News & Comment

Yaffe and colleagues discuss the issues surrounding the authentication and quality of induced pluripotent stem cells.

The laboratory mouse is widely considered the model organism of choice for studying the diseases of humans, with whom they share 99% of their genes. A distinguished history of mouse genetic experimentation has been further advanced by the development of powerful new tools to manipulate the mouse genome. The recent launch of several international initiatives to analyse the function of all mouse genes through mutagenesis, molecular analysis and phenotyping underscores the utility of the mouse for translating the information stored in the human genome into increasingly accurate models of human disease.

Scientists are seeking permission to generate human embryonic stem cells to study disease by introducing human genetic material into an animal oocyte. This has raised ethical questions that centre on whether the entities being generated are actually human. The answer to these questions will determine how this area of research will be regulated and whether such work will be legal. The function of the extra-nuclear mitochondrial genome lies at the heart of these issues and forms the focus of this commentary.

The irreversibility of cell-cycle transitions is commonly thought to derive from the irreversible degradation of certain regulatory proteins. We argue that irreversible transitions in the cell cycle (or in any other molecular control system) cannot be attributed to a single molecule or reaction, but that they derive from feedback signals in reaction networks. This systems-level view of irreversibility is supported by many experimental observations.

The nucleosome surface is decorated with an array of enzyme-catalysed modifications on histone tails. These modifications have well-defined roles in a variety of ongoing chromatin functions, often by acting as receptors for non-histone proteins, but their longer-term effects are less clear. Here, an attempt is made to define how histone modifications operate as part of a predictive and heritable epigenetic code that specifies patterns of gene expression through differentiation and development.

Regions of metazoan genomes replicate at defined times within S phase. This observation suggests that replication origins fire with a defined timing pattern that remains the same from cycle to cycle. However, an alterative model based on the stochastic firing of origins may also explain replication timing. This model assumes varying origin efficiency instead of a strict origin-timing programme. Here, we discuss the evidence for both models.

Generating and maintaining features that distinguish one organelle from another is essential for accurate membrane traffic. Recent work has revealed that organelles express 'identity' by the local generation of activated GTP-binding proteins and lipid species. These recruiting determinants are then recognized by cytosolic proteins that facilitate the formation and delivery of vesicles at the correct compartment.

It is widely observed that eukaryotic cells can polarize spontaneously in the absence of pre-established asymmetric cues. This phenomenon indicates that the principle of self-organization may be central to the establishment of cell polarity. Modelling work, as well as recent experimental data from several organisms, suggests that a combination of local positive feedback loops and global inhibitors could result in robust cell symmetry breaking through amplification of minute, stochastic variations.

The application of modern fluorescence microscopic methods to bacteria has revolutionized our view of their subcellular organization. Many proteins are now known to be targeted with exquisite precision to specific locations in the cell, or to undergo rapid directed changes in localization. Structural and functional homologues of tubulin (FtsZ) and actin (MreB) are now indisputably present in bacteria, overturning the textbook view that the cytoskeleton is unique to eukaryotes. These advances are stimulating a radical rethink about how various fundamental processes are organised in bacteria.

After exocytosis, synaptic vesicles are reformed by slow clathrin-mediated endocytosis. However, evidence also supports the existence of faster retreival mechanisms in neurons, including 'kiss-and-run', where vesicles fuse only partially with the presynaptic membrane before being retrieved. New insights in synaptic vesicle dynamics have been obtained from vesicle imaging and from studies with mutant animals. Recently, measurements of capacitance changes induced by the fusion of single synaptic vesicles in synapses corroborate the hypothesis that kiss-and-run operates in neurons. Here, we review the evidence supporting fast vesicle retrieval and evaluate its role in neurotransmitter release.

Phagocytes have long been known to engulf and degrade apoptotic cells. Recent studies in mammals and the nematode Caenorhabditis elegans have shed some light on the conserved molecular mechanisms involved in this process. A series of results now challenge the traditional view of phagocytes as simply scavengers, 'cleaning up' after apoptosis to prevent inflammatory responses, and hence tissue damage. Instead, they suggest that phagocytes are active in the induction and/or execution of apoptosis in target cells.

There are many quality-control mechanisms that ensure high fidelity of gene expression. One of these is the nonsense-mediated decay (NMD) pathway, which destroys aberrant mRNAs that contain premature termination codons generated as a result of biosynthetic errors or random and programmed gene mutations. Two complexes that initially bind to RNA in the nucleus have been suggested to be involved in NMD in the cytoplasm. Here we propose an alternative model that involves nuclear scanning, on the basis of recent evidence for nuclear translation.

The proteasome is a hollow cylindrical protease that contains active sites concealed within its central cavity. Proteasomes usually completely degrade substrates into small peptides, but in a few cases, degradation can yield biologically active protein fragments. Examples of this are the transcription factors NF-κB, Spt23p and Mga2p, which are generated from precursors by proteasomal processing. How distinct protein domains are spared from degradation remains a matter of debate. Here, we discuss several models and suggest a novel mechanism for proteasomal processing.

Multicellular organisms must coordinate signals from adhesion receptors with those from other signalling receptors (for example, growth factor receptors). Here, we briefly review paradigms of integrin–adhesion-receptor signalling. We discuss how adhesive signalling is coordinately regulated through intersecting networks. We also examine some examples of how some forms of integrin crosstalk may lead to unforeseen and potentially deleterious responses.

Cell signalling is essential for a plethora of inductive interactions during organogenesis. Surprisingly, only a few different classes of signalling molecules mediate many inductive interactions, and these molecules are used reiteratively during development. This raises the question of how generic signals can trigger tissue-specific responses. Recent studies in Drosophila melanogaster indicate that signalling molecules cooperate with selector genes to specify particular body parts and organ types. Selector and signalling inputs are integrated at the level of cis-regulatory elements, where direct binding of both selector proteins and signal transducers is required to activate tissue-specific enhancer elements of target genes. Such enhancers include autoregulatory enhancers of the selector genes themselves, which drive the refinement of expression patterns of selector genes.