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.

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’.

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.

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.