Wnt glycoproteins are signaling molecules that control a wide range of developmental processes in organisms ranging from the simple metazoan Hydra to vertebrates. Wnt signaling also plays a key role in the development of the nematode C. elegans, and is involved in cell fate specification and determination of cell polarity and cell migration. Surprisingly, the first genetic studies of Wnt signaling in C. elegans revealed major differences with the established (canonical) Wnt signaling pathways of Drosophila and vertebrates. Thus, the (...) Wnt-dependent induction of endoderm in the early embryo and the specification of several asymmetric cell divisions during larval development are mediated by as yet novel Wnt signaling pathways that repress, rather than activate the TCF/LEF-1 transcription factor POP-1. Recently, however, it has been shown that, in addition to these divergent Wnt pathways, C. elegans also has a canonical Wnt pathway that converts POP-1 into an activator and controls the expression of several homeobox genes. Interestingly, these different Wnt pathways use distinct beta-catenins to control POP-1 function: the endoderm induction pathway requires the beta-catenin WRM-1 and parallel input from a mitogen-activated kinase (MAPK) pathway to downregulate POP-1, whereas the canonical Wnt pathway employs the beta-catenin BAR-1 to activate Wnt target gene expression. (shrink)

Critical cellular functions, including stem cell maintenance, fate determination, and cellular behavior, are governed by canonical Wnt signaling, an evolutionarily conserved pathway whose intracellular signal is transduced by β‐catentin. Emerging evidence suggests that canonical Wnt signaling influences cellular aging, indicating that increases in Wnt signaling delay age‐related deficits.1 However, recent Science papers suggest that Wnt signaling accelerates the onset of aging.2,3 In an attempt to resolve this paradox and clarify how Wnt signaling affects aging, we provide a (...) selective review of research relevant to Wnt signaling and aging. BioEssays 30:102–106, 2008. © 2008 Wiley Periodicals, Inc. (shrink)

In a recent publication, Wikramanayake and colleagues have implicated the canonical Wnt/β-catenin signaling pathway as a mediator of axial polarity and germ-layer specification in embryos of the cnidarian Nematostella.1 In this anthozoan, β-catenin is localized in nuclei of blastomeres in one region of the 16- to 32-cell embryo whose descendants subsequently form the entoderm of the embryo. They claim that the pattern of nuclear localization is significant for two reasons: (1) when nuclear localization of β-catenin was inhibited, gastrulation (...) does not occur, and (2) when localization of β-catenin took place in all cells of the pregastrula embryo, the number of entodermal cells increases. Since the Wnt/β-catenin signaling pathway also plays a role in establishing axial polarity and specifying endoderm and mesoderm in a number of bilaterians,2-6 Wikramanayake et al. imply that this developmental mechanism is an evolutionary inheritance from a radially symmetrical ancestor. Some of the gaps in the current evidence, which must be filled to evaluate their interpretation, are discussed. BioEssays 26:474–478, 2004. © 2004 Wiley Periodicals, Inc. (shrink)

Wnt proteins can activate different intracellular signaling cascades in various organisms by interacting with receptors of the Frizzled family. The first identified Wnt signaling pathway, the Wnt/β‐catenin pathway, has been studied in much detail and is highly conserved among species. As to non‐canonical Wnt pathways, the current situation is more nebulous partly because the intracellular mediators of this pathway are not yet fully understood and, in some cases, even identified. However, there are increasing data that prove (...) the existence of non‐canonical Wnt signaling and demonstrate its involvement in different developmental processes. In vertebrates, Wnt‐11 and Wnt‐5A can activate the Wnt/JNK pathway, which resembles the planar cell polarity pathway in Drosophila. The Wnt/Ca2+‐pathway has only been described in Xenopus and zebrafish so far and it is unclear whether it also exists in other organisms. Two recent papers provide us with new insight into non‐canonical Wnt signaling by (1) presenting a new intracellular mediator of non‐canonical signaling in Xenopus1 and (2) implicating the existence of an additional non‐canonical Wnt signaling pathway in flies.2 BioEssays 24:881–884, 2002. © 2002 Wiley Periodicals, Inc. (shrink)

