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)

Wnt proteins are involved in a large number of events during development and disease. The crucial element in the transduction of the signal elicited by Wnt is the state and activity of β-catenin. There are two pools of β-catenin, one associated with cadherins at the cell surface and a soluble one in the cytolasm, whose state and concentration are critical for Wnt signalling. In the absence of Wnt, the cytoplasmic pool is low due to targetted degradation of β-catenin. Upon (...) Wnt signalling, β-catenin is stabilized. As a consequence, it can access the nucleus where it interacts with members of the Tcf family of transcription factors to modulate the expression of defined targets. Recent reports indicate that, in addition to Tcfs, β-catenin can interact with other nuclear proteins raising the possibility that Wnt signalling has a wider modulatory effect on transcription than is mediated by its interactions with Tcfs. BioEssays 23:311–318, 2001. © 2001 John Wiley & Sons, Inc. (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)

The Wnt family of developmental regulators were named after the Drosophila segmentation gene wingless and the murine proto‐oncogene int‐1. Homology between these two genes connected oncogenesis to cell‐cell signals in development. I review how wingless was initially characterized, and cloned, as part of the quest to identify developmental cell‐to‐cell signals, based on predictions of the Positional Information Model, and on the properties of homeotic and segmentation gene mutants. The requirements and cell‐nonautonomy of wingless in patterning multiple embryonic and adult structures (...) solidified its status as a candidate signaling molecule. The physical location of wingless mutations and transcription unit defined the gene and its developmental transcription pattern. When the Drosophila homolog of int‐1 was then isolated, and predicted to encode a secreted proto‐oncogene homolog, it's identity to the wingless gene confirmed that a developmental cell‐cell signal had been identified and connected cancer to development. (shrink)

Abstractβ‐Catenin/CTNNB1 is critical for leukemia initiation or the stem cell capacity of several hematological malignancies. This review focuses on a general evaluation of β‐catenin function in normal T‐cell development and T‐cell acute lymphoblastic leukemia (T‐ALL). The integration of the existing literature offers a state‐of‐the‐art dissection of the complexity of β‐catenin function in leukemia initiation and maintenance in both Notch‐dependent and independent contexts. In addition, β‐catenin mutations are screened for in T‐ALL primary samples, and it is found that they are rare (...) and with little clinical relevance. Transcriptional analysis of Wnt family members (Ctnnb1, Axin2, Tcf7, and Lef1) and Myc in different publicly available T‐ALL cohorts indicates that the expression of these genes may correlate with T‐ALL subtypes and/or therapy outcomes. (shrink)

R‐spondins (RSPOs) are a family of secreted proteins and stem cell growth factors that are potent co‐activators of Wnt signaling. Recently, RSPO2 and RSPO3 were shown to be multifunctional, not only amplifying Wnt‐ but also binding BMP‐ and FGF receptors to downregulate signaling. The common mechanism underlying these diverse functions is that RSPO2 and RSPO3 act as “endocytosers” that link transmembrane proteins to ZNRF3/RNF43 E3 ligases and trigger target internalization. Thus, RSPOs are natural protein targeting chimeras for cell surface proteins. (...) Conducting data mining and cell surface binding assays we report additional candidate RSPO targets, including SMO, PTC1,2, LGI1, ROBO4, and PTPR(F/S). We propose that there is an “R‐spondin code” that imparts combinatorial signaling ON‐OFF states of multiple growth factors. This code involves the modular RSPO domains, notably distinct motifs in the divergent RSPO‐TSP1 domains to mediate target interaction and internalization. The RSPO code offers a novel framework for the understanding how diverse signaling pathways may be coordinately regulated in development and disease. (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)

Neural crest cells are multipotent progenitors, capable of producing diverse cell types upon differentiation. Recent studies have identified significant heterogeneity in both the fates produced and genes expressed by different premigratory crest cells. While these cells may be specified toward particular fates prior to migration, transplant studies show that some may still be capable of respecification at this time. Here we summarize evidence that extracellular signals in the local environment may act to specify premigratory crest and thus generate diversity in (...) the population. Three main classes of signals–Wnts, BMP2/BMP4 and TGFβ1,2,3–have been shown to directly influence the production of particular neural crest cell fates, and all are expressed near the premigratory crest. This system may therefore provide a good model for integration of multiple signaling pathways during embryonic cell fate specification. BioEssays 22:708–716, 2000. © 2000 John Wiley & Sons, Inc. (shrink)

