithelial cells, which have been shown to be the in vivo source the naive state in its absence (Lyashenko et al., 2011). Reciprocally, of Wnt ligands (Kabiri et al., 2014). In addition, the Wnt target gene the use of GSK3 inhibitors to stimulate β-catenin signaling bypasses Lgr5 was found to be expressed exclusively in CBCs meaning that it the requirement for LIF in this process (Sato et al., 2004). Wnt could be used for lineage-tracing experiments; these experiments signaling is therefore not absolutely required for the maintenance of showed that Lgr5 CBCs could differentiate into all epithelial cell pluripotency, a finding supported by the analysis of porcupine KO types (Barker et al., 2007). Further supporting the possibility that mESCs that exhibit normal self-renewal properties (Biechele et al., Lgr5 CBCs are the intestinal tissue stem cells, dissociated single 2013). Paradoxical reports implicating Wnt-β-catenin signaling in Lgr5 cells were found to give rise to ‘mini-gut’ organoids in vitro, the self-renewal versus differentiation of ESCs have been reconciled which contain all intestinal cell types (Sato et al., 2009). with its seemingly opposite roles in promoting pluripotency in the naive state (Sato et al., 2004; ten Berge et al., 2011; Xu et al., 2016) Bone and differentiation in the primed state (Davidson et al., 2012; Kurek Bone tissue remodeling is crucial for maintaining a balance between et al., 2015), which is characterized by a distinct epigenetic and systemic calcium homeostasis and the biomechanical needs of the gene expression landscape (Nichols and Smith, 2009). Levels of skeleton. Human genetics data perhaps best highlight the crucial Wnt-β-catenin signaling therefore appear to control the transition role of Wnt-β-catenin signaling in bone tissue homeostasis. Indeed, between the naive and primed ESC states. In line with its role in rare pathological mutations within genes encoding components of embryonic development, the further differentiation of ESCs the Wnt-β-catenin pathway lead to either severely increased or into different germ layers requires the temporal activation of decreased bone mass. For example, Lrp5, which encodes a Wnt Wnt-β-catenin signaling to steer cells towards the mesendoderm co-receptor, was revealed as a critical gene directing bone mass lineage or inactivation to obtain neuroectoderm (Tabar and Studer, regulation when LRP5 loss-of-function mutations were identified in 2014). the low bone mass disorder osteoporosis-pseudoglioma syndrome (Gong et al., 2001) and when heterozygous missense mutations in Wnt signaling in adult tissue homeostasis LRP5 were observed in individuals with dominantly inherited high The self-renewal versus differentiation of stem cells is directed by bone mass (Boyden et al., 2002; Little et al., 2002). Another extrinsic short-ranged signals that emanate from the niche. example is mutations discovered in SOST (sclerostin), a negative Confirming the pervasive role of Wnt ligands as niche factors, regulator of LRP5/6 that was found to be causally linked to high lineage-tracing experiments using Wnt-target gene reporters have bone density pathology via loss-of-function mutations (Brunkow revealed labeled stem cells in several tissues, including the intestine et al., 2001) or mutations that decrease its expression (Balemans (Barker et al., 2007), the stomach (Barker et al., 2010), the skin (Lim et al., 2002; Loots et al., 2005). Corroborating this human genetic et al., 2013), the liver (Wang et al., 2015) and the mammary gland evidence are extensive genetic experiments performed in mice that (van Amerongen et al., 2012). Below, we describe three of the best- link Wnt-β-catenin signaling to the regulation of bone homeostasis studied tissues in which Wnt signaling has been demonstrated to (Baron and Kneissel, 2013). Leveraging these findings, several play crucial roles with regard to the function of tissue stem cells. pharmaceutical companies have developed anti-SOST antibodies to activate endogenous Wnt-β-catenin circuitries in bone tissues, and Intestine these have been shown in clinical trials to augment bone mass The best-characterized function of Wnt signaling in adult tissues is density and prevent fractures (Glorieux et al., 2017; Recker et al., in the maintenance of stem cell niches, where Wnt ligands promote 2015; Saag et al., 2017; Williams, 2017). At the cellular level, the the proliferation and self-renewal capability of tissue-specific stem process of bone remodeling results from the concerted actions of cells (Clevers et al., 2014). This has been particularly well studied in three different cell types: osteoblasts, which are responsible for DEVELOPMENT DEVELOPMENT AT A GLANCE Development (2018) 145, dev146589. doi:10.1242/dev.146589 bone matrix formation; osteoclasts, which are responsible for explained by our current linear view of the Wnt-β-catenin pathway. bone resorption; and osteocytes, which are responsible for bone More work is thus needed to reverse engineer the complex signaling