Although many regulators of skeletogenesis have been functionally characterized, one current challenge is to integrate this information into regulatory networks. Here, we discuss how the canonical Wnt and Smad‐dependent BMP pathways interact together and play antagonistic or cooperative roles at different steps of osteogenesis, in the context of the developing vertebrate embryo. Early on, BMP signaling specifies multipotent mesenchymal cells into osteochondroprogenitors. In turn, the function of Wnt signaling is to drive these osteochondroprogenitors towards an osteoblastic fate. Subsequently, both (...) pathways promote osteoblast differentiation, albeit with notable mechanistic differences. In osteocytes, the ultimate stage of osteogenic differentiation, the Wnt and BMP pathways exert opposite effects on the control of bone resorption by osteoclasts. We describe how the dynamic molecular wiring of the canonical Wnt and Smad‐dependent BMP signaling into the skeletal cell genetic programme is critical for the generation of bone‐specific cell types during development. (shrink)

Planar cell polarity (PCP), the alignment of cells within 2D tissue planes, involves a set of core molecular regulators highly conserved between animals and cell types. These include the transmembrane proteins Frizzled (Fz) and VanGogh and the cytoplasmic regulators Dishevelled (Dsh) and Prickle. It is widely accepted that this core forms part of a ‘PCP pathway’ for signal transduction, which can affect cell morphology through activation of an evolutionary ancient regulatory module involving Rho family GTPases and Myosin II, and/or (...) the JNK kinase cascade. We have re‐examined the evidence for interactions between the proposed PCP pathway components, and question the placing of the cell morphology regulators in the same pathway as the PCP core. While Fz and Dsh are clearly involved in both PCP and Rho‐based cell morphology regulation, available evidence cannot currently discriminate whether these processes are linked mechanistically by a shared Fz/Dsh population, or pass by two distinct pathways. (shrink)

Identification of Pygopus in Drosophila as a dedicated component of the Wg (fly homolog of mammalian Wnt) signaling cascade initiated many inquiries into the mechanism of its function. Surprisingly, the nearly exclusive role for Pygopus in Wg signal transduction in flies is not seen in mice, where Pygopus appears to have both Wnt‐related and Wnt‐independent functions. This review addresses the initial findings of Pygopus as a Wg/Wnt co‐activator in light of recent data from both fly and mammalian studies. We compare (...) and contrast the developmental phenotypes of pygopus mutants to those characterized for known Wg/Wnt transducers and explore the data regarding a role for mammalian Pygopus 2 in tumorigenesis. We further analyze the roles of the two conserved domains of Pygopus proteins in transcription, and propose a model for the molecular mechanism of Pygopus function in both Wg/Wnt signaling and Wnt‐independent transcriptional regulation. BioEssays 30:448–456, 2008. © 2008 Wiley Periodicals, Inc. (shrink)

Many targets of the Wnt/β-catenin signaling pathway are regulated by TCF transcription factors, which play important roles in animal development, stem cell biology, and oncogenesis. TCFs can regulate Wnt targets through a “transcriptional switch,” repressing gene expression in unstimulated cells and promoting transcription upon Wnt signaling. However, it is not clear whether this switch mechanism is a general feature of Wnt gene regulation or limited to a subset of Wnt targets. Co-repressors of the TLE family are known to contribute (...) to the repression of Wnt targets in the absence of signaling, but how they are inactivated or displaced by Wnt signaling is poorly understood. In this mini-review, we discuss several recent reports that address the prevalence and molecular mechanisms of the Wnt transcription switch, including the finding of Wnt-dependent ubiquitination/inactivation of TLEs. Together, these findings highlight the growing complexity of the regulation of gene expression by the Wnt pathway. Wnt targets are regulated by a “switch” where TLE co-repressors are displaced from TCFs by β-catenin, leading to activation of transcription. Recent reports challenge this view and suggest that additional processes, including exchange of specific TCF proteins and Wnt-dependent ubiquitination of TLEs, play important roles in the Wnt transcriptional switch. (shrink)

