The development of multicellular organisms proceeds through a series of morphogenetic and cell-state transitions, transforming homogeneous zygotes into complex adults by a process of ...self-organisation. Many of these transitions are achieved by spontaneous symmetry breaking mechanisms, allowing cells and tissues to acquire pattern and polarity by virtue of local interactions without an upstream supply of information. The combined work of theory and experiment has elucidated how these systems break symmetry during developmental transitions. Given that such transitions are multiple and their temporal ordering is crucial, an equally important question is how these developmental transitions are coordinated in time. Using a minimal mass-conserved substrate-depletion model for symmetry breaking as our case study, we elucidate mechanisms by which cells and tissues can couple reaction-diffusion-driven symmetry breaking to the timing of developmental transitions, arguing that the dependence of patterning mode on system size may be a generic principle by which developing organisms measure time. By analysing different regimes of our model, simulated on growing domains, we elaborate three distinct behaviours, allowing for clock-, timer- or switch-like dynamics. Relating these behaviours to experimentally documented case studies of developmental timing, we provide a minimal conceptual framework to interrogate how developing organisms coordinate developmental transitions.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Zoonotic diseases will maintain a high level of public policy attention in the coming decades. From the spectre of a global pandemic to anxieties over agricultural change, urbanization, social ...inequality and threats to natural ecosystems, effectively preparing and responding to endemic and emerging diseases will require technological, institutional and social innovation. Much current discussion emphasizes the need for a ‘One Health’ approach: bridging disciplines and sectors to tackle these complex dynamics. However, as attention has increased, so too has an appreciation of the practical challenges in linking multi-disciplinary, multi-sectoral research with policy, action and impact. In this commentary paper, we reflect on these issues with particular reference to the African sub-continent. We structure the themes of our analysis on the existing literature, expert opinion and 11 interviews with leading One Health scholars and practitioners, conducted at an international symposium in 2016. We highlight a variety of challenges in research and knowledge production, in the difficult terrain of implementation and outreach, and in the politicized nature of decision-making and priority setting. We then turn our attention to a number of strategies that might help reconfigure current pathways and accepted norms of practice. These include: (i) challenging scientific expertise; (ii) strengthening national multi-sectoral coordination; (iii) building on what works; and (iv) re-framing policy narratives. We argue that bridging the research-policy-action interface in Africa, and better connecting zoonoses, ecosystems and well-being in the twenty-first century, will ultimately require greater attention to the democratization of science and public policy.
This article is part of the themed issue ‘One Health for a changing world: zoonoses, ecosystems and human well-being’.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Stem-cell-based human and mouse embryo models Bao, Min; Cornwall-Scoones, Jake; Zernicka-Goetz, Magdalena
Current opinion in genetics & development,
10/2022, Volume:
76
Journal Article
Peer reviewed
Open access
Synthetic embryology aims to develop embryo-like structures from stem cells to provide new insight into early stages of mammalian development. Recent advances in synthetic embryology have highlighted ...the remarkable capacity of stem cells to self-organize under certain biochemical or biophysical stimulations, generating structures that recapitulate the fate and form of early mouse/human embryos, in which symmetry breaking, pattern formation, or proper morphogenesis can be observed spontaneously. Here we review recent progress on the design principles for different types of embryoids and discuss the impact of different biochemical and biophysical factors on the process of stem-cell self-organization. We also offer our thoughts about the principal future challenges.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Iterative joints are a hallmark of the tetrapod limb, and their positioning is a key step during limb development. Although the molecular regulation of joint formation is well studied, it remains ...unclear what controls the location, number and orientation (i.e. the pattern) of joints within each digit. Here, we propose the dot-stripe mechanism for joint patterning, comprising two coupled Turing systems inspired by published gene expression patterns. Our model can explain normal joint morphology in wild-type limbs, hyperphalangy in cetacean flippers, mutant phenotypes with misoriented joints and suggests a reinterpretation of the polydactylous Ichthyosaur fins as a polygonal joint lattice. By formulating a generic dot-stripe model, describing joint patterns rather than molecular joint markers, we demonstrate that the insights from the model should apply regardless of the biological specifics of the underlying mechanism, thus providing a unifying framework to interrogate joint patterning in the tetrapod limb.
Embryo polarization is critical for mouse development; however, neither the regulatory clock nor the molecular trigger that it activates is known. Here, we show that the embryo polarization clock ...reflects the onset of zygotic genome activation, and we identify three factors required to trigger polarization. Advancing the timing of transcription factor AP-2 gamma (Tfap2c) and TEA domain transcription factor 4 (Tead4) expression in the presence of activated Ras homolog family member A (RhoA) induces precocious polarization as well as subsequent cell fate specification and morphogenesis. Tfap2c and Tead4 induce expression of actin regulators that control the recruitment of apical proteins on the membrane, whereas RhoA regulates their lateral mobility, allowing the emergence of the apical domain. Thus, Tfap2c, Tead4, and RhoA are regulators for the onset of polarization and cell fate segregation in the mouse.
Breaking embryonic symmetry is an essential prerequisite to shape the initially symmetric embryo into a highly organized body plan that serves as the blueprint of the adult organism. This critical ...process is driven by morphogen signaling gradients that instruct anteroposterior axis specification. Despite its fundamental importance, what triggers symmetry breaking and how the signaling gradients are established in time and space in the mammalian embryo remain largely unknown. Stem cell-based in vitro models of embryogenesis offer an unprecedented opportunity to quantitatively dissect the multiple physical and molecular processes that shape the mammalian embryo. Here we review biochemical mechanisms governing early mammalian patterning in vivo and highlight recent advances to recreate this in vitro using stem cells. We discuss how the novel insights from these model systems extend previously proposed concepts to illuminate the extent to which embryonic cells have the intrinsic capability to generate specific, reproducible patterns during embryogenesis.
•We review decades of experimentation in the mouse for biochemical and biophysical mechanisms underlying embryo patterning.•We discuss advances in stem-cell based embryo models with a particular focus on symmetry breaking.•The role for embryonic geometry and size in governing mouse gastrulation is discussed.•We question yet unknown contributing factors to symmetry breaking events in mammalian embryos.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Mammalian embryos sequentially differentiate into trophectoderm and an inner cell mass, the latter of which differentiates into primitive endoderm and epiblast. Trophoblast stem (TS), extraembryonic ...endoderm (XEN) and embryonic stem (ES) cells derived from these three lineages can self-assemble into synthetic embryos, but the mechanisms remain unknown. Here, we show that a stem cell-specific cadherin code drives synthetic embryogenesis. The XEN cell cadherin code enables XEN cell sorting into a layer below ES cells, recapitulating the sorting of epiblast and primitive endoderm before implantation. The TS cell cadherin code enables TS cell sorting above ES cells, resembling extraembryonic ectoderm clustering above epiblast following implantation. Whereas differential cadherin expression drives initial cell sorting, cortical tension consolidates tissue organization. By optimizing cadherin code expression in different stem cell lines, we tripled the frequency of correctly formed synthetic embryos. Thus, by exploiting cadherin codes from different stages of development, lineage-specific stem cells bypass the preimplantation structure to directly assemble a postimplantation embryo.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
9.
Starting life in space Cornwall-Scoones, Jake; Zernicka-Goetz, Magdalena
National science review,
09/2020, Volume:
7, Issue:
9
Journal Article
Peer reviewed
Open access
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
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