Commentary in 2002

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.

It has long-been accepted that normal somatic cells have intrinsic mechanisms that limit their proliferative lifespan. Recent work has now challenged this view by demonstrating that extrinsic factors might be determining proliferative potential.

The vascular endothelium is a dynamic tissue with many active functions. Until recently, endothelial cell (EC) biology studies have used cultured ECs from various organs; these cell lines are considered representative of the blood vascular endothelium. Very few lymphatic EC lines have been available, and these were derived from lymphatic tumours or large collecting lymphatic ducts. In the past, lymphatic vessels were defined largely by the lack of erythrocytes in their lumen, a lack of junctional complexes and the lack of a well-defined basement membrane. Now that lymphatic-specific vascular endothelial growth factors (VEGF-C and VEGF-D) and molecular cell surface markers such as the VEGFR-3 receptor have been identified, this definition needs to be updated. Recent developments have highlighted the importance of lymphatic ECs, and they could become the next focus for angiogenesis and metastasis research.