News & Views in 2013

Signal integration is central to the regulation of patterning during plant development. During lateral root initiation, a signalling pathway controlled by the phloem-secreted TDIF peptide is found to activate the auxin signalling pathway independently of auxin, through phosphorylation of ARF transcription factors by GSK3 (Shaggy-like) kinases.

Macroautophagy is a key regulator of cellular integrity and viability, but how the process facilitates apoptosis has remained poorly defined. It has now become clear that autophagy degrades the Fap-1 protein phosphatase, a critical negative regulator of apoptotic cell death signalled by the TNF receptor family member, Fas.

Generation of differentiated kidney cell types from pluripotent stem cells would be enormously useful for research and therapeutic purposes, but progress towards this goal has so far been limited. In three recent reports, mature kidney cell types and three-dimensional nephron-like structures were generated from pluripotent cells rapidly and efficiently. A detailed understanding of the signals that drive nephrogenesis proved critical for these achievements.

Oxidation of actin methionine residues by the oxidation–reduction enzyme Mical is known to lead to actin filament depolymerization. SelR enzymes are now shown to reduce these oxidized actin methionines, revealing a regulated redox reaction mechanism through which cells control the assembly and disassembly of actin filaments.

Centrioles duplicate only once per cell cycle in proliferating cells, whereas in multiciliated cells, hundreds of centrioles form almost simultaneously. The molecular control mechanisms that govern centriole amplification in multiciliated cells are largely unknown. Two studies highlight Deup1 and CCDC78 as key players in this process.

Calcium enters mitochondria through a dedicated channel referred to as the mitochondrial calcium uniporter (MCU), whose molecular identity has long remained elusive. Since the discovery of the gene encoding the MCU protein two years ago, researchers have awaited the generation of a mouse lacking the MCU. These mice are fully viable and show defects limited to performance of high-energy-demanding exercises. Strikingly, no protection against necrosis is observed following ischaemia-reperfusion in the heart.

Error-free genome segregation depends on the spindle assembly checkpoint (SAC), a signalling network that delays anaphase onset until chromosomes have established proper spindle attachments. Three reports now quantitatively examine the sensitivity and robustness of the SAC response.

In vivo time-lapse imaging and functional tests bring fresh evidence that the morphogen Hedgehog is conveyed to target cells via long filopodia extensions, dubbed cytonemes. This study provides the tools and conceptual framework to understand how cytonemes form and carry morphogens.

The mTOR protein kinase controls anabolic processes as part of mTOR complexes 1 and 2 (mTORC1 and mTORC2). The two complexes are now shown to be involved in a negative feedback regulatory mechanism, in which mTORC1 stimulation inactivates mTORC2 through the inhibitory phosphorylation of the mTORC2 component Sin1.

The role of RNA splicing in the regulation of stem cell properties has remained largely unexplored. The splicing-associated protein SON is now shown to be necessary for embryonic stem cell maintenance, by influencing the splicing of pluripotency regulators.

mTOR is a central controller that integrates many inputs to regulate cell growth and ensure cellular homeostasis. The mTORC1 inhibitor TSC (tuberous sclerosis complex) on the peroxisome is found to inhibit mTORC1 in response to endogenous reactive oxygen species. Thus, mTOR may avoid confounding different inputs by sensing them at different cellular locations.

Cytoplasmic compartments containing misfolded proteins targeted for degradation, named Q-bodies, have been identified. Q-body formation is a dynamic process that actively manages the metastable state of the protein fold through small heat shock proteins and the Hsp70–Hsp90–Hsp110 proteostasis system to promote cellular fitness under both physiological and stress conditions.

During mitosis, kinetochores attach to microtubule plus ends, thus allowing dynamic microtubules to properly segregate chromosomes. How this type of 'end-on' attachment between microtubule plus ends and kinetochores is formed and maintained is unclear. CENP-E, a kinesin-7 family member, is now shown to have a role in associating kinetochores with dynamic microtubule plus ends.

Faithful genome segregation depends on the functions of the eukaryotic centromere, which is characterized by the histone variant CENP-A. Gene replacement in human cells and fission yeast has now been used to show how CENP-A biochemically encodes centromere identity, as well as reveal an unexpected role for CENP-B in centromere function.

The transcription factor p73, a close relative of p53, has complex yet poorly understood roles in tumorigenesis. TAp73, a p73 variant, has now been shown to promote cancer cell proliferation by regulating glucose metabolism to control cellular biosynthetic pathways and antioxidant capacity.

Common fragile sites (CFSs) are chromosomal regions that are prone to form breaks or gaps during mitosis, in particular following replication stress. The mechanisms modulating CFS expression and promoting safe chromatid transmission to daughter cells are not clear. Now CFS expression is shown to reflect the activity of the MUS81–EME1 resolvase complex which cooperates with the dissolving action of the BLM helicase to prevent uncontrolled chromosome breakage and to promote genome integrity.

Multiple activities cooperate to determine the architecture of the mitotic spindle. Kip3 is a kinesin-8 motor protein in budding yeast that acts as a microtubule depolymerase. Now Kip3 is shown to also crosslink and slide antiparallel microtubules, providing additional insights into how kinesin-8 motors control spindle integrity.

Senescence, a cell-autonomous tumour suppressor mechanism, also has pro-tumorigenic effects on neighbouring pre-malignant cells through the senescence-associated secretory phenotype (SASP). The SASP is now shown to be regulated by inflammasomes and to induce paracrine senescence in healthy cells, indicating that senescence may also represent a non-cell-autonomous tumour suppressor mechanism linked to innate immunity.

Fetal haematopoietic stem cells (HSCs) self-renew extensively to build the blood system from scratch. The protein Lin28b negatively regulates the microRNA let-7 to keep levels of its target Hmga2 high, hence conferring high self-renewal potential to fetal HSCs. This regulatory circuit can be experimentally modulated to boost the lower self-renewal activity of quiescent adult HSCs.

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.