maintenance. The precise roles of Wnt-β-catenin signaling in bone network formed by the 19 Wnt ligands, 10 Frizzled receptors and mass homeostasis still remain to be clarified but the prevailing multiple co-receptors to better understand how, when and where model is that it functions to regulate osteoblast differentiation and each of these components functions. Finally, elucidating which function (Bennett et al., 2005; Cui et al., 2011; Day et al., 2005; Hill Wnt-receptor pairs are involved in specific physiological functions et al., 2005; Tu et al., 2015). will likely provide more selective therapeutic strategies for treating diseases. Advances in cryoelectron microscopy and single-molecule Skin imaging, combined with progress in functional genomics-based The best-studied role of Wnt signaling in adult skin is its role in the approaches, will undoubtedly help us to fill these gaps. hair follicle cycle, where Wnt is an important factor in orchestrating Acknowledgements the control of hair follicle stem cells (HFSCs) (Veltri et al., 2018). We thank members of our laboratory for helpful discussions and Drs Gregory M. The adult hair follicle goes through continuous cycles of telogen Kelly, Daniel Schramek and Bradley Doble for their thoughts and comments to (rest), anagen (growth) and catagen (degeneration). The essential improve the manuscript. role of Wnt-β-catenin in hair follicle cycling was identified through the observations that loss of epidermal β-catenin or inhibition of Competing interests The authors declare no competing or financial interests. LRP5/6 via ectopic DKK1 expression leads to defects in hair follicle development and/or loss after a single hair cycle (Andl et al., 2002; Funding Huelsken et al., 2001). Specifically, Wnt-β-catenin signaling acts on The authors’ research is supported by grants from the Canadian Institute of Health multiple cell types to induce the telogen-anagen transition (Greco Research (364969) and the Canadian Cancer Society (705045). et al., 2009; Kishimoto et al., 2000; Van Mater et al., 2003). During telogen, HFSCs are slow cycling or quiescent, reside in the bulge Development at a Glance A high-resolution version of the poster is available for downloading in the online region of the hair follicle (Cotsarelis et al., 1990; Lyle et al., 1998), version of this article at http://dev.biologists.org/content/145/11/dev146589/F1.poster. are LGR5-positive (Jaks et al., 2008) and rely on autocrine Wnt jpg for maintenance (Lim et al., 2016). During the telogen-anagen transition, Wnt-β-catenin activity in the bulge HFSCs increases References (Lien et al., 2014) and cells from the bulge migrate to the base of the Amit, S., Hatzubai, A., Birman, Y., Andersen, J. S., Ben-Shushan, E., Mann, M., Ben-Neriah, Y. and Alkalay, I. (2002). Axin-mediated CKI phosphorylation of hair follicle and begin proliferating rapidly to produce cell lineages beta-catenin at Ser 45: a molecular switch for the Wnt pathway. Genes Dev. 16, of a new hair follicle (Oshima et al., 2001; Tumbar et al., 2004). This 1066-1076. proliferation is aided by concurrent Wnt-β-catenin activation in the Andl, T., Reddy, S. T., Gaddapara, T. and Millar, S. E. (2002). WNT signals are dermal papilla, which induces growth-promoting FGF signals required for the initiation of hair follicle development. Dev. Cell 2, 643-653. Angers, S. and Moon, R. T. (2009). Proximal events in Wnt signal transduction. Nat. (Enshell-Seijffers et al., 2010). Rev. Mol. Cell Biol 10, 468-477. Bafico, A., Liu, G., Yaniv, A., Gazit, A. and Aaronson, S. A. (2001). Novel Perspectives mechanism of Wnt signalling inhibition mediated by Dickkopf-1 interaction with Wnt ligands are crucial for the development and homeostasis of LRP6/Arrow. Nat. Cell Biol. 3, 683-686. Balemans, W., Patel, N., Ebeling, M., Van Hul, E., Wuyts, W., Lacza, C., virtually all tissues. In the past few decades, genetic, biochemical Dioszegi, M., Dikkers, F. G., Hildering, P., Willems, P. J. et al. (2002). and structural experiments have identified many Wnt signaling Identification of a 52 kb deletion downstream of the SOST gene in patients with components and have revealed their underlying mechanisms. van Buchem disease. J. Med. Genet. 39, 91-97. However, important gaps remain, specifically with respect to the Bä nziger, C., Soldini, D., Schü tt, C., Zipperlen, P., Hausmann, G. and Basler, K. mechanisms of signal transduction regulated by Wnt proteins and (2006). Wntless, a conserved membrane protein dedicated to the secretion of Wnt proteins from signaling cells. Cell 125, 509-522. β-catenin. For example, although structures of Wnt in complex Barker, N., van Es, J. H., Kuipers, J., Kujala, P., van den Born, M., Cozijnsen, M., with the Frizzled CRD have provided details about the mode of Haegebarth, A., Korving, J., Begthel, H., Peters, P. J. et al. (2007). binding, it remains unclear how this is coupled to potential Identification of stem cells in small intestine and colon by marker gene Lgr5. allosteric changes in the heptahelical