Review Articles in 2014

The subcellular localization of mRNAs enables the spatial regulation of protein translation and generates functional and structural asymmetries in cells. New imaging (and other) techniques for tracking single-mRNA dynamics have unravelled mechanisms of mRNA movements and localization patterns in various cell types.

Post-translational modification of proteins by NEDD8 has been mainly characterized in terms of the cullin–RING E3 ligase family. However, recent studies have indicated that there might be non-cullin neddylation targets that require further verification.

Intrinsically disordered proteins (IDPs) are key components of the cellular signalling machinery. Their flexible conformation enables them to interact with different partners and to participate in the assembly of signalling complexes and membrane-less organelles; this leads to different cellular outcomes. Post-translational modification of IDPs and alternative splicing add complexity to regulatory networks.

Lys and Arg methylation on non-histone proteins regulates various signalling pathways, and its crosstalk with other post-translational modifications and with histone methylation affects cellular processes such as transcription and DNA damage repair. Advances in proteomics now allow us to decode the methylproteome and elucidate its functions.

New insights into how iron–sulphur (Fe–S) clusters are incorporated into proteins, particularly the discovery of a role for Leu-Tyr-Arg motifs in Fe–S recipient proteins, are shedding light on the fundamental roles of Fe–S proteins in mammalian cells.

The extracellular matrix (ECM) regulates many cellular functions, and its remodelling by enzymes such as metalloproteinases has a crucial role during development, as exemplified by intestinal, lung, mammary gland and submandibular gland morphogenesis. ECM structure and composition are important therapeutic targets, as their dysregulation contributes to conditions such as fibrosis and invasive cancer.

The molecules that are associated with the extracellular matrix (ECM) in different tissues, including collagens, proteoglycans, laminins and fibronectin, and the manner in which they are assembled, determine the structure and the organization of the ECM. The resultant biochemical and biophysical properties of the ECM dictate its tissue-specific functions.

The physical properties of the extracellular environment — in terms of confinement, rigidity, surface topology and adhesion-ligand density — can have profound effects on the migration strategy and migration velocity of cells in differentin vivocontexts.

Somite formation relies on a molecular oscillator, the segmentation clock, which leads to oscillatory gene expression in the presomitic mesoderm; this is converted into the periodic generation of segments in response to signalling gradients referred to as the wavefront. Recent studies provide insights into the molecular mechanisms behind this intricate developmental system.

In soft connective tissues at the steady state, cells continually read environmental cues and respond to promote mechanical homeostasis of the extracellular matrix and ensure cellular and tissue health. Progress has been made into our understanding of the molecular, cellular and tissue scale responses to mechanical load that promote mechanical homeostasis.

It is unclear how totipotent embryonic cells acquire their fate and what role chromatin dynamics have in this process. Technological advances in studying single cells have begun to improve our understanding of the mechanisms underlying lineage allocation and cell plasticity in early mammalian development.

The mechanisms underlying spindle checkpoint signalling at the kinetochore, which ensures faithful chromosome segregation during cell division, are being unravelled. They indicate that the checkpoint response is graded rather than switch-like (completely on or off) as traditionally thought, and provide insights for the treatment of cancers in which the checkpoint is bypassed.

Recent advances in three-dimensional (3D) culture techniques have increased our understanding of the cellular mechanisms that drive epithelial tissue development, the genetic regulation of cell behaviours in epithelial tissues and the role of microenvironmental factors in normal development and disease. 3D culture can be used to build complex organs and to advance therapeutic approaches.

Mitochondria contain a genome that is inherited maternally; this complicates their segregation during cell division, oogenesis and development. Mechanisms that ensure mitochondrial integrity include fusion and fission processes, organelle transport, mitophagy and genetic selection. Defects in these processes can lead to cell and tissue pathologies.

The actin capping activity of capping protein (CP) is indirectly regulated by competing with other factors for filament binding, or directly by factors that bind CP and sterically inhibit its interactions with filaments. Other proteins interact with CP through their 'capping protein interaction' (CPI) motif and modulate its activity via allosteric effects.

Recent studies suggest that mechanisms ofde novo lumen formation in different systems — such as the zebrafish vasculature, C. elegans excretory cells, the D. melanogastertrachea and three-dimensional cultures of endothelial and MDCK cells — share some common features. They all involve expansion of the apical plasma membrane, vesicle transport and regulation of the microtubule and actin cytoskeletons.

RNAi is used for genome-wide functional screens in cultured cells and animals. New experimental and bioinformatics approaches, including the combination of RNAi with genome-editing strategies, has improved the efficacy of RNAi screening and follow-up experiments, and enhanced our understanding of gene function and regulatory networks.

Structural maintenance of chromosomes (SMC) complexes — cohesin, condensin and the SMC5/6 complex — regulate sister chromatid cohesion, chromosome condensation, and DNA replication, repair and transcription. Insights into how they may execute such a range of functions are emerging from analyses of their chromosomal binding, combined with their capacity to act as intermolecular and intramolecular linkers of DNA molecules.

Lamellipodial protrusion is powered by actin polymerization that is mediated through the actin-related protein 2/3 (ARP2/3)-induced nucleation of branched actin networks and the elongation of actin filaments. These processes are regulated by positive and negative feedback loops centred around the GTPase RAC, and the balance between them determines lamellipodial and directional persistence during cell migration.

Bidirectional movement by oppositely directed motors attached to the same cargo is frequently described as a 'tug of war'. However, some studies suggest that inhibiting one motor diminishes motility in both directions. To resolve this paradox, three bidirectional transport models, termed microtubule tethering, mechanical activation and steric disinhibition, are proposed, and a general mathematical modelling framework for bidirectional cargo transport is described.