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Although the road to cell therapeutics is rife with uncertainties — scientific, clinical and economic — its success could transform medicine. Five years into its mission, the California Institute of Regenerative Medicine is laying a foundation for this new form of medical treatment.
Microtubule-based mRNA transport participates in the establishment of cell asymmetries. An in vitro reconstitution assay demonstrates that localization signals present in an mRNA influence motor copy number on single RNA molecule cargoes, ultimately leading to highly polarized distributions of transcripts.
Meiotic recombination produces physical linkages between homologous chromosomes that enable their segregation to opposite poles during meiosis I. In the absence of recombination, chromosomes mis-segregate, resulting in aneuploidy associated with severe birth defects. A recent study provides exciting insights into how recombination is fine-tuned to enforce a robust meiotic program.
The transcription factor Twist1 is overexpressed in tumours and can induce the epithelial–mesenchymal transition, resulting in increased invasiveness. Twist1 is now shown to regulate cancer cell migration and invasion in three-dimensional environments by activating the RAC1 GTPase through suppression of a let-7 microRNA family member.
Cellular senescence is a stable proliferation arrest induced by triggers such as short telomeres, activated oncogenes and genotoxic stress. Two studies show that cellular senescence induced by genotoxic stress depends on chronic DNA-damage signalling from irreparable damage to telomeres. Hence, dysfunctional or damaged telomeres are the initiators of multiple modes of senescence.
Formation and fission of large membrane-bound carriers at the Golgi requires coordinated action by a myriad of proteins, including PI(4)KIIIβ and CtBP1-S/BARS. Corda and colleagues reveal that the scaffold protein 14-3-3γ bridges BARS to PI(4)KIIIβ, thus mechanistically linking carrier budding and tubulation with tubule fission.
D’Adda di Fagagna and colleagues observe that, after genotoxic treatment of cells and mice, unrepaired DNA-damage foci and DNA-damage signalling persist at telomeres. They show that introducing the telomeric protein TRF2 near a double-strand break elsewhere on the chromosomes prevents repair. Unrepaired foci are also observed at telomeres of ageing animals, suggesting a role for TRF2 in senescence establishment.
Yang and colleagues delineate a pathway that controls cell migration in 3D environments following Twist1-mediated epithelial-to-mesenchymal transition. They show that Twist1 represses the let-7i microRNA, leading to upregulation of the RAC1-activating factors NEDD9 and DOCK3, and inducing mesenchymal-mode motility and tumour invasion in vivo.
The SCF ubiquitin ligase subunit Fbxw7 is a tumour suppressor that is mutated in many cancers. Pagano and colleagues now show that in multiple myeloma, Fbxw7α instead functions as a pro-survival factor by activating the NF-κB pathway through the ubiquitin-mediated degradation of p100, an NF-κB pathway inhibitor.
Seamless tubes are found in Drosophila tracheal terminal cells, but it is still unclear how they grow. Ghabrial and colleagues find that the small GTPase Rab35, and its apically localized GAP, Whacked, direct tube shape and growth. They also highlight a role for dynein in this process.
Haematopoietic progenitor activity in the Drosophila lymph gland can respond to stress. Banerjee and colleagues show that systemic insulin and nutritional signals maintain these progenitors by modulating Wingless-dependent pathways.
Lrig1, a transmembrane glycoprotein, has previously been shown to inhibit ErbB signalling. Jensen and colleagues show that Lrig1 controls the size of the intestinal stem-cell niche by modulating the amplitude of ErbB signalling. Thus, ErbB activation acts in concert with Wnt, Notch and Bmpr inhibition, to modulate stem-cell proliferation in the crypt.
ER stress activates the unfolded protein response (UPR), which can ultimately result in apoptosis. Using a Drosophila model of ER stress, Ryoo and colleagues find that apoptosis is induced independently of the known UPR branches. They show that ER stress induces CDK5-mediated phosphorylation of MEKK1, which activates JNK and induces apoptosis.
Bullock and colleagues have reconstituted in vitro the microtubule-driven transport of RNAs to specific localizations in Drosophila melanogaster embryos. They show that a set of localized messenger nucleoproteins (mRNPs) exhibits a strong bias in motility towards microtubule minus ends, correlating with an increase in the binding of dynein components (when compared with non-localizing bidirectionally moving mRNPs). They also find that a single mRNA transcript can be found within motile mRNPs, both in vitro and in vivo.
Meiotic recombination involves the generation of double-strand breaks, that needs to be carefully controlled to avoid fetal aneuploidy. In worms and yeast, crossover numbers are constant regardless of the amount of double-strand breaks. Jasin and colleagues now show that such crossover homeostasis mechanisms exist at two stages in mammalian meiosis.
Entry into the cilium is restricted by a network of proteins at its base. Verhey and colleagues now show that nucleoporins, which localize to the nuclear envelope and regulate nuclear–cytoplasmic traffic, are also present at the cilium base, where they form a size-dependent exclusion barrier.