bundles of Frizzled to Nature 449, 1003-1007. Barker, N., Huch, M., Kujala, P., van de Wetering, M., Snippert, H. J., van Es, transduce signaling to the intracellular components. How Wnts J. H., Sato, T., Stange, D. E., Begthel, H., van den Born, M. et al. (2010). Lgr5 co-engage Frizzled and LRP5/6 co-receptors, and the precise +ve stem cells drive self-renewal in the stomach and build long-lived gastric units nature of the activated complex, also remains poorly characterized. in vitro. Cell Stem Cell 6, 25-36. Another loosely understood step is the recruitment of Dishevelled Baron, R. and Kneissel, M. (2013). WNT signaling in bone homeostasis and proteins by activated Frizzled receptors, and how this leads to disease: from human mutations to treatments. Nat. Med. 19, 179-192. Bartscherer, K., Pelte, N., Ingelfinger, D. and Boutros, M. (2006). Secretion of inactivation of destruction complex activity. Furthermore, despite Wnt ligands requires Evi, a conserved transmembrane protein. Cell 125, 523-533. close investigation, the biochemical nature of the destruction Behrens, J. (1998). Functional interaction of an axin homolog, conductin, with complex and the precise molecular mechanisms underlying its -catenin, APC, and GSK3. Science 280, 596-599. function and regulation remain ill defined. The role of β-catenin as Behrens, J., von Kries, J. P., Kü hl, M., Bruhn, L., Wedlich, D., Grosschedl, R. and Birchmeier, W. (1996). Functional interaction of β-catenin with the a cell-adhesion component when bound to cadherin molecules and transcription factor LEF-1. Nature 382, 638-642. whether this pool of β-catenin at the plasma membrane interacts Bennett, C. N., Longo, K. A., Wright, W. S., Suva, L. J., Lane, T. F., Hankenson, functionally with the transcriptional pool in specific contexts also K. D. and MacDougald, O. A. (2005). Regulation of osteoblastogenesis and bone needs to be evaluated. Similarly, β-catenin transcriptional mass by Wnt10b. Proc. Natl. Acad. Sci. USA 102, 3324-3329. Bhanot, P., Brink, M., Samos, C. H., Hsieh, J.-C., Wang, Y., Macke, J. P., Andrew, functions, which are independent of Wnt ligands and influenced D., Nathans, J. and Nusse, R. (1996). A new member of the frizzled family from by signaling crosstalk with other signaling pathways, need to be Drosophila functions as a Wingless receptor. Nature 382, 225-230. considered. In addition, how various levels of Wnt signals are Biechele, S., Cockburn, K., Lanner, F., Cox, B. J. and Rossant, J. (2013). Porcn- ultimately translated into precise changes in nuclear β-catenin, and dependent Wnt signaling is not required prior to mouse gastrulation. Development hence spatiotemporal modulation of gene expression, is incompletely 140, 2961-2971. DEVELOPMENT DEVELOPMENT AT A GLANCE Development (2018) 145, dev146589. doi:10.1242/dev.146589 Boyden, L. M., Mao, J., Belsky, J., Mitzner, L., Farhi, A., Mitnick, M. A., Wu, D., Glorieux, F. H., Devogelaer, J. P. and Durigova, M. (2017). BPS804 anti-sclerostin Insogna, K. and Lifton, R. P. (2002). High bone density due to a mutation in LDL- antibody in adults with moderate osteogenesis imperfecta: results of a receptor–related protein 5. N. Engl. J. Med. 346, 1513-1521. randomized Phase 2a trial. J. Bone Miner Res. 32, 1496-1504. Brunkow, M. E., Gardner, J. C., Van Ness, J., Paeper, B. W., Kovacevich, B. R., Goentoro, L. and Kirschner, M. W. (2009). Evidence that fold-change, and not Proll, S., Skonier, J. E., Zhao, L., Sabo, P. J., Fu, Y.-H. et al. (2001). Bone absolute level, of β-catenin dictates Wnt signaling. Mol. Cell 36, 872-884. dysplasia sclerosteosis results from loss of the SOST gene product, a novel Gong, Y., Slee, R. B., Fukai, N., Rawadi, G., Roman-Roman, S., Reginato, A. M., cystine knot-containing protein. Am. J. Hum. Genet. 68, 577-589. Wang, H., Cundy, T., Glorieux, F. H., Lev, D. et al. (2001). LDL receptor-related Cancer Genome Atlas Network (2012). Comprehensive molecular protein 5 (LRP5) affects bone accrual and eye development. Cell 107, 513-523. characterization of human colon and rectal cancer. Nature 487, 330-337. González-Sancho, J. M., Aguilera, O., Garcıa,́ J. M., Pendás-Franco, N., Pena, Carmon, K. S., Gong, X., Lin, Q., Thomas, A. and Liu, Q. (2011). R-spondins C., Cal, S., de Herreros, A. G., Bonilla, F. and Munoz, A. (2005). The Wnt function as ligands of the orphan receptors LGR4 and LGR5 to regulate Wnt/beta- antagonist DICKKOPF-1 gene is a downstream target of β-catenin/TCF and is catenin signaling. Proc. Natl. Acad. Sci. USA 108, 11452-11457. downregulated in human colon cancer. Oncogene 24, 1098-1103. Cavallo, R. A., Cox, R. T., Moline, M. M., Roose, J., Polevoy, G. A., Clevers, H., Goodman, R. M., Thombre, S., Firtina, Z., Gray, D., Betts, D., Roebuck, J., Peifer, M. and Bejsovec, A. (1998). Drosophila Tcf and Groucho interact to Spana, E. P. and Selva, E. M. (2006). Sprinter: a novel transmembrane protein repress Wingless signalling activity. Nature 395, 604-608. required for Wg secretion and signaling. Development 133, 4901-4911. Chen, S., Bubeck, D., MacDonald, B. T., Liang, W.