Neural crest cells are multipotent progenitors, capable of producing diverse cell types upon differentiation. Recent studies have identified significant heterogeneity in both the fates produced and genes expressed by different premigratory crest cells. While these cells may be specified toward particular fates prior to migration, transplant studies show that some may still be capable of respecification at this time. Here we summarize evidence that extracellular signals in the local environment may act to specify premigratory crest and thus generate diversity in (...) the population. Three main classes of signals–Wnts, BMP2/BMP4 and TGFβ1,2,3–have been shown to directly influence the production of particular neural crest cell fates, and all are expressed near the premigratory crest. This system may therefore provide a good model for integration of multiple signaling pathways during embryonic cell fate specification. BioEssays 22:708–716, 2000. © 2000 John Wiley & Sons, Inc. (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)

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)

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)

The vertebrate Cdx genes (Cdx1 Cdx2 and Cdx4 in the mouse) encode homeodomain transcription factors related to the Drosophila caudal gene. The vertebrate Cdx gene products have been implicated in the development of the posterior embryo. In particular, loss‐ and gain‐of‐function experiments suggest that Cdx members are direct regulators of Hox genes and likely impart posterior information, in part, through this mechanism. Several signaling molecules, notably retinoic acid (RA*) and members of the Wnt (wingless) and fibroblast growth factor (FGF) families, (...) are also implicated in patterning of the posterior vertebrate embryo. Interestingly, recent work indicates that members of the Cdx family are targets of Wnt, RA and FGF signaling, suggesting that Cdx factors act to convey the activity of these signaling molecules to Hox genes. This article will briefly review Cdx expression and function, with particular emphasis on vertebrate model systems. BioEssays 25:971–980, 2003. © 2003 Wiley Periodicals, Inc. (shrink)

Wnts are a recently described family of secreted glycoproteins related to the Drosophila segment polarity gene, wingless, and to the proto‐oncogene, int‐1. Wnts are thought to function as developmental modulators, with signalling distances of only a few cell diameters. In Xenopus, at least six Wnts, including Xwnts‐1, ‐3A, and ‐4, are expressed initially in the developing central nervous system, with some regions expressing multiple Xwnts. Xwnt‐8 is expressed by mid‐blastula stage, in ventral and lateral mesoderm. Xwnt‐5A mRNAs are stored (...) in the egg, and later are expressed throughout the embryo in both ectoderm and mesoderm, but with a pronounced enrichment in the head and tail. Recent studies in Xenopus have pursued the diverse roles of Xwnts in early development, the mechanisms by which Xwnts signal information between cells, and the cell physiological responses to Xwnt signals. (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)

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)

The intracellular multiprotein complex β‐catenin destruction complex plays a key role in Wnt/β‐catenin signaling. Wnt stimulation induces the assembly of the receptor‐associated signalosome and the inactivation of the destruction complex, leading to β‐catenin accumulation and transcriptional activation of the target genes. The core components of the destruction complex include Axin, APC, GSK3β, CK1α and other proteins. Recent studies demonstrated that Axin and APC undergo liquid–liquid phase separation (LLPS), which is critical for their function to regulate Wnt/β‐catenin signaling. Here, we discuss (...) the possible roles of LLPS in Wnt/β‐catenin signaling and regulation of Axin LLPS by post‐translational modifications. (shrink)

Fertilization triggers cytoplasmic movements in the frog egg that lead in mysterious ways to the stabilization of β‐catenin on the dorsal side of the embryo. The novel Huluwa (Hwa) transmembrane protein, identified in China, is translated specifically in the dorsal side, acting as an egg cytoplasmic determinant essential for β‐catenin stabilization. The Wnt signaling pathway requires macropinocytosis and the sequestration inside multivesicular bodies (MVBs, the precursors of endolysosomes) of Axin1 and Glycogen Synthase Kinase 3 (GSK3) that normally destroy β‐catenin. In (...) Xenopus, the Wnt‐like activity of GSK3 inhibitors and of Hwa mRNA can be blocked by brief treatment with inhibitors of membrane trafficking or lysosomes at the 32‐cell stage. In dorsal blastomeres, lysosomal cathepsin is activated and intriguing MVBs surrounded by electron dense vesicles are formed at the 64‐cell stage. We conclude that membrane trafficking and lysosomal activity are critically important for the earliest asymmetries in vertebrate embryonic development. (shrink)