The Wnt signalling cascade is a highly conserved signalling pathway throughout the animal kingdom. In Xenopus, Wnt signalling functions in mesodermal dorsoventral patterning. Earlier work on deciphering the components of the wnt signalling cascade left a gap between cytosolic β‐catenin, the final member of the cascade, and the nuclear target genes. Several recent papers now reveal how the Wnt signal is transmitted into the nucleus. Surprisingly, β‐catenin directly interacts with the transcription factor LEF‐1/XTCF‐3, and thereby is not only translocated (...) into the nucleus but also modulates the properties of LEF‐1/XTCF‐3 as a transcription factor(1–5). (shrink)

The activity of Wnt and Notch signalling is central to many cell fate decisions during development and to the maintenance and differentiation of stem cell populations in homeostasis. While classical views refer to these pathways as independent signal transduction devices that co‐operate in different systems, recent work has revealed intricate connections between their components. These observations suggest that rather than operating as two separate pathways, elements of Wnt and Notch signalling configure an integrated molecular device whose main function is to (...) regulate transitions between cell states in development and homeostasis. Here, we propose a general framework for the structure and function of the interactions between these signalling systems that is focused on the notion of ‘transition states’, i.e. intermediates that arise during cell fate decision processes. These intermediates act as checkpoints in cell fate decision processes and are characterised by the mixed molecular identities of the states involved in these processes.Editor's suggested further reading in BioEssays: Notch: Implications of endogenous inhibitors for therapy Abstract. (shrink)

Recent studies indicate that plakoglobin may have a similar function to that of β-catenin within the Wnt signaling pathway. β-catenin is known to be an oncogene in many forms of human cancer, following acquisition of stabilizing mutations in amino terminal sequences. Kolligs1 and coworkers show, however, that unlike β-catenin, plakoglobin induces neoplastic transformation of rat epithelial cells in the absence of such stabilizing mutations. Cellular transformation by plakoglobin also appears to be distinct from that of β-catenin in that it (...) requires activation of the proto-oncogene c-myc. Surprisingly, c-myc is activated more efficiently by plakoglobin than β-catenin, despite its previous identification as a target of Tcf/β-catenin.2 In contrast, a synthetic Tcf reporter gene is activated to a much greater extent by β-catenin than plakoglobin. Plakoglobin and β-catenin may therefore have different roles in Wnt signaling and cancer, which reflect their differential effects on target gene activity. BioEssays 22:961–965, 2000. © 2000 John Wiley & Sons, Inc. (shrink)

Organismal form arises by the coordinated movement, arrangement, and activity of cells. In metazoans, most morphogenetic programs that establish the recognizable body plan of any given species are initiated during the developmental period, although in many species growth continues throughout life. By comparing the cellular and molecular development of the bilaterians (bilaterally symmetrical animals) to the development of their closest outgroup, the cnidarians, it appears that morphogenesis and the cell fate specification associated with germ layer formation during the process of (...) gastrulation are separately controlled by two distinct downstream pathways (canonical and planar cell polarity) of Wnt signaling. Furthermore, a fundamental change in the early developmental program, the positioning of the site of gastrulation, allowed the spatial separation of gene regulatory networks that facilitated the rapid diversification of bilaterian body plans. (shrink)

The precise orchestration of two opposing protein complexes – one in the cytoplasm (β‐catenin destruction complex) and the other at the plasma membrane (LRP6 signaling complex) – is critical for controlling levels of the transcriptional co‐factor β‐catenin, and subsequent activation of the Wnt/β‐catenin signal transduction pathway. The Wnt pathway component Axin acts as an essential scaffold for the assembly of both complexes. How the β‐catenin destruction and LRP6 signaling complexes are modulated following Wnt stimulation remains controversial. A recent (...) study in Science by He and coworkers reveals an underlying logic for Wnt pathway control in which Axin phosphorylation toggles a switch between the active and inactive states. This mini‐review focuses on this and two other recent studies that provide insight into the initial signaling events triggered by Wnt exposure. We emphasize regulation of the β‐catenin destruction and LRP6 signaling complexes and propose a framework for future work in this area. (shrink)