-X., Mao, J.-H., Malinauskas, Greco, V., Chen, T., Rendl, M., Schober, M., Pasolli, H. A., Stokes, N., Dela Cruz- T., Llorca, O., Aricescu, A. R., Siebold, C., He, X. et al. (2011). Structural and Racelis, J. and Fuchs, E. (2009). A two-step mechanism for stem cell activation functional studies of LRP6 ectodomain reveal a platform for Wnt signaling. Dev. during hair regeneration. Cell Stem Cell 4, 155-169. Cell 21, 848-861. Green, D., Whitener, A. E., Mohanty, S. and Lekven, A. C. (2015). Vertebrate Chen, P.-H., Chen, X., Lin, Z., Fang, D. and He, X. (2013). The structural basis of nervous system posteriorization: Grading the function of Wnt signaling. Dev. Dyn. R-spondin recognition by LGR5 and RNF43. Genes Dev. 27, 1345-1350. 244, 507-512. Chia, I. V. and Costantini, F. (2005). Mouse axin and axin2/conductin proteins are Hao, H.-X., Xie, Y., Zhang, Y., Charlat, O., Oster, E., Avello, M., Lei, H., Mickanin, functionally equivalent in vivo. Mol. Cell. Biol. 25, 4371-4376. C., Liu, D., Ruffner, H. et al. (2012). ZNRF3 promotes Wnt receptor turnover in an Clevers, H. (2013). The intestinal crypt, a prototype stem cell compartment. Cell R-spondin-sensitive manner. Nature 485, 195-200. 154, 274-284. Hart, M. J., de los Santos, R., Albert, I. N., Rubinfeld, B. and Polakis, P. (1998). Clevers, H., Loh, K. M. and Nusse, R. (2014). Stem cell signaling. An integral Downregulation of β-catenin by human Axin and its association with the APC program for tissue renewal and regeneration: Wnt signaling and stem cell control. tumor suppressor, β-catenin and GSK3β. Curr. Biol. 8, 573-581. Science 346, 1248012. Hart, M., Concordet, J.-P., Lassot, I., Albert, I., del los Santos, R., Durand, H., Cong, F., Schweizer, L. and Varmus, H. (2004). Wnt signals across the plasma Perret, C., Rubinfeld, B., Margottin, F., Benarous, R. et al. (1999). The F-box membrane to activate the beta-catenin pathway by forming oligomers containing protein β-TrCP associates with phosphorylated β-catenin and regulates its activity its receptors, Frizzled and LRP. Development 131, 5103-5115. in the cell. Curr. Biol. 9, 207-211. Cotsarelis, G., Sun, T.-T. and Lavker, R. M. (1990). Label-retaining cells reside in Herr, P. and Basler, K. (2012). Porcupine-mediated lipidation is required for Wnt the bulge area of pilosebaceous unit: implications for follicular stem cells, hair recognition by Wls. Dev. Biol. 361, 392-402. cycle, and skin carcinogenesis. Cell 61, 1329-1337. Hill, T. P., Spä ter, D., Taketo, M. M., Birchmeier, W. and Hartmann, C. (2005). Cselenyi, C. S., Jernigan, K. K., Tahinci, E., Thorne, C. A., Lee, L. A. and Lee, E. Canonical Wnt/β-catenin signaling prevents osteoblasts from differentiating into (2008). LRP6 transduces a canonical Wnt signal independently of Axin chondrocytes. Dev. Cell 8, 727-738. degradation by inhibiting GSK3’s phosphorylation of -catenin. Proc. Natl Acad. Hsieh, J.-C., Kodjabachian, L., Rebbert, M. L., Rattner, A., Smallwood, P. M., Sci. USA 105, 8032-8037. Samos, C. H., Nusse, R., Dawid, I. B. and Nathans, J. (1999). A new secreted Cui, Y., Niziolek, P. J., MacDonald, B. T., Zylstra, C. R., Alenina, N., Robinson, protein that binds to Wnt proteins and inhibits their activities. Nature 398, 431-436. D. R., Zhong, Z., Matthes, S., Jacobsen, C. M., Conlon, R. A. et al. (2011). Lrp5 Huelsken, J., Vogel, R., Erdmann, B., Cotsarelis, G. and Birchmeier, W. (2001). functions in bone to regulate bone mass. Nat. Med. 17, 684-691. beta-Catenin controls hair follicle morphogenesis and stem cell differentiation in Davidson, G., Wu, W., Shen, J., Bilic, J., Fenger, U., Stannek, P., Glinka, A. and the skin. Cell 105, 533-545. Niehrs, C. (2005). Casein kinase 1 gamma couples Wnt receptor activation to Jaks, V., Barker, N., Kasper, M., van Es, J. H., Snippert, H. J., Clevers, H. and cytoplasmic signal transduction. Nature 438, 867-872. Toftgård, R. (2008). Lgr5 marks cycling, yet long-lived, hair follicle stem cells. Nat. Davidson, G., Shen, J., Huang, Y.-L., Su, Y., Karaulanov, E., Bartscherer, K., Genet. 40, 1291-1299. Hassler, C., Stannek, P., Boutros, M. and Niehrs, C. (2009). Cell cycle control of Janda, C. Y., Waghray, D., Levin, A. M., Thomas, C. and Garcia, K. C. (2012). wnt receptor activation. Dev. Cell 17, 788-799. Structural basis of Wnt recognition by Frizzled. Science 337, 59-64. Davidson, K. C., Adams, A. M., Goodson, J. M., McDonald, C. E., Potter, J. C., Janda, C. Y., Dang, L. T., You, C., Chang, J., de Lau, W., Zhong, Z. A., Yan, K. S., Berndt, J. D., Biechele, T. L., Taylor, R. J. and Moon, R. T. (2012). Wnt/ -catenin Marecic, O., Siepe, D., Li, X. et al. (2017). Surrogate Wnt agonists that signaling promotes differentiation, not self-renewal, of human embryonic stem phenocopy canonical Wnt and β-catenin signalling. Nature 545, 234-237. cells and is repressed by Oct4. Proc. Natl Acad. Sci. USA 109, 4485-4490. Jho, E.-H., Zhang, T., Domon, C., Joo, C.-K., Freund, J.