Bone morphogenetic proteins (BMPs) are typically members of the transforming growth factor β (TGF-β) family with diverse roles in embryonic development. At least five genes with homology to BMPs are expressed during Xenopus development, along with their receptors and intracellular signalling pathways. The evidence suggests that BMPs have roles to play in both mesoderm induction and dorsoventral patterning. Studies in Xenopus have also identified a number of inhibitory binding proteins for the classical BMPs, encoded by genes such as chordin and (...) noggin. These proteins appear to be responsible for establishing a morphogen gradient of BMP4 activity, which specifies different dorsoventral fates in early gastrulae. An emerging theme is that inhibition of BMP signalling is an important mechanism regulating cell fate decisions in early development. BioEssays 21:751–760, 1999. © 1999 John Wiley & Sons, Inc. (shrink)

Members of the astacin family of metalloproteinases such as human bone morphogenetic protein 1 (BMP‐1) have previously been linked to cell differentiation and pattern formation during development through a proposed role in the activation of latent growth factors of the TGF‐β superfamily. Recent finding(1) indicate that BMP‐1 is identical to pro‐collagen C‐proteinase, which is a metalloproteinase involved in extracellular matrix (ECM) formation. This observation suggests that a functional link may exist between astacin metalloproteinases, growth factors and cell differentiation and pattern (...) formation during development. Taken together, current studies indicate that BMP‐1 and possibly other astacin metalloproteinases are multifunctional enzymes that act directly on growth factors and the ECM. In combination, these dual actions would have profound effects on developmental processes. (shrink)

Secreted signaling molecules act as morphogens to control patterning and growth in many developing tissues. Since locally produced morphogens spread to form a concentration gradient in the surrounding tissue, spreading is generally thought to be the key step in the non‐autonomous actions. Here, we review recent advances in tool development to investigate morphogen function using the role of decapentaplegic (Dpp)/bone morphogenetic protein (BMP)‐type ligand in the Drosophila wing disc as an example. By applying protein binder tools to distinguish between the (...) roles of Dpp spreading and local Dpp signaling, we found that Dpp signaling in the source cells is important for wing patterning and growth but Dpp spreading from this source cells is not as strictly required as previously thought. Given recent studies showing unexpected requirements of long‐range action of different morphogens, manipulating endogenous morphogen gradients by synthetic protein binder tools could shed more light on how morphogens act in developing tissues. (shrink)

Both W9 and OP3‐4 were known to bind the receptor activator of NF‐κB ligand (RANKL), inhibiting osteoclastogenesis. Recently, both peptides were shown to stimulate osteoblast differentiation; however, the mechanism underlying the activity of these peptides remains to be clarified. A primary osteoblast culture showed that rapamycin, an mTORC1 inhibitor, which was recently demonstrated to be an important serine/threonine kinase for bone formation, inhibited the peptide‐induced alkaline phosphatase activity. Furthermore, both peptides promoted the phosphorylation of Akt and S6K1, an upstream molecule (...) of mTORC1 and the effector molecule of mTORC1, respectively. In the in vivo calvarial defect model, W9 and OP3‐4 accelerated BMP‐2‐induced bone formation to a similar extent, which was confirmed by histomorphometric analyses using fluorescence images of undecalcified sections. Our data suggest that these RANKL‐binding peptides could stimulate the mTORC1 activity, which might play a role in the acceleration of BMP‐2‐induced bone regeneration by the RANKL‐binding peptides. (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)

Scaling of pattern with size has been described and studied for over a century, yet its molecular basis is understood in only a few cases. In a recent, elegant study, Inomata and colleagues proposed a new model explaining how bone morphogenic protein (BMP) activity gradient scales with embryo size in the early Xenopus laevis embryo. We discuss their results in conjunction with an alternative model we proposed previously. The expansion‐repression mechanism (ExR) provides a conceptual framework unifying both mechanisms. Results of (...) Inomata and colleagues implicate the chordin‐stabilizing protein sizzled as the expander molecule enabling scaling, while we attributed this role to the BMP ligand Admp. The two expanders may work in concert, as suggested by the mathematical model of Inomata et al. We discuss approaches for differentiating the contribution of sizzled and Admp to pattern scaling. (shrink)