Wnt proteins form a family of secreted signaling proteins that play a key role in various developmental events such as cell differentiation, cell migration, cell polarity and cell proliferation. It is currently thought that Wnt proteins activate at least three different signaling pathways by binding to seven transmembrane receptors of the Frizzled family and the co-receptor LRP6. Despite our growing knowledge of intracellular components that mediate a Wnt signal, the molecular events at the membrane have remained rather unclear. Now several (...) publications1-4 indicate that Frizzled receptors are G-protein coupled and kinases were identified that phosphorylate the co-receptor LRP6. These data deepen our understanding of Wnt-mediated signal transduction and provide more insight into how specificity may be achieved. BioEssays 28: 339–343, 2006. © 2006 Wiley Periodicals, Inc. (shrink)

Signal transduction pathways are largely conserved throughout the animal kingdom. The repertoire of pathways is limited and each pathway is used in different intercellular signaling events during the development of a given animal. For example, Wnt signaling is recruited, sometimes redundantly with other molecular pathways, in four cell specification events during Caenorhabditis elegans vulva development, including the activation of vulval differentiation. Strikingly,a recent study finds that Wnts act to repress vulval differentiation in the nematode Pristionchus pacificus,1 demonstrating evolutionary flexibility (...) in the use of intercellular signaling pathways. BioEssays 27:765–769, 2005. © 2005 Wiley Periodicals, Inc. (shrink)

The Notch proteins play a vital role in cell fate decisions in both invertebrate and vertebrate development. Careful analysis of this role has led to a model of signalling downstream of these receptors, via the CSL (CBF1, Suppressor of Hairless, Lag-1) family of transcription factors. There have been suggestions, however, that Notch can signal through other pathways. In the current paper, Ramain et al.1 provide compelling evidence for Notch signalling through a CSL-independent pathway and they demonstrate that the cytoplasmic (...) protein, Deltex, is required for this signal. In addition, they show that Wnt signalling may regulate this Deltex-dependent signal. (shrink)

Hedgehog (Hh) signaling is a widely studied signaling pathway because of its critical roles during development and in cell homeostasis. Vertebrate canonical and non‐canonical Hh signaling are typically assumed to be distinct and occur in different cellular compartments. While research has primarily focused on the canonical form of Hh signaling and its dependency on primary cilia – microtubule‐based signaling hubs – an extensive list of crucial functions mediated by non‐canonical Hh signaling has emerged. Moreover, amounting (...) evidence indicates that canonical and non‐canonical modes of Hh signaling are interlinked, and that they can overlap spatially, and in many cases interact functionally. Here, we discuss some of the many cellular effects of non‐canonical signaling and discuss new evidence indicating inter‐relationships with canonical signaling. We discuss how Smoothened (Smo), a key component of the Hh pathway, might coordinate such diverse downstream effects. Collectively, pursuit of questions such as those proposed here will aid in elucidating the full extent of Smo function in development and advance its use as a target for cancer therapeutics. (shrink)

v. 1. Proceedings, Rome, 2001-2004 -- v. 2. Giornate di studi, 2005-2008.

Este artículo expone la emergencia de expresiones de la espiritualidad no vinculadas a la experiencia religiosa y, en particular, aquella manifestación que pretende situar esta dimensión humana como un fenómeno natural, reconocible y, por ello, transformable desde el método de las ciencias de la Naturaleza. Se presenta un amplio marco que sitúa este fenómeno en el desarrollo de las teorías que establecen un continuo entre biología y cultura. Se ofrecen ejemplos de autores que han presentado propuestas de espiritualidad sin Dios (...) y algunas que responden al llamado «problema realmente difícil», de cómo dar cuenta desde la ciencia natural de este fenómeno de la consciencia. Se cierra señalando límites y remitiendo a la presentación de una propuesta de modelo antropológico con fundamentos clínicos y teóricos, que para dar cuenta del fenómeno de la espiritualidad precisa un marco teórico que supera los límites de la ciencia natural y acude, en este caso, al psicoanálisis. Este mismo modelo muestra también que la espiritualidad elaborada sobre la experiencia religiosa del sujeto es una de las vías de maduración humana. (shrink)