-N. and Costantini, F. Day, T. F., Guo, X., Garrett-Beal, L. and Yang, Y. (2005). Wnt/beta-catenin (2002). Wnt/ -catenin/Tcf signaling induces the transcription of Axin2, a negative signaling in mesenchymal progenitors controls osteoblast and chondrocyte regulator of the signaling pathway. Mol. Cell. Biol. 22, 1172-1183. differentiation during vertebrate skeletogenesis. Dev. Cell 8, 739-750. Kabiri, Z., Greicius, G., Madan, B., Biechele, S., Zhong, Z., Zaribafzadeh, H., de Lau, W., Barker, N., Low, T. Y., Koo, B.-K., Li, V. S. W., Teunissen, H., Kujala, Edison, Aliyev, J., Wu, Y., Bunte, R. et al. (2014). Stroma provides an intestinal P., Haegebarth, A., Peters, P. J., van de Wetering, M. et al. (2011). Lgr5 stem cell niche in the absence of epithelial Wnts. Development 141, 2206-2215. homologues associate with Wnt receptors and mediate R-spondin signalling. Kakugawa, S., Langton, P. F., Zebisch, M., Howell, S. A., Chang, T.-H., Liu, Y., Nature 476, 293-297. Feizi, T., Bineva, G., O’Reilly, N., Snijders, A. P. et al. (2015). Notum deacylates Enshell-Seijffers, D., Lindon, C., Kashiwagi, M. and Morgan, B. A. (2010). beta- Wnt proteins to suppress signalling activity. Nature 519, 187-192. catenin activity in the dermal papilla regulates morphogenesis and regeneration of Kishimoto, J., Burgeson, R. E. and Morgan, B. A. (2000). Wnt signaling maintains hair. Dev. Cell 18, 633-642. the hair-inducing activity of the dermal papilla. Genes Dev. 14, 1181-1185. Farin, H. F., Jordens, I., Mosa, M. H., Basak, O., Korving, J., Tauriello, D. V. F., de Klingensmith, J., Nusse, R. and Perrimon, N. (1994). The Drosophila segment Punder, K., Angers, S., Peters, P. J., Maurice, M. M. et al. (2016). Visualization polarity gene dishevelled encodes a novel protein required for response to the of a short-range Wnt gradient in the intestinal stem-cell niche. Nature 530, wingless signal. Genes Dev. 8, 118-130. 340-343. Koo, B.-K., Spit, M., Jordens, I., Low, T. Y., Stange, D. E., van de Wetering, M., Fevr, T., Robine, S., Louvard, D. and Huelsken, J. (2007). Wnt/beta-catenin is van Es, J. H., Mohammed, S., Heck, A. J. R., Maurice, M. M. et al. (2012). essential for intestinal homeostasis and maintenance of intestinal stem cells. Mol. Tumour suppressor RNF43 is a stem-cell E3 ligase that induces endocytosis of Cell. Biol. 27, 7551-7559. Wnt receptors. Nature 488, 665-669. Flack, J. E., Mieszczanek, J., Novcic, N. and Bienz, M. (2017). Wnt-dependent Korinek, V., Barker, N., Moerer, P., van Donselaar, E., Huls, G., Peters, P. J. and inactivation of the groucho/TLE co-repressor by the HECT E3 ubiquitin ligase Hyd/ Clevers, H. (1998). Depletion of epithelial stem-cell compartments in the small UBR5. Mol. Cell 67, 181-193.e5. intestine of mice lacking Tcf-4. Nat. Genet. 19, 379-383. Genikhovich, G. and Technau, U. (2017). On the evolution of bilaterality. Kosinski, C., Li, V. S. W., Chan, A. S. Y., Zhang, J., Ho, C., Tsui, W. Y., Chan, T. L., Development 144, 3392-3404. Mifflin, R. C., Powell, D. W., Yuen, S. T. et al. (2007). Gene expression patterns Glinka, A., Wu, W., Delius, H., Monaghan, A. P., Blumenstock, C. and Niehrs, C. of human colon tops and basal crypts and BMP antagonists as intestinal stem cell (1998). Dickkopf-1 is a member of a new family of secreted proteins and functions niche factors. Proc. Natl. Acad. Sci. USA 104, 15418-15423. in head induction. Nature 391, 357-362. Krasnow, R. E., Wong, L. L. and Adler, P. N. (1995). Dishevelled is a component of Glinka, A., Dolde, C., Kirsch, N., Huang, Y.-L., Kazanskaya, O., Ingelfinger, D., the frizzled signaling pathway in Drosophila. Development 121, 4095-4102. Boutros, M., Cruciat, C.-M. and Niehrs, C. (2011). LGR4 and LGR5 are R- Kurek, D., Neagu, A., Tastemel, M., Tü ysü z, N., Lehmann, J., van de Werken, spondin receptors mediating Wnt/β-catenin and Wnt/PCP signalling. EMBO Rep. H. J. G., Philipsen, S., van der Linden, R., Maas, A., van IJcken, W. F. J. et al. 12, 1055-1061. (2015). Endogenous WNT signals mediate BMP-induced and spontaneous DEVELOPMENT DEVELOPMENT AT A GLANCE Development (2018) 145, dev146589. doi:10.1242/dev.146589 differentiation of epiblast stem cells and human embryonic stem cells. Stem Cell Piao, S., Lee, S.-H., Kim, H., Yum, S., Stamos, J. L., Xu, Y., Lee, S.-J., Lee, J., Oh, Rep. 4, 114-128. S., Han, J.-K. et al. (2008). Direct inhibition of GSK3β by the phosphorylated Lebensohn, A. M. and Rohatgi, R. (2018). R-spondins can potentiate WNT cytoplasmic domain of LRP6 in Wnt/β-catenin signaling. PLoS One 3, e4046. signaling without LGRs. Elife 7, e33126. Pinson, K. I., Brennan, J., Monkley, S., Avery, B. J. and Skarnes, W. C. (2000). Lee, E., Salic, A., Krü ger, R., Heinrich, R. and Kirschner, M. W. (2003). The roles An LDL-receptor-related protein mediates Wnt signalling in mice. Nature 407, of APC and Axin derived from experimental and theoretical analysis of the Wnt 535-538. pathway. PLoS Biol. 1, e10. Pinto, D., Gregorieff, A., Begthel, H. and Clevers, H. (2003). Canonical Wnt Leyns, L., Bouwmeester, T., Kim, S.