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Coordination of cell division and pattern formation is central to tissue and organ development, particularly in plants where walls prevent cell migration. Auxin and cytokinin are both critical for division and patterning, but it is unknown how these hormones converge upon tissue development. We identify a genetic network that reinforces an early embryonic bias in auxin distribution to create a local, nonresponding cytokinin source within the root vascular tissue. Experimental and theoretical evidence shows that these cells act as a tissue organizer by positioning the domain of oriented cell divisions. We further demonstrate that the auxin-cytokinin interaction acts as a spatial incoherent feed-forward loop, which is essential to generate distinct hormonal response zones, thus establishing a stable pattern within a growing vascular tissue.

The vertebrate left–right axis is specified during embryogenesis by a transient organ: the left–right organizer (LRO). Species including fish, amphibians, rodents and humans deploy motile cilia in the LRO to break bilateral symmetry, while reptiles, birds, even-toed mammals and cetaceans are believed to have LROs without motile cilia. We searched for genes whose loss during vertebrate evolution follows this pattern and identified five genes encoding extracellular proteins, including a putative protease with hitherto unknown functions that we named ciliated left–right organizer metallopeptidase (CIROP). Here, we show that CIROP is specifically expressed in ciliated LROs. In zebrafish and Xenopus , CIROP is required solely on the left side, downstream of the leftward flow, but upstream of DAND5 , the first asymmetrically expressed gene. We further ascertained 21 human patients with loss-of-function CIROP mutations presenting with recessive situs anomalies. Our findings posit the existence of an ancestral genetic module that has twice disappeared during vertebrate evolution but remains essential for distinguishing left from right in humans. Phylogenomic and genetic analyses identify an ancestral module of genes expressed specifically in ciliated left–right organizer tissue and required for left–right axis specification in humans and certain vertebrates.

To translate insights in developmental biology into medical applications, techniques are needed to ensure correct cell localization. Morphogen gradients allow precise and highly reproducible pattern formation during development. Through in vitro experiments and modeling, Li et al. tested the effects of unusual properties of Hedgehog (HH) signaling. The HH morphogen's receptor, Patched (PTCH), sends an inhibitory signal when no ligand is bound, which is relieved by ligand binding. PTCH also regulates spatial distribution of the signal by sequestering the HH ligand. Furthermore, signaling through the receptor promotes synthesis of more inhibitory receptor. These characteristics help speed gradient formation and explain the robustness of the system to changes in the rate of morphogen production. Science , this issue p. 543 Insights from building a morphogen gradient in cell culture are discussed. In developing tissues, cells estimate their spatial position by sensing graded concentrations of diffusible signaling proteins called morphogens. Morphogen-sensing pathways exhibit diverse molecular architectures, whose roles in controlling patterning dynamics and precision have been unclear. In this work, combining cell-based in vitro gradient reconstitution, genetic rewiring, and mathematical modeling, we systematically analyzed the distinctive architectural features of the Sonic Hedgehog pathway. We found that the combination of double-negative regulatory logic and negative feedback through the PTCH receptor accelerates gradient formation and improves robustness to variation in the morphogen production rate compared with alternative designs. The ability to isolate morphogen patterning from concurrent developmental processes and to compare the patterning behaviors of alternative, rewired pathway architectures offers a powerful way to understand and engineer multicellular patterning.

Sensory hairs on the back of a fruit fly are lined up in neat rows. The orderliness of this arrangement has encouraged models based on organized specification of the hairs. Corson et al. now show that development is both less precise and more effective than that. They used mathematical modeling to recapitulate genetic effects as the developing epidermis becomes organized into enough rows and single lines of hairs. Their work suggests that the sensory field develops through self-organizing patterning that can adjust to the size of the epidermis. Science , this issue p. eaai7407 Distributed and flexible patterning combines with cell-cell interactions to establish rows of sensory bristles on the fly thorax. The emergence of spatial patterns in developing multicellular organisms relies on positional cues and cell-cell communication. Drosophila sensory organs have informed a paradigm in which these operate in two distinct steps: Prepattern factors drive localized proneural activity, then Notch-mediated lateral inhibition singles out neural precursors. Here we show that self-organization through Notch signaling also establishes the proneural stripes that resolve into rows of sensory bristles on the fly thorax. Patterning, initiated by a gradient of Delta ligand expression, progresses through inhibitory signaling between and within stripes. Thus, Notch signaling can support self-organized tissue patterning as a prepattern is transduced by cell-cell interactions into a refined arrangement of cellular fates.