The link between oncogenesis and normal development is well illustrated by the study of the Wnt family of proteins. The first Wnt gene (int‐1) was identified over a decade ago as a proto‐oncogene, activated in response to proviral insertion of a mouse mammary tumor virus. Subsequently, the discovery that Drosophila wingless, a developmentally important gene, is homologous to int‐1 supported the notion that int‐1 may have a role in normal development. In the last few years it has been recognized that (...) int‐1 and Wingless belong to a large family of related glyco‐proteins found in vertebrates and invertebrates. In recognition of this, members of this family have been renamed Wnts, an amalgam of int and Wingless. Investigation of Wnt genes in Xenopus and mouse indicates that Wnts have a role in cell proliferation, differentiation and body axis formation. Further analysis in Drosophila has revealed that Wingless function is required in several developmental processes in the embryo and imaginal discs. In addition, a genetic approach has identified some of the molecules required for the transmission and reception of the Wingless signal. We will review recent data which have contributed to our growing understanding of the function and mechanism of Drosophila Wingless signaling in cell fate determination, growth and specification of pattern. (shrink)

Beta‐catenin is a multifunctional protein with critical roles in cell‐cell adhesion, Wnt‐signaling and the centrosome cycle. Whereas the roles of β‐catenin in cell‐cell adhesion and Wnt‐signaling have been studied extensively, the mechanism(s) involving β‐catenin in centrosome functions are poorly understood. β‐Catenin localizes to centrosomes and promotes mitotic progression. NIMA‐related protein kinase 2 (Nek2), which stimulates centrosome separation, binds to and phosphorylates β‐catenin. β‐Catenin interacting proteins involved in Wnt signaling such as adenomatous polyposis coli, Axin, and GSK3β, are also localized at (...) centrosomes and play roles in promoting mitotic progression. Additionally, proteins associated with cell‐cell adhesion sites, such as dynein, regulate mitotic spindle positioning. These roles of proteins at the cell cortex and Wnt signaling that involve β‐catenin indicate a cross‐talk between different sub‐cellular sites in the cell at mitosis, and that different pools of β‐catenin may co‐ordinate centrosome functions and cell cycle progression. (shrink)

Wnt signalling through β‐catenin plays a pivotal role during embryonic pattern formation, cell fate determination and tissue homeostasis in the adult organism. In the skin, as in many other tissues, Wnt/β‐catenin signalling can control lineage determination and differentiation. However, it was not known whether Wnt/β‐catenin signalling is an immediate regulator of the stem cell niche in skin tissue. A recent publication now provides evidence that Wnt/β‐catenin signalling exerts a direct effect on the stem cell compartment by (...) inducing quiescent stem cells to enter the cell cycle during early stages of hair follicle regeneration. In addition, the authors demonstrate that β‐catenin is required for maintenance of the stem cell pool in the tissue.1 The data suggest that a gradient in Wnt/β‐catenin activity levels can induce different responses within distinct cell populations reflected by activation of distinct transcriptional profiles. BioEssays 28:1–5, 2006. © 2005 Wiley Periodicals, Inc. (shrink)

The Wnt family of secreted glycoproteins is involved in the regulation of diverse developmental processes. The classical Wnt/β-catenin pathway has been thoroughly investigated resulting in the identification of a plethora of components involved in the activation of β-catenin target genes. Moreover, two additional Wnt-triggered pathways have been identified. These various signalling cascades require at least one component that confers signalling specificity. This function is fulfilled at least in part by the Wnt receptor Frizzled. The recent identification of a (...) potential Frizzled co-receptor, an LDL-receptor-related-protein (LRP),(1-3) sheds more light on Wnt-signal transduction specificity and promises more exciting revelations. BioEssays 23:207–210, 2001. © 2001 John Wiley & Sons, 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)