-H., Piccolo, S. and De Robertis, E. M. signals are essential for homeostasis of the intestinal epithelium. Genes Dev. 17, (1997). Frzb-1 is a secreted antagonist of Wnt signaling expressed in the 1709-1713. spemann organizer. Cell 88, 747-756. Povelones, M. and Nusse, R. (2005). The role of the cysteine-rich domain of Lien, W.-H., Polak, L., Lin, M., Lay, K., Zheng, D. and Fuchs, E. (2014). In vivo Frizzled in Wingless-Armadillo signaling. EMBO J. 24, 3493-3503. transcriptional governance of hair follicle stem cells by canonical Wnt regulators. Proffitt, K. D. and Virshup, D. M. (2012). Precise regulation of porcupine activity is Nat. Cell Biol. 16, 179-190. required for physiological Wnt signaling. J. Biol. Chem. 287, 34167-34178. Lim, X., Tan, S. H., Koh, W. L. C., Chau, R. M. W., Yan, K. S., Kuo, C. J., van Rattner, A., Hsieh, J.-C., Smallwood, P. M., Gilbert, D. J., Copeland, N. G., Amerongen, R., Klein, A. M. and Nusse, R. (2013). Interfollicular epidermal stem Jenkins, N. A. and Nathans, J. (1997). A family of secreted proteins contains cells self-renew via autocrine Wnt signaling. Science 342, 1226-1230. homology to the cysteine-rich ligand-binding domain of frizzled receptors. Proc. Lim, X., Tan, S. H., Yu, K. L., Lim, S. B. H. and Nusse, R. (2016). Axin2 marks Natl. Acad. Sci. USA 94, 2859-2863. quiescent hair follicle bulge stem cells that are maintained by autocrine Wnt/β- Recker, R. R., Benson, C. T., Matsumoto, T., Bolognese, M. A., Robins, D. A., catenin signaling. Proc. Natl. Acad. Sci. USA 113, E1498-E1505. Alam, J., Chiang, A. Y., Hu, L., Krege, J. H., Sowa, H. et al. (2015). A Little, R. D., Folz, C., Manning, S. P., Swain, P. M., Zhao, S.-C., Eustace, B., randomized, double-blind phase 2 clinical trial of blosozumab, a sclerostin Lappe, M. M., Spitzer, L., Zweier, S., Braunschweiger, K. et al. (2002). A antibody, in postmenopausal women with low bone mineral density. J. Bone mutation in the LDL receptor–related protein 5 gene results in the autosomal Miner. Res. 30, 216-224. dominant high–bone-mass trait. Am. J. Hum. Genet. 70, 11-19. Rijsewijk, F., Schuermann, M., Wagenaar, E., Parren, P., Weigel, D. and Nusse, Liu, C., Li, Y., Semenov, M., Han, C., Baeg, G.-H., Tan, Y., Zhang, Z., Lin, X. and R. (1987). The Drosophila homolog of the mouse mammary oncogene int-1 is He, X. (2002). Control of beta-catenin phosphorylation/degradation by a dual- identical to the segment polarity gene wingless. Cell 50, 649-657. kinase mechanism. Cell 108, 837-847. Roose, J., Molenaar, M., Peterson, J., Hurenkamp, J., Brantjes, H., Moerer, P., Logan, C. Y. and Nusse, R. (2004). The Wnt signaling pathway in development and van de Wetering, M., Destrée, O. and Clevers, H. (1998). The Xenopus Wnt disease. Annu. Rev. Cell Dev. Biol. 20, 781-810. effector XTcf-3 interacts with Groucho-related transcriptional repressors. Nature Loots, G. G., Kneissel, M., Keller, H., Baptist, M., Chang, J., Collette, N. M., 395, 608-612. Ovcharenko, D., Plajzer-Frick, I. and Rubin, E. M. (2005). Genomic deletion of a Rousset, R., Mack, J. A., Wharton, K. A., Jr, Axelrod, J. D., Cadigan, K. M., Fish, long-range bone enhancer misregulates sclerostin in Van Buchem disease. M. P., Nusse, R. and Scott, M. P. (2001). Naked cuticle targets dishevelled to Genome Res. 15, 928-935. antagonize Wnt signal transduction. Genes Dev. 15, 658-671. Lustig, B., Jerchow, B., Sachs, M., Weiler, S., Pietsch, T., Karsten, U., van de Rubinfeld, B., Souza, B., Albert, I., Mü ller, O., Chamberlain, S. H., Masiarz, F. R., Wetering, M., Clevers, H., Schlag, P. M., Birchmeier, W. et al. (2002). Negative Munemitsu, S. and Polakis, P. (1993). Association of the APC gene product with feedback loop of Wnt signaling through upregulation of conductin/axin2 in beta-catenin. Science 262, 1731-1734. colorectal and liver tumors. Mol. Cell. Biol. 22, 1184-1193. Rubinfeld, B., Albert, I., Porfiri, E., Fiol, C., Munemitsu, S. and Polakis, P. (1996). Lyashenko, N., Winter, M., Migliorini, D., Biechele, T., Moon, R. T. and Binding of GSK3beta to the APC-beta-catenin complex and regulation of complex Hartmann, C. (2011). Differential requirement for the dual functions of β-catenin assembly. Science 272, 1023-1026. in embryonic stem cell self-renewal and germ layer formation. Nat. Cell Biol. 13, Saag, K. G., Petersen, J., Brandi, M. L., Karaplis, A. C., Lorentzon, M., Thomas, 753-761. T., Maddox, J., Fan, M., Meisner, P. D. and Grauer, A. (2017). Romosozumab or Lyle, S., Christofidou-Solomidou, M., Liu, Y., Elder, D. E., Albelda, S. and alendronate for fracture prevention in women with osteoporosis. N. Engl. J. Med. Cotsarelis, G. (1998). The C8/144B monoclonal antibody recognizes cytokeratin 377, 1417-1427. 15 and defines the location of human hair follicle stem cells. J. Cell Sci. 111, Sato, N., Meijer, L., Skaltsounis, L., Greengard, P. and Brivanlou, A. H. (2004). 