During gastrulation, the pluripotent epiblast self-organizes into the 3 germ layers-endoderm, mesoderm and ectoderm, which eventually form the entire embryo. Decades of research in the mouse embryo have revealed that a signaling cascade involving the Bone Morphogenic Protein (BMP), WNT, and NODAL pathways is necessary for gastrulation. In vivo, WNT and NODAL ligands are expressed near the site of gastrulation in the posterior of the embryo, and knockout of these ligands leads to a failure to gastrulate. These data have led to the prevailing view that a signaling gradient in WNT and NODAL underlies patterning during gastrulation; however, the activities of these pathways in space and time have never been directly observed. In this study, we quantify BMP, WNT, and NODAL signaling dynamics in an in vitro model of human gastrulation. Our data suggest that BMP signaling initiates waves of WNT and NODAL signaling activity that move toward the colony center at a constant rate. Using a simple mathematical model, we show that this wave-like behavior is inconsistent with a reaction-diffusion-based Turing system, indicating that there is no stable signaling gradient of WNT/NODAL. Instead, the final signaling state is homogeneous, and spatial differences arise only from boundary effects. We further show that the durations of WNT and NODAL signaling control mesoderm differentiation, while the duration of BMP signaling controls differentiation of CDX2-positive extra-embryonic cells. The identity of these extra-embryonic cells has been controversial, and we use RNA sequencing (RNA-seq) to obtain their transcriptomes and show that they closely resemble human trophoblast cells in vivo. The domain of BMP signaling is identical to the domain of differentiation of these trophoblast-like cells; however, neither WNT nor NODAL forms a spatial pattern that maps directly to the mesodermal region, suggesting that mesoderm differentiation is controlled dynamically by the combinatorial effect of multiple signals. We synthesize our data into a mathematical model that accurately recapitulates signaling dynamics and predicts cell fate patterning upon chemical and physical perturbations. Taken together, our study shows that the dynamics of signaling events in the BMP, WNT, and NODAL cascade in the absence of a stable signaling gradient control fate patterning of human gastruloids.

The origin of the pentaradial body plan of echinoderms from a bilateral ancestor is one of the most enduring zoological puzzles 1 , 2 . Because echinoderms are defined by morphological novelty, even the most basic axial comparisons with their bilaterian relatives are problematic. To revisit this classical question, we used conserved anteroposterior axial molecular markers to determine whether the highly derived adult body plan of echinoderms masks underlying patterning similarities with other deuterostomes. We investigated the expression of a suite of conserved transcription factors with well-established roles in the establishment of anteroposterior polarity in deuterostomes 3 – 5 and other bilaterians 6 – 8 using RNA tomography and in situ hybridization in the sea star Patiria miniata . The relative spatial expression of these markers in P. miniata ambulacral ectoderm shows similarity with other deuterostomes, with the midline of each ray representing the most anterior territory and the most lateral parts exhibiting a more posterior identity. Strikingly, there is no ectodermal territory in the sea star that expresses the characteristic bilaterian trunk genetic patterning programme. This finding suggests that from the perspective of ectoderm patterning, echinoderms are mostly head-like animals and provides a developmental rationale for the re-evaluation of the events that led to the evolution of the derived adult body plan of echinoderms. RNA tomography and in situ hybridization in echinoderms suggest a new ambulacral-anterior model to relate echinoderm pentaradial symmetry to the ancestral bilateral symmetry.

