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The mechanisms that control intracellular Wnt trafficking and secretion are beginning to be unravelled. However, little is known about how Wnt proteins are transported once they reach extracellular space. Boutros and colleagues show that active Wnt proteins are secreted on exosomes from Drosophila and human cells, and provide insight into the cellular machinery that regulates their transport and release.
Persistent ER stress in pancreatic β-cells contributes to the pathogenesis of type 2 diabetes. Fonseca and colleagues show that the ER membrane glycoprotein WFS1, which is mutated in people with Wolfram syndrome, has a known role in the ER stress response. It regulates insulin production and secretion in β-cells by associating with adenylyl cyclase 8 at the plasma membrane and generating cAMP. ER stress prevents WFS1 plasma membrane localization, attenuating cAMP production and insulin secretion.
Bennett and colleagues find that auxin modulates water uptake in Arabidopsis roots by negatively regulating the expression of water channel aquaporins to allow lateral root emergence. The functional importance of aquaporins is supported by a mathematical model that shows delayed lateral root emergence when aquaporin levels are perturbed, as well as by the effects observed after aquaporin overexpression or mutation.
Cai and colleagues show that the function of adult hypothalamic neural stem cells in mice is impaired following NF-κB activation associated with a chronic high-fat diet, resulting in development of obesity and neurodegenerative features. Mechanistically, NF-κB affects both Notch signalling and apoptosis in these cells.
In plants, the heterotrimeric G-protein α subunit is kept inactive by binding to the regulator of G protein signalling 1 (RGS1) protein. Jones and colleagues show that G-protein β and γ subunits recruit the WNK8 kinase to the plasma membrane, where WNK8 phosphorylates RGS1 and facilitates its internalization. This effect de-represses Gα signalling and is required for sugar signalling and cell proliferation.
Intraflagellar transport (IFT) particles are essential for the biogenesis and maintenance of cilia. They assemble at the cilium base and travel up and down the cilia, turning around at the tip, but the mechanisms that regulate these processes were not clear. Hu and colleagues reveal a role for the BBSome in IFT assembly and turnaround.
The CDKL5 kinase is mutated in several neurodevelopmental disorders. Broccoli and colleagues find that CDKL5 regulates dendritic spine formation by phosphorylating the adhesion molecule NGL-1, which acts on synaptic contacts. They also show that neurons (derived from induced pluripotent stem cells) from patients carrying the CDKL5 mutation have aberrant dendritic spines, similarly to rodents with impaired CDKL5 function.
Membrane deformation is necessary to generate endocytic vesicles, but the molecular mechanisms proposed to drive membrane bending are controversial. Stachowiak and Schmid et al. report that crowding of proteins at the membrane is sufficient to induce curvature in vitro.
Tanentzapf and colleagues use genetic mutations that alter tensile force at the Drosophila myotendinous junction to demonstrate that mechanical force controls in vivo turnover of integrin and intracellular adhesion complexes.
The last step in autophagy involves fusion of autophagosomes with lysosomes to generate autolysosomes. Through proteomics analysis and an RNAi screen, Yu and colleagues provide mechanistic insight into how lysosomes are regenerated from autolysosomes. Their analyses reveal a key role for clathrin and phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P2) in this process.
Marine and colleagues use mouse models to show that loss of Dicer or its downstream microRNA cluster miR-17–92 in retinal progenitors prevents retinoblastoma formation through a synthetic lethal interaction with Rb and p53 deficiency.
Brown and colleagues take a systems-level approach to the DNA damage response by analysing the changes in localization and abundance of proteins in response to replication stress, using a budding yeast GFP fusion library and high-throughput microscopy.
By performing a screen for genes that regulate epithelial architecture, Martín–Belmonte and colleagues identify key roles for the synaptotagmin-like proteins Slp2-a and Slp4-a in restricting lumen generation. They find that Slp2-a targets Rab27a/b-positive vesicles to PtdIns(4,5)P2-enriched apical membranes, whereas Slp4-a controls subsequent vesicle tethering and fusion. Their coordinated activities ensure the creation of a single lumen per cell.
Wang and colleagues have uncovered a direct functional relationship between the brassinosteroid-activated transcription factor BZR1 and the light- and heat-sensitive transcription factor PIF4. This interplay integrates hormonal and environmental signals to modulate cell elongation during plant growth.
Coffer and colleagues report that the transcription factor FOXO3 regulates the induction of autophagy. In response to PI(3)K–Akt signalling, FOXO3 directly induces expression of glutamine synthase, which upregulates glutamine levels and triggers autophagy.
Wang and colleagues show that, in Arabidopsis thaliana, brassinosteroid and light-dependent transcription factors are required for giberellin effects on hypocotyl elongation, by modulating transcription of giberellin-induced genes involved in cell wall synthesis and photosynthesis. Conversely, giberellin relieves the brassinosteroid component BZR1 from inhibition by DELLA proteins.
Microvilli are essential for the function of intestinal cells. Bos and colleagues have found that the polarity kinase LKB-1 induces PtdIns(4,5)P2 enrichment at the apical membrane. This leads to the successive accumulation of phosphatidic acid and the small GTPase Rap2A with its GEF and its effectors. These, in turn, trigger the changes in the actin cytoskeleton responsible for microvilli formation.
Shakhova, Sommer and colleagues use mouse models to demonstrate that the Sox10 transcription factor is crucial for the formation and maintenance of giant congenital naevi and melanoma. They show, in human melanoma cells, that Sox10 promotes neural crest stem cell properties, cell proliferation and cell survival.
It is unclear whether proliferating and differentiating cells produce energy through different metabolic pathways. Harris and colleagues show, in the embryonic Xenopus retina, that dividing progenitors use glycogen for glycolysis, and that a transition to oxidative phosphorylation occurs as cells differentiate.
Zhang, McNaughton and colleagues show that inflammatory stimuli promote a direct association between the heterotrimeric G-protein subunit Gαq and the temperature-sensitive ion channel TRPM8. This interaction inhibits TRPM8 channel activity, providing a mechanism by which inflammation produces aberrant sensations of temperature changes.