En los años ochenta emergió la cuestión de la licitud moral de la mejora por relación a la terapia. Para presentar la problemática actual sobre el tema se ofrece el constructo denominado Práctica de Intervención del Cuerpo caracterizado por cinco parámetros: M o la materia de la transformación, CT o la tecnociencia disponible, A o las concepciones vigentes de lo natural y lo artificial, N o las visiones de la naturaleza humana culturalmente compartidas y V o las valoraciones éticas a (...) las que se apela para legitimar la transformación. Se apunta el nivel ontológico como necesario para comprender y debatir las diferencias existentes en criterio moral. El concepto de naturaleza humana como referente normativo está en crisis, pero su ausencia deja un vacío que hace urgente una deliberación para llegar a una instancia normativa común. (shrink)

El modelo paradigmático de Justicia Transicional se caracteriza por la protección de derechos civiles y políticos y el predominio de la justicia retributiva. La exportación de este modelo a sociedades en posconflicto ha develado las conexiones entre cuestiones sociales y económicas, tales como, pobreza, corrupción y desigualdades, y el logro de una transición efectiva a la democracia. Este artículo analiza la relación entre dichas cuestiones sociales y económicas y la Justicia Transicional a la luz de la teoría del discurso y (...) de las categorías de discurso anormal y normal, utilizadas por Nancy Fraser en el análisis de la teoría de la justicia. (shrink)

The church in Africa, like its counterparts elsewhere in the world, is called to fulfil the mission of God as expressed in the call ‘Missio Dei’ and influentially remains with the integrity of the mission of Christ, which is liberative and practical. For Christ was not only concerned with the spiritual needs of the people, but also with their material well-being. The following question therefore arises: how can the church in Africa, in general, and in Zimbabwe, in particular, actively do (...) God’s mission and remain with integrity in the midst of the reality of suffering. Furthermore, how can the church for mission and reconstruction be understood in a post-colonial Zimbabwe given the contextual realities of political crises, corruption, poverty, moral decadence, defined or censored truth, leadership crises and no freedom of expression? This article argues that, although the church is faced with these arduous realities, it remains called by God to do God’s mission. While in post-colonial Zimbabwe the socio-political, socio-economic and socio-religious situation might seem hopeless, the church has remained vibrant and alive for reconstruction theology. The transformation of society is possible given the authority and mission mandate of the church. This article argues that the church is a key player in reconstruction theology and in the transformation of society. For transformation to be possible, the church should witness to the gospel of Christ without fear of being labelled, castrated and persecuted. The article asserts that the spirit of the Bible should be revived in a time of reconstruction in Zimbabwe. The assumption in this article is that Zimbabwe is ready for reconstruction discourse. For this to happen, the researchers argue that the church as a critical relevant player in reconstruction needs to ‘be church’ in its missional mandates. Integrity is essential if a church wants to be relevantly missional and reconstructive. Integrity means that the church has to embrace the risks and opportunities associated with mission. (shrink)

Some time ago I had a shock. I was reading, in the Mathematical Gazette for March 1931, Sir A. S. Eddington's presidential address to the Mathematical Association in 1930. And quite suddenly I came on the statement that the number of protons in the universe is either 7 or 14 with 78 noughts after it. My breath was taken away. Readers of R. L. Stevenson's story, Providence and the Guitar, will remember the maiden lady who, after hearing what the Commissary (...) said when he was woken up in the night, felt her maiden modesty so outraged that she doubted if she ranked any longer as a maiden lady. I felt just like that. I felt that my philosophic modesty had been so outraged that I doubted if I ranked any longer as a humble student of philosophy. Sir Arthur has certainly not counted them. Then how in the world does he know that they are what he says they are? (shrink)