New research demonstrates that mechanics can serve as a means of information propagation in developing embryos. Historically, the study of embryonic development has had a dichotomy between morphogens and pattern formation on the one hand and morphogenesis and mechanics on the other. Secreted signals are the preeminent means of information propagation between cells and used to control cell fate, while physical forces act downstream or in parallel to shape tissue morphogenesis. However, recent work has blurred this division of function by (...) demonstrating that mechanics can serve as a means of information propagation. Adhesive or repulsive interactions can propagate through a tissue as a wave. These waves are rapid and directional and can be used to control the flux of cells through a developmental trajectory. Here, two examples are reviewed in which mechanics both guides and mediates morphogenesis and two examples in which mechanics intertwines with morphogens to regulate cell fate. (shrink)

Attempts to understand farmer conservation behavior based on quantitative socio-demographic, attitude, and awareness variables have been largely inconclusive. In order to understand fully how farmers are making conservation decisions, 32 in-depth interviews were conducted in the Eagle Creek watershed in central Indiana. Coding for environmental attitudes and practice adoption revealed several dominant themes, representing multi-dimensional aspects of environmental attitudes. Farmers who were motivated by off-farm environmental benefits and those who identified responsibilities to others (stewardship) were most likely to adopt conservation (...) practices. Those farmers who focused on the farm as business and were most concerned about profitability were less likely to adopt practices. The notion of environmental stewardship in particular was found to be much more complex than the way it is traditionally measured in quantitative studies. The interplay between on-farm and off-farm benefits to practice adoption is an issue that quantitative studies largely do not address. This study seeks to increase understanding of farmers’ environmental attitudes and the connections to conservation behavior. (shrink)

Understanding factors that motivate farmers to perform conservation behaviors is seen as key to enhancing efforts to address agri-environmental challenges. This study uses survey data collected from 277 farmers in the La Moine River watershed in western Illinois to develop new measures of farmers’ environmental attitudes and examine their influence on current usage of agricultural best management practices. The results suggest that a Dual Interest Theory approach reflecting two separate, competing psychological frames representing a stewardship view of the environment and (...) a farm as a business view of the environment are present within the decision making domain. Using a cluster analysis technique to examine the interaction between these attitude frames reveals four groups of farmers who hold distinct views of the environment. Further exploration of these distinct belief systems reveals little evidence of differences in participation or willingness to participate in agricultural BMPs; however, we observe significant differences between these groups with regard to their willingness to support rural conservation planning priorities that address agri-environmental challenges. Further discussion focuses on the implications of these interactive dual interest typologies and the implications of these findings on efforts to engage farmers in conservation efforts. (shrink)

Purpose: The purpose of this mixed-methods study was to determine whether Facebook use affects biological response to stress and to characterize participants’ use of Facebook during a stressful event. Methods: College students completed a modified Trier Social Stress Test including video recording. Participants were randomly assigned to the Facebook group or control group (no preparatory materials). Pulse and salivary cortisol were measured and compared using t tests. Trained coders assessed videos for 13 common Facebook actions and categorized them as purposeful (...) (tool based) or nonpurposeful (distraction); pulse was compared between groups using Fisher’s exact test. Results: Of 41 participants, 14 (36%) were male and 36 (88%) were Caucasian, mean age was 19.6 ± 1.4 years; 19 participants were randomized to the Facebook group. Comparing Time 1 and Time 3, there were no significant differences in cortisol or pulse change between the Facebook group and the control group. However, males in the control group had a mean pulse reduction of −3.5 ± 0.2 bpm between baseline and Time 3; males in the Facebook group had a mean pulse increase of 10 ± 8.6 bmp (p =.01). Overall, 58.8% of videos were categorized as primarily tool based. Participants who primarily demonstrated distracted use of Facebook had higher than average pulse rates at Time 3 (mean 85.1 vs. 73.6 bpm, p =.03). Discussion: Male Facebook users and participants who demonstrated distracted Facebook use showed increased biologic signs of stress during a stressful event. Some college students may find Facebook use detrimental to performance in stressful situations, but this may vary by gender and type of use. (shrink)

Genetic analysis of Drosophila has shown that a morphogenetic gradient of the Transforming Growth Factor‐β family member dpp patterns the embryonic dorsalventral axis. Molecular and embryological evidence from Xenopus has strongly suggested a similar role for Bmp‐4, the dpp homolog, in patterning the dorsalventral axis of chordates. A recent report has now identified mutations in two genes, dino and swirl, that disrupt dorsal‐ventral patterning in the zebrafish Danio rerio(1). Characterization of these mutations parallels findings from Drosophila, thus establishing a genetic (...) framework for the analysis of dorsalventral patterning in a vertebrate. (shrink)