3179-3188. Maintenance of pluripotency in human and mouse embryonic stem cells through MacDonald, B. T. and He, X. (2012). Frizzled and LRP5/6 receptors for Wnt/β- activation of Wnt signaling by a pharmacological GSK-3-specific inhibitor. Nat. catenin signaling. Cold Spring Harb. Perspect. Biol. 4, a007880. Med. 10, 55-63. Mao, J., Wang, J., Liu, B., Pan, W., Farr, G. H., III, Flynn, C., Yuan, H., Takada, S., Sato, T., Vries, R. G., Snippert, H. J., van de Wetering, M., Barker, N., Stange, Kimelman, D., Li, L. et al. (2001). Low-density lipoprotein receptor-related D. E., van Es, J. H., Abo, A., Kujala, P., Peters, P. J. et al. (2009). Single Lgr5 protein-5 binds to Axin and regulates the canonical Wnt signaling pathway. Mol. stem cells build crypt-villus structures in vitro without a mesenchymal niche. Cell 7, 801-809. Nature 459, 262-265. McMahon, A. P. and Moon, R. T. (1989). Ectopic expression of the proto-oncogene Satoh, K., Kasai, M., Ishidao, T., Tago, K., Ohwada, S., Hasegawa, Y., Senda, T., int-1 in Xenopus embryos leads to duplication of the embryonic axis. Cell 58, Takada, S., Nada, S., Nakamura, T. et al. (2004). Anteriorization of neural fate by 1075-1084. inhibitor of beta-catenin and T cell factor (ICAT), a negative regulator of Wnt Molenaar, M., van de Wetering, M., Oosterwegel, M., Peterson-Maduro, J., signaling. Proc. Natl. Acad. Sci. USA 101, 8017-8021. Godsave, S., Korinek, V., Roose, J., Destrée, O. and Clevers, H. (1996). XTcf-3 Semë nov, M. V., Tamai, K., Brott, B. K., Kü hl, M., Sokol, S. and He, X. (2001). transcription factor mediates β-catenin-induced axis formation in xenopus Head inducer Dickkopf-1 is a ligand for Wnt coreceptor LRP6. Curr. Biol. 11, embryos. Cell 86, 391-399. 951-961. Moon, R. T. and Kimelman, D. (1998). From cortical rotation to organizer gene Sharma, R. P. and Chopra, V. L. (1976). Effect of the Wingless (wg1) mutation on expression: toward a molecular explanation of axis specification in Xenopus. wing and haltere development in Drosophila melanogaster. Dev. Biol. 48, BioEssays 20, 536-545. 461-465. Morin, P. J. (1997). Activation of beta -Catenin-Tcf signaling in colon cancer by Stamos, J. L. and Weis, W. I. (2012). The -catenin destruction complex. Cold Spring mutations in beta -catenin or APC. Science 275, 1787-1790. Harb. Perspect. Biol. 5, a007898-a007898. Munemitsu, S., Albert, I., Souza, B., Rubinfeld, B. and Polakis, P. (1995). Stamos, J. L., Chu, M. L.-H., Enos, M. D., Shah, N. and Weis, W. I. (2014). Regulation of intracellular beta-catenin levels by the adenomatous polyposis coli Structural basis of GSK-3 inhibition by N-terminal phosphorylation and by the Wnt (APC) tumor-suppressor protein. Proc. Natl Acad. Sci. USA 92, 3046-3050. receptor LRP6. Elife 3, e01998. Nakamura, Y., de Paiva Alves, E., Veenstra, G. J. C. and Hoppler, S. (2016). Tabar, V. and Studer, L. (2014). Pluripotent stem cells in regenerative medicine: Tissue- and stage-specific Wnt target gene expression is controlled subsequent challenges and recent progress. Nat. Rev. Genet. 15, 82-92. to β-catenin recruitment to cis-regulatory modules. Development 143, 1914-1925. Tamai, K., Semenov, M., Kato, Y., Spokony, R., Liu, C., Katsuyama, Y., Hess, F., Nichols, J. and Smith, A. (2009). Naive and primed pluripotent states. Cell Stem Saint-Jeannet, J. P. and He, X. (2000). LDL-receptor-related proteins in Wnt Cell 4, 487-492. signal transduction. Nature 407, 530-535. Niehrs, C. (2010). On growth and form: a Cartesian coordinate system of Wnt and Tamai, K., Zeng, X., Liu, C., Zhang, X., Harada, Y., Chang, Z. and He, X. (2004). A BMP signaling specifies bilaterian body axes. Development 137, 845-857. mechanism for Wnt coreceptor activation. Mol. Cell 13, 149-156. Nusse, R. (2001). An ancient cluster of Wnt paralogues. Trends Genet. 17, 443. Tao, Q., Yokota, C., Puck, H., Kofron, M., Birsoy, B., Yan, D., Asashima, M., Nusse, R. and Clevers, H. (2017). Wnt/β-catenin signaling, disease, and emerging therapeutic modalities. Cell 169, 985-999. Wylie, C. C., Lin, X. and Heasman, J. (2005). Maternal wnt11 activates the canonical wnt signaling pathway required for axis formation in Xenopus embryos. Nü sslein-Volhard, C. and Wieschaus, E. (1980). Mutations affecting segment number and polarity in Drosophila. Nature 287, 795-801. Cell 120, 857-871. Tauriello, D. V. F., Jordens, I., Kirchner, K., Slootstra, J. W., Kruitwagen, T., Oshima, H., Rochat, A., Kedzia, C., Kobayashi, K. and Barrandon, Y. (2001). Morphogenesis and renewal of hair follicles from adult multipotent stem cells. Cell Bouwman, B. A. M., Noutsou, M., Rü diger, S. G. D., Schwamborn, K., 104, 233-245. Schambony, A. et al. (2012). Wnt/β-catenin signaling requires interaction of the DEVELOPMENT DEVELOPMENT AT A GLANCE Development (2018) 145, dev146589. doi:10.1242/dev.146589 Dishevelled DEP domain and C terminus with a discontinuous motif in Frizzled. an LDL-receptor-related protein essential for Wingless signalling. Nature 407, Proc. Natl. Acad. Sci. USA 109, E812-E820. 