More than a century ago, Thomas Hunt Morgan attempted to explain the extraordinary regenerative ability of planarians such as Dugesia japonica , which can regenerate a complete individual even from a tail fragment, by proposing that two opposing morphogenetic gradients along the anterior–posterior axis are required for regeneration; here ERK and β-catenin signalling are shown to form these gradients. Controlling planarian regeneration capacity Planarians are flatworms common in streams and ponds whose capacity for tissue regeneration is legendary. But with more limited regenerative capacities are known. Three papers published in Nature this week study Planaria with differing regenerative capacities and identify the Wnt/β-catenin molecular signalling pathway, important in embryonic development and adult homeostasis in multicellular organisms, as central to the regeneration mechanism. Yoshihiko Umesono et al . identify ERK and β-catenin signalling as the basis for a morphogenetic gradient along the anterior–posterior axis that is required for regeneration. These authors also demonstrate that inhibition of β-catenin can rescue head regeneration in Phagocata kawakatsui , a planarian that otherwise cannot regenerate heads from the posterior pieces. James Sikes and Phillip Newmark show in Procotyla fluviatilis , which has restricted ability to replace missing tissues, that Wnt signalling is aberrantly regulated in regeneration-deficient tissues. Downregulation of Wnt signalling in these regions restores regenerative abilities, including the formation of blastemas and even new heads. Jochen Rink and colleagues show that in the otherwise regeneration-incompetent Dendrocoelum lacteum , knockdown of components in the Wnt signalling pathway introduces the ability to regenerate lost tissues. The planarian Dugesia japonica can regenerate a complete individual from a head, trunk or tail fragment via activation of somatic pluripotent stem cells 1 , 2 . About a century ago, Thomas Hunt Morgan attempted to explain the extraordinary regenerative ability of planarians by positing two opposing morphogenetic gradients of formative “head stuff” and “tail stuff” along the anterior–posterior axis 3 , 4 . However, Morgan’s hypothesis remains open to debate. Here we show that extracellular signal-related kinase (ERK) and Wnt/β-catenin signalling pathways establish a solid framework for planarian regeneration. Our data suggest that ERK signalling forms a spatial gradient in the anterior region during regeneration. The fibroblast growth factor receptor-like gene nou-darake 5 (which serves as an output of ERK signalling in the differentiating head) and posteriorly biased β-catenin activity 6 , 7 , 8 negatively regulate ERK signalling along the anterior–posterior axis in distinct manners, and thereby posteriorize regenerating tissues outside the head region to reconstruct a complete head-to-tail axis. On the basis of this knowledge about D. japonica , we proposed that β-catenin signalling is responsible for the lack of head-regenerative ability of tail fragments in the planarian Phagocata kawakatsui , and our confirmation thereof supports the notion that posterior β-catenin signalling negatively modulates the ERK signalling involved in anteriorization across planarian species. These findings suggest that ERK signalling has a pivotal role in triggering globally dynamic differentiation of stem cells in a head-to-tail sequence through a default program that promotes head tissue specification in the absence of posteriorizing signals. Thus, we have confirmed the broad outline of Morgan’s hypothesis, and refined it on the basis of our proposed default property of planarian stem cells.

Stomata play a pivotal role in the regulation of gas exchange in flowering plants and are distributed throughout the aerial epidermis. In leaves, the pattern of stomatal distribution is highly variable between species but is regulated by a mechanism that maintains a minimum of one cell spacing between stomata. In Arabidopsis, a number of the genetic components of this mechanism have been identified and include, SDD1, EPF1 and the putative receptors TMM and the ERECTA-gene family. A mitogen-activated protein (MAP) kinase signalling cascade is believed to act downstream of these putative receptors while a number of transcription factors including SPCH, MUTE and FAMA have been identified that control consecutive steps of stomatal development. The environment also has significant effects on stomatal development. In a number of species both light intensity and CO₂ concentrations have been shown to influence the frequency at which stomata develop on leaves. Long-distance signalling mechanisms have been implicated in these environmental responses with the conditions sensed by mature leaves determining the stomatal frequency in developing leaves. Thus, changes in the environment appear to act by modulating the developmental and patterning pathways to determine stomatal frequency.

Early amniote development is highly self-organized, capable of adapting to interference through local and long-range cell–cell interactions. This process, called embryonic regulation 1 , has been well illustrated in experiments on avian embryos, in which subdividing the epiblast disk into different parts not only redirects cell fates to eventually form a complete and well-proportioned embryo at its original location, but also leads to the self-organization of additional, fully formed embryos 2 , 3 in the other separated parts. The cellular interactions underlying embryonic self-organization are widely believed to be mediated by molecular signals, yet the identity of such signals is unclear. Here, by analysing intact and mechanically perturbed quail embryos, we show that the mechanical forces that drive embryogenesis self-organize, with contractility locally self-activating and the ensuing tension acting as a long-range inhibitor. This mechanical feedback governs the persistent pattern of tissue flows that shape the embryo 4 – 6 and also steers the concomitant emergence of embryonic territories by modulating gene expression, ensuring the formation of a single embryo under normal conditions, yet allowing the emergence of multiple, well-proportioned embryos after perturbations. Thus, mechanical forces act at the core of embryonic self-organization, shaping both tissues and gene expression to robustly yet plastically canalize early development. Mechanical forces act at the core of bird embryonic self-organization, shaping both tissues and gene expression to robustly yet plastically canalize early development.

Tribolium castaneum is a member of the most species-rich eukaryotic order, a powerful model organism for the study of generalized insect development, and an important pest of stored agricultural products. We describe its genome sequence here. This omnivorous beetle has evolved the ability to interact with a diverse chemical environment, as shown by large expansions in odorant and gustatory receptors, as well as P450 and other detoxification enzymes. Development in Tribolium is more representative of other insects than is Drosophila, a fact reflected in gene content and function. For example, Tribolium has retained more ancestral genes involved in cell-cell communication than Drosophila, some being expressed in the growth zone crucial for axial elongation in short-germ development. Systemic RNA interference in T. castaneum functions differently from that in Caenorhabditis elegans, but nevertheless offers similar power for the elucidation of gene function and identification of targets for selective insect control.