Signaling through both the transforming growth factor β (TGFβ) superfamily of growth factors and Notch play crucial roles during embryonic pattern formation and cell fate determination. Although both pathways are able to exert similar biological responses in certain cell types, a functional interaction between these two signaling pathways has not been described. Now, three papers provide evidence of both synergy and antagonism between TGFβ and Notch signaling.1-3 These reports describe a requirement for Notch signal transducers in TGFβ- and BMP-induced expression (...) of Notch target genes, as well as in BMP-controlled cell differentiation and migration. These papers uncover a direct link between the Notch and TGFβ pathways and suggest a critical role for Notch in some of the biological responses to TGFβ family signaling. BioEssays 27:115–118, 2005. © 2005 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)

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)

Understanding the events that led to the emergence of the bilaterians is a daunting task, impaired by the huge evolutionary gap separating us from the pre‐Cambrian. During gastrulation, the expression of the transcription factor Brachyury is remarkably well conserved around the blastopore of bilaterians and cnidarians. Only the bilaterian Brachyury proteins, however, share a distinctive N‐terminal sequence not found in outgroups such as cnidarians, sponges or placozoans. We now know that, in vertebrates, this N‐terminal domain confers specific transcriptional activity, by (...) recruiting Smad1, the first identified co‐factor for Brachyury. Smad1 is an effector of the BMP pathway, and has been isolated in bilaterians and cnidarians. Here, I propose that the protein–protein interaction between Brachyury and Smad1 represents an evolutionary novelty of the Urbilateria. The gain of the N‐terminal domain might have been selected to spatially modulate the activity of Brachyury, thereby facilitating the establishment of bilateral symmetry during gastrulation movements. BioEssays 28: 413–420, 2006. © 2006 Wiley Periodicals, Inc. (shrink)

The embryonic vertebrate face is composed of similarly sized buds of neural crest‐derived mesenchyme encased in epithelium. These buds or facial prominences grow and fuse together to give the postnatal morphology characteristic of each species. Here we review the role of neural crest cells and foregut endoderm in differentiating facial features. We relate the developing facial prominences to the skeletal structure of the face and review the signals and genes that have been shown to play an important role in facial (...) morphogenesis. We also examine two experiments one at the genetic level and one at the signal level in which transformation of facial prominences and subsequent change of jaw identity was induced. We propose that signals such as retinoids and BMPs and downstream transcription factors such as Distal‐less related genes specify jaw identity. BioEssays 25:554–568, 2003. © 2003 Wiley Periodicals, Inc. (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)

The Transforming growth factor beta (TGF‐β) family of secreted proteins regulates a variety of key events in normal development and physiology. In mammals, this family, represented by 33 ligands, including TGF‐β, activins, nodal, bone morphogenetic proteins (BMPs), and growth and differentiation factors (GDFs), regulate biological processes as diverse as cell proliferation, differentiation, apoptosis, metabolism, homeostasis, immune response, wound repair, and endocrine functions. In Drosophila, only 7 members of this family are present, with 4 TGF‐β/BMP and 3 TGF‐β/activin ligands. Studies in (...) the fly have illustrated the role of TGF‐β/BMP ligands during embryogenesis and organ patterning, while the TGF‐β/activin ligands have been implicated in the control of wing growth and neuronal functions. In this review, we focus on the emerging roles of Drosophila TGF‐β/activins in inter‐organ communication via long‐distance regulation, especially in systemic lipid and carbohydrate homeostasis, and discuss findings relevant to metabolic diseases in humans. -/- . (shrink)

The correct positioning of organs during embryonic development requires multiple cues. The Xenopus cement gland is a mucus‐secreting epithelium that is a simple model for organogenesis, allowing detailed analysis of this complex process. The cement gland forms at a conserved anterior position, where embryonic ectoderm and endoderm touch. In all deuterostomes, this region will form the stomodeum (primitive mouth) and, in some aquatic larva, will also form a cement gland. In recent years, a model has been put forward suggesting that (...) an intermediate level of BMP signaling in the ectoderm leads to cement gland formation. We propose an alternative model whereby, during gastrulation, the cement gland (CG) is positioned by the overlap of three domains, corresponding to anterodorsal identity (AD), ventrolateral identity (VL), and ectodermal outer layer identity (EO), defining the equation (AD + VL + EO = CG). Anterodorsal identity requires a contribution by the transcription factor Otx2 while ventrolateral identity requires the BMP4 signaling pathway. These postional cues are integrated to activate cement gland differentiation. This integration appears to require intermediate steps, including expression of pitx genes, and members of the ATF/CREB and Ets transcription factor families. BioEssays 25:717–726, 2003. © 2003 Wiley Periodicals, Inc. (shrink)