Volume 15 Issue 7, July 2013

Disseminated tumour cells (DTCs) can adopt a state of long-term dormancy. However, when and why they emerge from quiescence has remained unclear. Distinct microvascular niches are now shown to regulate this process. Mature blood vessels produce signals that sustain tumour cell quiescence, whereas sprouting microvasculature provides stimuli that reactivate DTCs, leading to metastatic relapse.

Cell morphological plasticity is controlled by intracellular signalling pathways. By combining large-scale imaging with quantitative analysis, an RNA interference (RNAi) screen in Drosophila melanogaster haemocytes reveals that most targeted genes regulate transitions between discrete shapes. Loss of gene function changes shape frequencies or reduces diversity, rather than producing new morphologies.

Addition of a specific set of transcription factors reprograms somatic cell nuclei to a pluripotent state. Sequential addition of these factors, rather than the simultaneous exposure used in standard protocols, improves reprogramming efficiency. This sequential method favours a transition through a state with enhanced mesenchymal characteristics before driving an epithelial transformation on the way to the pluripotent state.

The substrates of mammalian ULK1/2 and its yeast homologue Atg1 in autophagy have remained elusive. The class III phosphatidylinositol 3-kinase component Beclin-1 has now been identified as a physiological substrate of the ULK kinases in autophagy following amino acid starvation, therefore suggesting a critical molecular link between the upstream kinases and the autophagy core machinery.

Centrosome amplification is often seen in cancer cells and may cause aneuploidy. Basto and colleagues unexpectedly find that centrosome amplification (induced by Plk4 overexpression) in the mouse central nervous system causes microcephaly due to depletion of the neural stem cell pool through aneuploidy and cell death.

The protein kinase ULK1 regulates autophagy induction but its mode of action is poorly understood. Guan and colleagues show that following nutrient starvation, ULK1-mediated phosphorylation of Beclin-1 is required for the activation of VPS34 lipid kinase within the autophagy complex ATG1–VPS34–Beclin-1. They also find that during starvation, the inhibitory effect of mTOR on ULK1 is relieved to increase the phosphorylation of Beclin-1.

Sahai and colleagues present a computational model of cell motility based on experimentally derived parameters. They show that the model predicts the behaviour of cells in in vitro and in vivo settings with respect to the migration strategy and response of cancer cells to specific experimental interventions.

Mayor and colleagues observed that placodal cell movements in Xenopus and zebrafish embryos are controlled by their interaction with adjacent neural crest cells. Neural crest cells chemotactically migrated towards placodal cells and, on contact, induced neural crest cells to migrate away, revealing a ‘chase-and-run’ behaviour.

Recovery of neurotransmitter involves the endocytic retrieval of vesicles from the plasma membrane. Jonas and colleagues show that in hippocampal synapses, the anti-apoptotic protein Bcl-x_L enhances the recovery of a vesicle pool. It does this independently of its mitochondrial function, through its calmodulin-stimulated translocation to clathrin-coated pits and recruitment of the dynamin-related protein Drp1.

Chromosome segregation requires the capture of kinetochores by microtubules, a process that in yeast mitosis is facilitated by kinetochores being tethered to spindle poles. Sato and colleagues find that in meiosis I, when kinetochores are not tethered to poles, a microtubule array associated with TACC (Alp7) and TOG proteins (Alp14 and Dis1) retrieves kinetochores in a Polo-kinase-dependent manner.

The Emi1 protein inhibits the anaphase promoting complex (APC), an E3 ubiquitin ligase and critical cell cycle regulator, but it has remained unclear how it does this. Wang and Kirschner demonstrate that Emi1 suppresses the elongation of ubiquitin chains on APC substrates by interfering in different ways with the activities of the E2 enzymes UBCH10 and Ube2S.

Bissell, Ghajar and colleagues use organotypic culture systems and in vivo mouse and zebrafish models to reveal the distinct effects of different microvascular niches on tumour cell dormancy. They report that although the stable microvasculature promotes cancer cell quiescence through the production of thrombospondin-1, cancer cells residing near neovascular tips are induced to grow through the action of TGF-β and periostin.

Gilson and colleagues report that increased expression of the telomeric protein TRF2 in tumour cells promotes tumorigenesis in a non-cell-autonomous manner, by inhibiting the recruitment and activation of natural killer cells at the tumour site.

Pei and colleagues show that introduction of the pluripotency reprogramming factors in sequence (Oct4–Klf4, c-Myc and finally Sox-2), rather than introducing them all together, increases reprogramming efficiency. This sequential delivery activates the epithelial-to-mesenchymal transition (EMT) before the mesenchymal-to-epithelial transition (MET), which was previously reported to occur during reprogramming. The authors also show that addition of EMT modulators influences reprogramming in a similar manner.

Emergence of primordial germ cells (PGCs) from the syncytial Drosophila embryo is not well understood. Lehmann and colleagues show that a cytokinetic furrow emerges for PGC formation that does not require a canonical anaphase spindle cleavage pathway but involves regulators of the small GTPase Rho and the BTB-domain protein Germ cell-less.

The polycomb protein BMI1 has been linked to maintenance of adult stem cells. Klein and colleagues find that BMI1 is also required for the maintenance of stem cells in the continuously growing mouse incisor, through repression of the Ink4a/Arf locus to modulate the proliferation of stem cells and repression of Hox genes to prevent inappropriate lineage decisions in stem cell progeny.

Mabuchi, Balasubramanian and colleagues develop a system to study the contraction of the fission yeast contractile ring in vitro. They identify components required for this process and find that myosin ATPase activity, but not actin disassembly, is needed.

Bakal, Wong and colleagues performed an RNAi screen in Drosophila cells, as well as imaging and systems-level analyses, to identify genes regulating morphological complexity in heterogeneous cell populations. They report that rather than generating novel shapes, most genes control a switch-like transition between distinct morphologies. The authors also extend their findings to mouse and human melanoma cells.

Plath and colleagues survey the global histone modification changes linked to reprogramming. They delineate that the H3K9-methylation-associated protein Cbx3 restricts late events of reprogramming and, in particular, prevents the expression of the pluripotent gene Nanog.