News & Views

Wnt/β-catenin signalling is an important regulator of liver development, zonation and regeneration. The cell surface complex RSPO–LGR4/5–ZNF3/RNF43 is now shown to direct Wnt/β-catenin signalling in orchestrating the division of the liver into functionally distinct metabolic zones, providing insights into the mechanisms that influence organ development and regeneration.

A powerful combination of cell labelling, genetic tools and rapid imaging techniques in vivo has now led to a high-resolution description of lumen formation during angiogenesis in zebrafish. The study reveals a haemodynamic-force-driven and myosin-II-dependent cellular mechanism (termed inverse membrane blebbing) as the basis for lumen expansion in unicellular and multicellular angiogenic sprouts.

Primary cilia are cellular structures that have important functions in development and disease. The suppression of multiciliate differentiation of choroid plexus precursors, and maintenance of a single primary cilium by Notch1, is now shown to be involved in choroid plexus tumour formation.

Broken ends of a budding yeast chromosome exhibit increased mobility, presumably to facilitate repair by recombination. A new study reports that increased mobility reflects the untethering of the broken chromosome, triggered by a DNA damage response that phosphorylates the Cep3 kinetochore protein and weakens the association between the centromere and the spindle pole body.

Transporting epithelia commonly consist of tubes that mediate between the body and its environment. Lumen formation is closely linked to epithelial morphogenesis, but an open question is how luminal symmetry is broken to generate tubes rather than hollow cysts. A report about the biomechanics of intercellular contacts might now provide some answers.

An actin filament coat promotes cargo expulsion from large exocytosing vesicles, but the mechanisms of coat formation and force generation have been poorly characterized. Elegant imaging studies of the Drosophila melanogaster salivary gland now reveal how actin and myosin are recruited, and show that myosin II forms a contractile 'cage' that facilitates exocytosis.

The first hours of mammalian embryogenesis are devoted to extensive epigenetic reprogramming. One hallmark is active demethylation of the paternal genome by Tet (ten-eleven translocation) enzymes. However, the process is now shown to be Tet-independent at first, with Tet enzymes only counteracting hitherto underappreciated de novo DNA methylation activity in later zygotic stages.

The control of proteasome-mediated protein degradation is thought to occur mainly at the level of polyubiquitylation of the substrate. However, the proteasome can also be regulated directly, as now demonstrated by a study in which DYRK2-mediated phosphorylation of the 19S subunit Rpt3 is found to increase proteasome activity.

The heart is a complex organ, consisting of multiple cell types that coordinately regulate blood flow. Reciprocal Notch pathway signalling in endocardial and myocardial cells is now shown to promote maturation of the ventricular chambers. These insights reveal mechanisms that, when disrupted, can lead to cardiomyopathies.

The heptameric Arp2/3 complex generates branched actin filament networks that drive lamellipodium protrusion, vesicle trafficking and pathogen motility. Distinct variants of the Arp2/3 complex are now shown to have different roles in tuning actin assembly and disassembly, in concert with the prominent actin regulators cortactin and coronin.

Spatiotemporally distinct pluripotent states captured in vitro provide an accessible way of modelling early human development. An intricate interplay between the metabolome and histone modifications is now shown to drive the metabolic switch from human naive to primed pluripotency, one of the earliest steps of embryogenesis.

A powerful combination of two-colour imaging in vivo, Fourier-filtered kymography and simulations provides a high-resolution view of kinesin-2 transport dynamics in cilia. This study reveals heterotrimeric kinesin-II as an 'obstacle-course runner' and homodimeric OSM-3 (KIF17) as a 'long-distance runner', and elucidates the 'baton handoff' between these two kinesin-2 motors on the microtubule track.

Tumours reprogram their metabolism to maximize macromolecule biosynthesis for growth. However, which of the common tumour-associated metabolic activities are critical for proliferation remains unclear. Glutamate-derived glutamine is now shown to satisfy the glutamine needs of glioblastoma, indicating that glutamine anaplerosis is dispensable for growth.

The mechanisms underlying integrin-dependent signalling are a topic of continued study. Endocytosed integrins are now shown to drive assembly of signalling complexes on the cytoplasmic face of endocytic membranes to promote cancer cell survival and increase metastatic capacity following cell detachment.

Two studies show that the E3 ubiquitin ligase RNF138 is recruited to DNA double-strand break sites, where it ubiquitylates key repair factors to promote DNA-end resection and homologous recombination. These findings add insights into the multilayered regulatory mechanisms underlying DNA double-strand break repair pathway choice in mammalian cells.

Protein ubiquitylation in mammals is known to trigger selective autophagy of peroxisomes through a process termed pexophagy. The physiological peroxisomal target for pexophagy-related ubiquitylation has been controversial, but two studies have now identified the protein PEX5 as the real candidate.

Cellular senescence is often accompanied by the production of secreted proteins that mediate the diverse effects of senescence on the tissue microenvironment. The mammalian target of rapamycin (mTOR), a master regulator of protein synthesis, is now shown to control the senescence-associated secretory phenotype by modulating gene transcription and mRNA translation and stabilization.

Decreases in endoplasmic reticulum calcium content are sensed by resident STIM proteins, which can activate plasma membrane Orai channels to facilitate Ca²⁺ entry. The role of STIMATE, a previously unknown component of the store-operated calcium entry complex, has now been identified and defined.

Compared with most intracellular vesicles, the autophagosome is formed by an unusual event of vesicle budding involving an elusive sequence of membrane expansions that ends with a double membrane vesicle. It is now shown that actin polymerization inside the forming autophagosome is a driving force for the expansion and assembly of a functional autophagosome.

A new study suggests that fumarase, a metabolic enzyme normally associated with ATP production in mitochondria, is recruited to sites of DNA damage where it produces fumarate to inhibit histone demethylation and promote repair of DNA double strand breaks.