527-530. ten Berge, D., Kurek, D., Blauwkamp, T., Koole, W., Maas, A., Eroglu, E., Siu, Willert, K., Brown, J. D., Danenberg, E., Duncan, A. W., Weissman, I. L., Reya, T., R. K. and Nusse, R. (2011). Embryonic stem cells require Wnt proteins to prevent Yates, J. R., III and Nusse, R. (2003). Wnt proteins are lipid-modified and can act differentiation to epiblast stem cells. Nat. Cell Biol. 13, 1070-1075. as stem cell growth factors. Nature 423, 448-452. Tu, X., Delgado-Calle, J., Condon, K. W., Maycas, M., Zhang, H., Carlesso, N., Williams, B. O. (2017). LRP5: From bedside to bench to bone. Bone 102, 26-30. Taketo, M. M., Burr, D. B., Plotkin, L. I. and Bellido, T. (2015). Osteocytes Williams, L. A., Davis-Dusenbery, B. N. and Eggan, K. C. (2012). SnapShot: mediate the anabolic actions of canonical Wnt/β-catenin signaling in bone. Proc. directed differentiation of pluripotent stem cells. Cell 149, 1174-1174.e1. Natl. Acad. Sci. USA 112, E478-E486. Winston, J. T., Strack, P., Beer-Romero, P., Chu, C. Y., Elledge, S. J. and Harper, Tumbar,T.,Guasch,G.,Greco,V.,Blanpain,C.,Lowry,W.E.,Rendl,M.andFuchs, J. W. (1999). The SCFbeta-TRCP-ubiquitin ligase complex associates E. (2004). Defining the epithelial stem cell niche in skin. Science 303, 359-363. specifically with phosphorylated destruction motifs in IkappaBalpha and beta- van Amerongen, R., Bowman, A. N. and Nusse, R. (2012). Developmental stage catenin and stimulates IkappaBalpha ubiquitination in vitro. Genes Dev. 13, and time dictate the fate of Wnt/β-catenin-responsive stem cells in the mammary 270-283. gland. Cell Stem Cell 11, 387-400. Xu, Z., Robitaille, A. M., Berndt, J. D., Davidson, K. C., Fischer, K. A., Mathieu, van de Wetering, M., Cavallo, R., Dooijes, D., van Beest, M., van Es, J., Loureiro, J., Potter, J. C., Ruohola-Baker, H. and Moon, R. T. (2016). Wnt/β-catenin J., Ypma, A., Hursh, D., Jones, T., Bejsovec, A. et al. (1997). Armadillo signaling promotes self-renewal and inhibits the primed state transition in naïve coactivates transcription driven by the product of the Drosophila segment polarity human embryonic stem cells. Proc. Natl. Acad. Sci. USA 113, E6382-E6390. gene dTCF. Cell 88, 789-799. Yan, K. S., Janda, C. Y., Chang, J., Zheng, G. X. Y., Larkin, K. A., Luca, V. C., van den Heuvel, M., Harryman-Samos, C., Klingensmith, J., Perrimon, N. and Chia, L. A., Mah, A. T., Han, A., Terry, J. M. et al. (2017). Non-equivalence of Wnt Nusse, R. (1993). Mutations in the segment polarity genes wingless and and R-spondin ligands during Lgr5(+) intestinal stem-cell self-renewal. Nature porcupine impair secretion of the wingless protein. EMBO J. 12, 5293-5302. 545, 238-242. Van der Flier, L. G., Sabates–Bellver, J., Oving, I., Haegebarth, A., De Palo, M., Yang-Snyder, J., Miller, J. R., Brown, J. D., Lai, C.-J. and Moon, R. T. (1996). A Anti, M., Van Gijn, M. E., Suijkerbuijk, S., Van de Wetering, M., Marra, G. et al. frizzled homolog functions in a vertebrate Wnt signaling pathway. Curr. Biol. 6, (2007). The intestinal Wnt/TCF signature. Gastroenterology 132, 628-632. 1302-1306. Van Mater, D., Kolligs, F. T., Dlugosz, A. A. and Fearon, E. R. (2003). Transient Zebisch, M., Xu, Y., Krastev, C., MacDonald, B. T., Chen, M., Gilbert, R. J. C., He, activation of beta -catenin signaling in cutaneous keratinocytes is sufficient to trigger X. and Jones, E. Y. (2013). Structural and molecular basis of ZNRF3/RNF43 the active growth phase of the hair cycle in mice. Genes Dev. 17, 1219-1224. transmembrane ubiquitin ligase inhibition by the Wnt agonist R-spondin. Nat. Van Raay, T. J., Fortino, N. J., Miller, B. W., Ma, H., Lau, G., Li, C., Franklin, J. L., Commun. 4, 2787. Attisano, L., Solnica-Krezel, L. and Coffey, R. J. (2011). Naked1 antagonizes Zeng, X., Tamai, K., Doble, B., Li, S., Huang, H., Habas, R., Okamura, H., Wnt signaling by preventing nuclear accumulation of β-catenin. PLoS One 6, Woodgett, J. and He, X. (2005). A dual-kinase mechanism for Wnt co-receptor e18650. phosphorylation and activation. Nature 438, 873-877. Veltri, A., Lang, C. and Lien, W.-H. (2018). Concise review: Wnt signaling pathways Zhang, X., Abreu, J. G., Yokota, C., MacDonald, B. T., Singh, S., Coburn, K. L. A., in skin development and epidermal stem cells. Stem Cells 36, 22-35. Cheong, S.-M., Zhang, M. M., Ye, Q.-Z., Hang, H. C. et al. (2012). Tiki1 is Wang, S., Krinks, M., Lin, K., Luyten, F. P. and Moos, M. Jr. (1997). Frzb, a required for head formation via Wnt cleavage-oxidation and inactivation. Cell 149, secreted protein expressed in the Spemann organizer, binds and inhibits Wnt-8. Cell 88, 757-766. 1565-1577. Zhang, X., Cheong, S.-M., Amado, N. G., Reis, A. H., MacDonald, B. T., Zebisch, Wang, B., Zhao, L., Fish, M., Logan, C. Y. and Nusse, R. (2015). Self-renewing diploid Axin2(+) cells fuel homeostatic renewal of the liver. Nature 524, 180-185. M., Jones, E. Y., Abreu, J. G. and He, X. (2015). Notum is required for neural and Wehrli, M., Dougan, S. T., Caldwell, K., O’Keefe, L., Schwartz, S., Vaizel- head induction via Wnt deacylation, oxidation, and inactivation. Dev. Cell 32, Ohayon, D., Schejter, E., Tomlinson, A. and DiNardo, S. (2000). arrow encodes 719-730. DEVELOPMENT
Journal
Development – The Company of Biologists
Published: Jun 1, 2018