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)

Understanding how the chordate body plan originated and evolved is still controversial. The discovery by Spemann and Mangold in 1924 of the vertebrate organizer and its inductive properties in patterning the AP and DV axis was followed by a long gap until the 1960s when scientists started characterizing the molecular events responsible for such inductions. However, the evolutionary origin of the organizer itself remained obscure until very recently; did it appear together with the origin and radiation of vertebrates, or was (...) it a chordate affair? A recent study by Yu and collaborators,1 which analyses the expression of several organizer‐specific genes in amphioxus together with recent phylogenetic data that reversed the position of invertebrate extant chordates (e.g. urochordates and cephalochordates), indicates that the organizer probably appeared in early chordates. It likely had separate signalling centres generating BMP and Wnt signalling gradients along the DV and AP axis. The organizer was then lost in the urochordate lineage, most probably as an adaptation to a rapid and determinate development. BioEssays 29:619–624, 2007. © 2007 Wiley Periodicals, Inc. (shrink)

Autophagy and YAP1‐WWTR1/TAZ signalling are tightly linked in a complex control system of forward and feedback pathways which determine different cellular outcomes in differing cell types at different time‐points after perturbations. Here we extend our previous experimental and modelling approaches to consider two possibilities. First, we have performed additional mathematical modelling to explore how the autophagy‐YAP1 crosstalk may be controlled by posttranslational modifications of components of the pathways. Second, since analogous contrasting results have also been reported for autophagy as (...) a regulator of other transduction pathways engaged in tumorigenesis (Wnt/β‐catenin, TGF‐β/Smads, NF‐kB or XIAP/cIAPs), we have considered if such discrepancies may be explicable through situations involving competing pathways and feedback loops in different cell types, analogous to the autophagy‐YAP/TAZ situation. Since distinct posttranslational modifications dominate those pathways in distinct cells, these need to be understood to enable appropriate cell type‐specific therapeutic strategies for cancers and other diseases. (shrink)

In this article we discuss the molecular signaling mechanisms that coordinate interactions between Schwann cells and the neurons of the peripheral nervous system. Such interactions take place perpetually during development and in adulthood, and are critical for the homeostasis of the peripheral nervous system (PNS). Neurons provide essential signals to control Schwann cell functions, whereas Schwann cells promote neuronal survival and allow efficient transduction of action potentials. Deregulation of neuron–Schwann cell interactions often results in developmental abnormalities and diseases. Recent investigations (...) have shown that during development, neuronally provided signals, such as Neuregulin, Jagged, and Wnt interact to fine‐tune the Schwann cell lineage progression. In adult, the signal exchange between neurons and Schwann cells ensures proper nerve function and regeneration. Identification of the mechanisms of neuron–Schwann cell interactions is therefore essential for our understanding of the development, function and pathology of the peripheral nervous system as a whole. -/- . (shrink)

Mixed lineage leukemia (MLL) fusion protein (FP)‐induced acute leukemia is highly aggressive and often refractory to therapy. Recent progress in the field has unraveled novel mechanisms and targets to combat this disease. Menin, a nuclear protein, interacts with wild‐type (WT) MLL, MLL‐FPs, and other partners such as the chromatin‐associated protein LEDGF and the transcription factor C‐Myb to promote leukemogenesis. The newly solved co‐crystal structure illustrating the menin–MLL interaction, coupled with the role of menin in recruiting both WT MLL and MLL‐FPs (...) to target genes, highlights menin as a scaffold protein and a central hub controlling this type of leukemia. The menin/WT MLL/MLL‐FP hub may also cooperate with several signaling pathways, including Wnt, GSK3, and bromodomain‐containing Brd4‐related pathways to sustain MLL‐FP‐induced leukemogenesis, revealing new therapeutic targets to improve the treatment of MLL‐FP leukemias. (shrink)

