Cellscience最新文献

The central nervous system (CNS) consists of trillions of interconnected neurons. The specialised regions of intercellular contact between neurons where information, usually in chemical form, is transmitted are called synapses. The last decade has seen an unprecedented advance in our understanding of the molecular nature, formation and maintenance of synapses. A major question that remains is how synaptic identity is established to ensure the coordinated recruitment of the correct synaptic components on both sides of the synapse so that the neurotransmitter accumulating on the presynaptic side is matched with its cognate receptor on the postsynaptic membrane. Until recently, Fibroblast Growth Factors (FGFs) have been thought of as general regulators of synaptic aptitude through their ability to increase the expression of synaptic proteins or promote neurite branching. A recent study shows that the decision to form an excitatory vs. inhibitory synapse may to a large extent be determined by the identity of the FGF ligand present at the postsynaptic membrane. This observation establishes FGFs as key target-derived cues that are involved in determining synaptic identity.

Epigenetics has been proposed as a molecular mechanism involved in encoding long-term memories. Specifically DNA methylation, an epigenetic mechanism thought to be static following cell differentiation, has been implicated as a dynamic transcription regulatory mechanism underlying the process of longterm memory storage. Now recent findings published in Nature Neuroscience explore the possibility that stable DNA methylation changes within the cortex contributes to memory maintenance.

Influenza virus remains an important human pathogen causing recurring 'flu', largely due to its ability to constantly modify the antigenicity of its major glycoprotein, hemagglutinin (HA), in processes named 'antigenic shift' and 'antigenic drift'. A better understanding of the driving force for antigenic drift is critical for enhancing the effectiveness of annual flu vaccine, which is the primary tool for combating seasonal influenza. With solid experimental data, a recent study published on Science proposed a new antigenic drift model in which receptor binding avidity plays a critical role in influenza antigenic drift. This commentary discusses the new study in the context of historic influenza research and poses a few key questions on antigenic drift that need to be addressed in future research.

The cystic fibrosis transmembrane conductance regulator (CFTR) anion channel represents the rate-limiting step for chloride and fluid secretion in most epithelial tissues in the body. More recently, CFTR activity has also been shown to regulate muscle contraction, neuroendocrine function, and cartilage formation, implicating the channel in many important physiological activities from diverse systems. A major interest in the channel stems from the fact that loss of function mutations in the gene encoding CFTR result in the inherited disease cystic fibrosis, one of the most common, life threatening, diseases found in the Caucasian population. At the other end of the spectrum, and affecting far more people globally, over active CFTR causes clinically important secretory diarrhoea induced by toxins from pathogenic bacteria like cholera. Therefore, it is not surprising that much research has focussed on understanding how CFTR channel activity is regulated and what goes wrong in disease states. For the channel to open, it must be first phosphorylated by PKA, and then ATP must also bind to CFTR's cytoplasmic domains. Now a recent Nature Cell Biology paper has shown that CFTR can also be activated by increases in membrane tension (or stretch), through a phosphorylation and ATP- independent mechanism. This unexpected and novel finding identifies CFTR as a mechanosensitive ion channel. This work could have major implications for our understanding of the biological control of CFTR as well identifying new roles for this channel in mechanosensitive tissues and processes such as regulatory volume decrease and muscle contraction.

There is growing interest in the neural basis of human moral cognition, in hopes that neuroscience can help to explain the general process of moral judgment. The role of emotion and cognition in moral judgment has yet to be determined. The study of psychopathic traits may be able to give us some insight into this because of their deficits in emotional responding. Our recent publication in Molecular Psychiatry addresses this issue by examining how brain functioning during moral decision-making varies as a function of psychopathic traits.

A recent study suggested that a rise of cholecystokinin (CCK8) in the duodenum may bring about an inhibition of hepatic glucose production. The authors made use of the pancreatic clamp technique to characterize a gut-brain-liver signal generated by CCK8 that reduces glucose output by the liver. The pancreatic clamp conditions used created a situation in which the liver was markedly deficient in both insulin and glucagon. Although the data presented indicated that CCK8 can reduce glucose production, the authors do not establish a role for this inhibition in the reduction of glucose output seen in response to feeding. It must be remembered that in response to a meal the insulin level in the hepatic sinusoids rises markedly, as does the insulin level to which the brain is exposed. It therefore seems likely that either or both of these effects will drive the suppression of glucose production rather than any effect of CCK8. The importance of the CCK8 effect needs to be determined in the presence of elevated arterial and sinusoidal insulin before any conclusion can be drawn about its relevance.

Nearly half of our genomes are repetitive sequences derived from retrotransposons. These repeats have accumulated by a 'copy-and-paste' mechanism whereby: (i.) a genomic template sequence is transcribed to RNA, (ii.) the RNA is reverse-transcribed, and (iii.) the DNA copy is inserted at a new location in the host genome. As we remain susceptible to new retrotransposition events, many of these insertions are highly polymorphic. Transposons are of interest since insertions into both coding and non-coding gene regions have been associated with a wide variety of functional sequelae and because transposable elements can be involved in genomic rearrangements in transformed cells. In this review, we highlight how expression of retrotransposons, de novo and polymorphic transposon insertions, and genomic rearrangements that these repeats potentiate contribute to both benign and neoplastic hematopoietic diseases.

The CCN family of matricellular proteins is essential for cell communication and mediation of epithelial stromal cross-talks with roles in development and cancer. In particular, loss of CCN6 messenger RNA expression has been recognized in highly aggressive breast cancers, especially in inflammatory breast cancer and breast cancers with axillary lymph node metastasis. Recent findings can better explain the relevance of CCN6's reduced expression on human invasive breast carcinomas. CCN6 has been shown to play a role in the process of epithelial to mesenchymal transition (EMT), which converts epithelial cells into migratory mesenchymal-like cells with invasive abilities. Although the mechanism by which CCN6 promotes EMT and invasion has not been fully elucidated, current data suggest that it involves the recruitment of the transcriptional regulators Snai1 and ZEB1 to the E-cadherin promoter.

Because ionotropic glutamate receptors play critical roles in numerous CNS functions, there has been considerable interest in understanding molecular mechanisms regulating their properties. In particular, the search for ligands and corresponding binding sites providing allosteric regulation of agonist binding and channel opening and closing has been intensely pursued in the hope of developing new approaches for the treatment of a variety of CNS diseases associated with abnormal functioning of glutamatergic systems. Several recent publications have reported detailed structures of the N-terminal domains of NMDA and AMPA receptors and have generated interesting predictions regarding the possibility of finding new ways to control glutamate receptor function. Together with the recently reported control of the receptors by transmembrane proteins, there is now a whole set of potential regulators of these important families of receptors.

Histone deacetylases (HDACs) have previously been shown to be critical for the formation of long-term memories. Recent findings now show that a specific HDAC isoform, HDAC2, negatively regulates formation of hippocampus-dependent memory. These recent findings published in Nature highlight potential new therapeutic interventions for the treatment of memory impairments associated with human neurological disorders.