Research articles

Until the recent discovery of the mitochondrial calcium uniporter (MCU), the effect of increases in mitochondrial calcium levels could not be tested in vivo. Finkel and colleagues have knocked out the gene coding for MCU in adult mice, and show that MCU is required for transport of calcium into the mitochondria. They also show that, in its absence, the function of skeletal muscle is altered; however, surprisingly, no effects are observed on the sensitivity to cell-death-inducing agents.

In an insertional mutagenesis screen, Sabatini and colleagues identify the small G protein ARF4 as a mediator of cell death in response to brefeldin A (BFA) treatment. BFA-induced Golgi stress upregulates ARF4, and loss of ARF protects against propagation of pathogens known to induce Golgi fragmentation.

Aguirre-Ghiso and colleagues report that the intensity of TGF-β2 signalling dictates dormancy or metastatic growth of disseminated tumour cells by regulating the activity of p38α/β in different target organs.

Schiebel and colleagues use in vitro techniques and yeast genetics to study the role of GTP binding in the microtubule nucleation activity of γ-tubulin.

Wei and colleagues report that phosphorylation of Sin1 by S6K or Akt results in its dissociation from mTORC2, thus suppressing mTORC2 activity. A cancer-patient-derived Sin1 mutation that impairs this phosphorylation leads to mTORC2 hyperactivation and increased tumour formation in mice.

During vertebrate embryogenesis, the pharyngeal arch arteries (PAA) connect segments of the primitive circulation. Burns and colleagues show that Nkx2.5⁺ heart precursors from the lateral plate mesoderm surprisingly give rise to the PAA angioblasts, and that Nkx2.5 is required for PAA development.

Hauf and colleagues modulate the amount of spindle assembly checkpoint (SAC) proteins in fission yeast, revealing that a small reduction can cause checkpoint errors. However, levels of critical proteins normally show little variation, which explains the robustness of the SAC.

Reactivation of fetal gene programs has been linked to hypertrophy of postnatal cardiomyocytes and heart disease, but so far the transcription factors responsible for this effect have not been well defined. De Windt and colleagues have found that the fetal cardiac transcription factor Hand2 is re-expressed in response to stress signalling and induces cardiac hypertrophy.

Devreotes and colleagues analyse cytoskeletal regulator and signal transduction networks and use computational simulations to provide a model for cell migration. They propose that activation of an excitable signalling network needs to engage an oscillatory cytoskeletal network to promote formation of large protrusions and cell motility.

The microcephaly protein ASPM is required for correct spindle positioning in neuroepithelial cells. Basto and colleagues demonstrate that, in addition to having a role in cell division, the fly ASPM orthologue Asp is important for the maintenance of neuroepithelium integrity by mediating myosin II apico-basal polarity.

Hedgehog (Hh) acts as a morphogen to regulate growth and cell fate specification, and several hypotheses have been proposed for its movement. Using in vivo imaging, Bischoff and colleagues find that cytonemes drive Hh movement in the wing imaginal disc epithelium and that Hh gradient establishment correlates spatially and temporally with cytoneme formation.

The spindle assembly checkpoint (SAC) keeps the APC/C ubiquitin ligase inactive until all chromosomes are attached to the spindle. Pines and colleagues tagged endogenous cyclin A with a fluorescent protein by gene targeting and used cyclin A degradation as an assay for SAC activity. They found that the SAC does not show an all-or-nothing response—instead, SAC strength depends on the amount of MAD2 (a checkpoint protein) at kinetochores.

The spindle assembly checkpoint (SAC) arrests cells in metaphase until all chromosomes are attached to the spindle. Dick and Gerlich used laser microsurgery to detach individual chromosomes, revealing that the SAC does not have a switch-like response — instead, SAC strength depends on the number of unattached chromosomes.

Adult differentiated cells can be reprogrammed to lineage-restricted proliferating neural precursors in vitro. Zhang and colleagues show that the transcription factor SOX2 is sufficient to reprogram resident astrocytes in the mouse brain to neuroblasts that can proliferate and differentiate following treatment with histone deacetylase inhibitors and differentiating factors BDNF and noggin.

The RAS-like GTPase RALB mediates cellular responses to nutrient availability or viral infection by engaging two distinct exocyst complex proteins: EXO84 to modulate autophagy and SEC5 to regulate innate immune signalling. Sablina and colleagues find that whereas ubiquitylation of RALB at K47 promotes its interaction with SEC5, the de-ubiquitylase USP33 switches RALB to the EXO84–beclin complex to promote autophagy during nutrient starvation.

ER–Golgi transport and autophagy are tightly connected. Liang and colleagues find that UVRAG binds to PtdIns(3)P to localize it to the ER, from where, under normal conditions, it regulates the transport of COPI cargo transfer to the ER and Golgi integrity, but from where, following autophagy induction, it dissociates to modulate ATG9 transfer to autophagosomes.

Quality control of misfolded proteins is thought to involve proteasome-dependent degradation or, if this fails, sequestration into inclusion bodies. Frydman and colleagues reveal the existence of endoplasmic-reticulum-associated structures, termed Q-bodies, that concentrate misfolded proteins in a chaperone-dependent manner before degradation.

How injured mitochondria are targeted for autophagic degradation is not well understood. Chu and colleagues find that pro-mitophagy stimuli induce externalization of cardiolipin to the outer mitochondrial membrane of neuronal cells, and find that this is required for binding of the autophagy protein LC3 to mitochondria and mitophagy.

Ng and colleagues show that the spliceosome-associated factor SON is essential for the maintenance of pluripotency and the survival of human embryonic stem cells. Using genome-wide RNA profiling to identify SON-regulated transcripts, they find that it modulates splicing of transcripts of pluripotency regulators such as OCT4, PRDM14, E4F1 and MED24.

Actin is abundant in the nuclei of oocytes but its role has been unclear. Feric and Brangwynne find that actin forms a network that prevents the sedimentation of RNA and protein bodies caused by gravitational forces.