Early in animal development, gradients of secreted morphogenic molecules, such as Sonic hedgehog (Shh), Wnt and TGFβ/Bmp family members, regulate cell proliferation and determine the fate and phenotype of the target cells by activating well‐characterized signalling pathways, which ultimately control gene transcription. Shh, Wnt and TGFβ/Bmp signalling also play an important and evolutionary conserved role in neural circuit assembly. They regulate neuronal polarization, axon and dendrite development and synaptogenesis, processes that require rapid and local changes in cytoskeletal organization (...) and plasma membrane components. A key question then is whether morphogen signalling at the growth cone uses similar mechanisms and intracellular pathway components to those described for morphogen‐mediated cell specification. This review discusses recent advances towards the understanding of this problem, showing how Shh, Wnt and TGFβ/Bmp have adapted their ‘classical’ signalling pathways or adopted alternative and novel molecular mechanisms to influence different aspects of neuronal circuit formation. (shrink)

Secreted Frizzled‐related proteins (SFRPs) are modulators of the intermeshing pathways in which signals are transduced by Wnt ligands through Frizzled (Fz) membrane receptors. The Wnt networks influence biological processes ranging from developmental cell fate, cell polarity and adhesion to tumorigenesis and apoptosis. In the five or six years since their discovery, the SFRPs have emerged as dynamically expressed proteins able to bind both Wnts and Fz, with distinctive structural properties in which cysteine‐rich domains from Fz‐ and from netrin‐like proteins are (...) juxtaposed. The abundant expression of SFRP genes in the early embryo, altered expression patterns in disease states, and potential significance in the evolution of the vertebrate body plan, make these intriguing molecules relevant to investigations in diverse fields of biology and biomedical sciences. BioEssays 24:811–820, 2002. © 2002 Wiley Periodicals, Inc. (shrink)

Stem cell self renewal, maintenance and differentiation are influenced by the convergence of intrinsic cellular signals and extrinsic microenvironmental cues from the surrounding stem cell niche. However, the specific signals involved are often still poorly understood. This is also true for skin epithelial stem cells. Recently, by transcriptionally profiling of embryonic hair progenitors in mice, Rhee et al.1 have managed to define how murine hair follicle epithelial stem cells are specified and maintained in an undifferentiated state. These authors have identified (...) Lhx2 as a transcription factor functionally positioned downstream of signals necessary to specify hair follicle stem cells such as p63 or NFκB, but upstream of signals like Wnt/β‐catenin, Bmp or Shh that are required to drive activated stem cells via the production of transient amplifying cells into terminal differentiation. BioEssays 28: 1157–1160, 2006. © 2006 Wiley Periodicals, Inc. (shrink)

What initiates vertebrate limb development and induces limbs to form where they do? For several years the answer to this intriguing question has been framed in terms of a working model that limb induction depends on a dialogue between two members of the Fibroblast Growth Factor (FGF) family of intercellular signaling molecules, FGF8 and FGF10. Now, a recent paper has written roles for signals encoded by WNT genes, the vertebrate relatives of the Drosophila wingless gene, into the script.(1) BioEssays 23:865–868, (...) 2001. © 2001 John Wiley & Sons, Inc. (shrink)

Although the popularity of Humane Education Programs as a method of teaching compassion and caring for all living beings is increasing, there is a need for rigorous, methodologically sound research evaluating the efficacy of HEP. Recent calls for the inclusion of HEP within broader humanistic, environmental, and social justice frameworks underline the importance of HEP beyond a simple “treatment of animals” model. Lack of methodological rigor in the majority of published HEP studies and dispersal across disparate fields , however, means (...) that there is a potential for the popular use of HEP to outstrip our understanding of the variables that impact efficacy. The current study discusses some of these issues and presents a pilot study of a literature-only HEP intervention. Comparisons with an age-matched control group indicated that the four-week HEP resulted in an increase in measures of empathy and treatment of animals, although only the increase in empathy levels was significant. This paper discusses the implications of the current results and areas in need of future consideration. (shrink)

This study examines the practices of Equine Assisted Therapy and Learning in Australia. Among Equine Assisted Therapy and Equine Assisted Learning centers there is a large degree of variation in practice worldwide. The current study outlines a range of practices in two states in Australia whereeatandealhave arisen and evolved from models developed elsewhere. The philosophical foundations, training and certification processes followed along with the types and training of horses involved are compared across facilities. The findings of the study illustrated the (...) large variation ineatandealin current practice in Australia. The results suggested that if the practices ofeatandealare to move out of the “fringe” of mental health and learning professional practice and into the mainstream, their theoretical underpinnings, certification and licensure procedures, and methodology of practice must become more clearly defined. (shrink)

Although the popularity of Humane Education Programs as a method of teaching compassion and caring for all living beings is increasing, there is a need for rigorous, methodologically sound research evaluating the efficacy of HEP. Recent calls for the inclusion of HEP within broader humanistic, environmental, and social justice frameworks underline the importance of HEP beyond a simple “treatment of animals” model. Lack of methodological rigor in the majority of published HEP studies and dispersal across disparate fields , however, means (...) that there is a potential for the popular use of HEP to outstrip our understanding of the variables that impact efficacy. The current study discusses some of these issues and presents a pilot study of a literature-only HEP intervention. Comparisons with an age-matched control group indicated that the four-week HEP resulted in an increase in measures of empathy and treatment of animals, although only the increase in empathy levels was significant. This paper discusses the implications of the current results and areas in need of future consideration. (shrink)

Paramedics encounter ethical dilemmas at work, and while previous research has improved ethics education and practice, more can be learned from the lived experience of paramedics facing ethical challenges. This paper explores the lived experience of two paramedics, one with five years’ experience, the other twenty, presented with comparable cases. The participants, who were interviewed in a broader qualitative study exploring practical wisdom, were asked to select a case involving ethical decision-making from their own practice experience. Semi-structured interviews employed the (...) five-step Critical Decision Method as a framework to explore various aspects of the decision-making process. The two cases were identified as exemplars of prominent themes suitable for discussion. The findings highlighted several factors that influence paramedic ethical decision-making, including practical wisdom, communication and teamwork, clinical support, and education. This case comparison identifies a greater need to focus education on the fostering of practical wisdom, and the development of non-technical skills such as communication and teamwork, supported by interprofessional education endeavours. Furthermore, greater access to support for paramedics must be available to further evolve practical wisdom. The combination of improved education and support will likely cater for the full spectrum of ethical challenges faced by paramedics in their work. (shrink)

In Australia, paramedics are obliged to practice ethically. Graduates of baccalaureate degrees in paramedicine should therefore possess a common grounding in ethics to meet the professional capabilities expected of registered paramedics. However, there is a lack of clarity regarding ethics education for paramedicine students, including what is taught, how it is taught, and how it is assessed. This paper explores ethics education for paramedicine students in Australia, how it aligns with current professional expectations, and how it may be enhanced. Point-in-time (...) data regarding ethics education was collected from websites of fifteen Australian universities offering undergraduate baccalaureate degrees in paramedicine. Data collection was supported by consultation with academics from several institutions. Content analysis was utilised to categorise and analyse data to explore similarities and differences in curricula. Similarities included approaches to learning and teaching and the use of case-based learning, with variability found across teaching staff profiles and content areas. Findings suggest it is time for collaboration to develop a model ethics curriculum for paramedicine students in Australia. (shrink)

‘Virtue signaling’ is the practice of using moral talk in order to enhance one’s moral reputation. Many find this kind of behavior irritating. However, some philosophers have gone further, arguing that virtue signaling actively undermines the proper functioning of public moral discourse and impedes moral progress. Against this view, I argue that widespread virtue signaling is not a social ill, and that it can actually serve as an invaluable instrument for moral change, especially in cases where moral argument alone does (...) not suffice. Specifically, virtue signaling can change the broader public’s social expectations, which can in turn motivate the adoption of new, positive social norms. I also argue that the reputation-seeking motives underlying virtue signaling impose important constraints on virtue signalers’ behavior, which serve to keep the worst excesses of virtue signaling in check. (shrink)

Why do people share or publicly engage with fake stories? Two possible answers come to mind: (a) people are deeply irrational and believe these stories to be true; or (b) they intend to deceive their audience. Both answers presuppose the idea that people put the stories forward as true. But I argue that in some cases, these outlandish (yet also very popular) stories function as signals of one's group membership. This signaling function can make better sense of why, despite their (...) unusual nature or lack of a factual basis, some of these stories are so widespread. (shrink)

Natural languages are compositional in that the meaning of complex expressions depends on those of the parts and how they are put together. Here, I ask the following question: why are languages compositional? I answer this question by extending Lewis–Skyrms signaling games with a rudimentary form of compositional signaling and exploring simple reinforcement learning therein. As it turns out: in complex worlds, having compositional signaling helps simple agents learn to communicate. I am also able to show that learning the meaning (...) of a function word, once meanings of atomic words are known, presents no difficulty. (shrink)

Ethological theories usually attribute semantic content to animal signals. To account for this fact, many biologists and philosophers appeal to some version of teleosemantics. However, this picture has recently came under attack: while mainstream teleosemantics assumes that representational systems must cooperate, some biologists and philosophers argue that in certain cases signaling can evolve within systems lacking common interest. In this paper I defend the standard view from this objection.

The signaling theory of religion has many claimed virtues, but these are not necessarily all realizable at the same time. Modeling choices involve trade-offs, and the available options here have not traditionally been well understood. This paper offers an overview of signaling theory relevant to the signaling theory of religion, arguing for a narrow, “core” reading of it. I outline a broad taxonomy of the choices on offer for signaling models, and examples of how previous and potential approaches to modeling (...) religious signaling meet or fail to meet the initial promise of the theory. A pluralist approach to religious signaling seems possible, but this would require a high level of detail and specificity with respect to both formal models and target systems. (shrink)

Tosi and Warmke discuss cases where the speaker intends for the audience to take their expressions as evidence of good moral character. However, another possibility exists that similarly exploits the social communicative architecture. A contribution to public moral discourse may also attempt to strut by demonstrating evidence of bad moral character, by purposely failing to meet the evaluative standards of its audience—or, paradigmatically for my purposes, a particular section of its actual or notional audience. I call this kind of communication (...) vice signaling. On their face, virtue signaling and vice signaling may seem to be opposites, since the labels imply that they are signaling opposite things. But certain cases of vice signaling are in fact also cases of virtue signaling. These are the cases where someone flaunts the standards of an out-group in order to demonstrate solidarity, seriousness, or some other virtue to their in-group. In this paper I attempt to describe these cases and point out the moral risks and opportunities they present. (shrink)

Brian Skyrms offers a fascinating demonstration of how fundamental signals are to our world. He uses various scientific tools to investigate how meaning and communication develop. Signals operate in networks of senders and receivers at all levels of life, transmitting and processing information. That is how humans and animals think and interact.

Virtue signaling—using public moral discourse to enhance one’s moral reputation—is a familiar concept. But, what about profile pictures framed by “Vaccines work!”? Or memes posted to anti-vaccine groups echoing the group’s view that “Only sheep believe Big Pharma!”? These actions don’t express moral views—both claims are empirical (if imprecise). Nevertheless, they serve a similar purpose: to influence the judgments of their audience. But, where rainbow profiles guide their audience to view the agent as morally good, these acts guide their audience (...) to view the agent as epistemically good. They are instances of epistemic virtue signaling. The first goal of this paper is to offer an account of epistemic virtue signaling. I argue that epistemic virtue signaling occurs through both behavioral and propositional signals, and serves purposes similar to those of moral virtue signaling across a wide variety of discourses. The second is to show that there is much work for this concept to do. In particular, this concept illuminates a double bind faced by those who suffer from and seek to overcome testimonial injustice. I close by demonstrating how this double bind arises in the dissolution of medical autonomy, focusing on the care gap faced by pregnant women of color in the United States today, as compared with their white counterparts. (shrink)

Starting from logical structures of classical and quantum mechanics we reconstruct the logic of so-called no-signaling theories, where the correlations among subsystems of a composite system are restricted only by a simplest form of causality forbidding an instantaneous communication. Although such theories are, as it seems, irrelevant for the description of physical reality, they are helpful in understanding the relevance of quantum mechanics. The logical structure of each theory has an epistemological flavor, as it is based on analysis of possible (...) results of experiments. In this note we emphasize that not only logical structures of classical, quantum and no-signaling theory may be treated on the same ground but it is also possible to give to all of them a common ontological basis by constructing a “phase space” in all cases. In non-classical cases the phase space is not a set, as in classical theory, but a more general object obtained by means of category theory, but conceptually it plays the same role as the phase space in classical physics. (shrink)