Picket and other fences in biological membranes

Nakada et al. revisit the controversial question of whether membrane lipids are able to diffuse from the axon of a neuron into the soma. Using single molecule imaging of a fluorescent phospholipid, the authors show that a diffusion barrier in the axon initial segment blocks the diffusion of lipids.     

Axonal spectrins: All-purpose fences

A membrane barrier important for assembly of the nodes of Ranvier is found at the paranodal junction. This junction is comprised of axonal and glial adhesion molecules linked to the axonal actin–spectrin membrane cytoskeleton through specific adaptors. In this issue, Zhang et al. (2013. J. Cell Biol. http://dx.doi.org/10.1083/jcb.201308116) show that axonal βII spectrin maintains the diffusion barrier at the paranodal junction. Thus, βII spectrin serves to compartmentalize the membrane of myelinated axons at specific locations that are determined either intrinsically (i.e., at the axonal initial segment), or by axoglial contacts (i.e., at the paranodal junction).Cell polarization is an essential feature that allows many cell types to fulfill their unique functions. Upon differentiation, polarized cells establish specialized membrane domains with distinct protein composition. In myelinated axons, such membrane compartmentalization is essential for fast and efficient propagation of action potentials in a saltatory manner. The membrane of these axons is divided into several distinct domains that include (1) the nodes of Ranvier, which are gaps between myelin segments where sodium channels are clustered; (2) the paranodal axoglial junction, where the terminal loops of the myelin attach to the axon; (3) the juxtaparanodal region, where Kv1 potassium channels are concentrated; and (4) the internode, which are covered by compact myelin (Fig. 1). In the peripheral nervous system (PNS), this intricate axonal organization requires specific intercellular contact sites between the axon and myelinating Schwann cells (Poliak and Peles, 2003; Eshed-Eisenbach and Peles, 2013), as well as the formation of membrane diffusion barriers that restrict the movement of proteins and lipids in the plasma membrane across different domains (Lasiecka et al., 2009; Katsuki et al., 2011).Open in a separate windowFigure 1.βII spectrin helps organize membrane domains in myelinated axons. A schematic view depicting the organization of myelinated peripheral nerves around the nodes of Ranvier of wild type (WT, top), and mice mutants lacking axonal βII spectrin (middle) or the adhesion molecule Caspr (bottom). The presence of intact paranodal junction (PNJ) is marked by green vertical lines between the paranodal loops (PNL) and the axon. In wild-type nerves (top), both the paranodal junction and the cytoskeletal barrier are intact, resulting in the sequestering of Kv1 channels (blue) in the juxtaparanodal region (JXP) away from nodal sodium channels (red). In contrast to the paranodes in Caspr knockout that lack both the junction and the barrier function (bottom), in the βII spectrin mutant (middle) the barrier is compromised while the junction is intact. Note that the nodes in both mutants are wider compared to the wild type.The main membrane barrier that plays an important role in the assembly of the nodes of Ranvier is present at the paranodal junction (Feinberg et al., 2010; Susuki et al., 2013). These septate-like junctions are composed of axonal (Caspr and contactin) and glial (neurofascin 155-kD isoform) adhesion molecules, and are linked through specific adaptor proteins to the actin–spectrin membrane cytoskeleton (Ogawa et al., 2006; Perkins et al., 2008; Nans et al., 2011). Cytoskeletal components of the paranodal junction include the scaffold protein 4.1B, which is required for the organization of myelinated axons (Horresh et al., 2010; Buttermore et al., 2011; Cifuentes-Diaz et al., 2011; Einheber et al., 2013), as well as ankyrin B and αII and βII spectrin (Ogawa et al., 2006). A paranodal membrane barrier has long been described as the boundary separating nodal and juxtaparanodal ion channels. The barrier function has been attributed to the axoglial contact and formation of the septate-like junctions (Bhat et al., 2001; Boyle et al., 2001). Nonetheless, the molecular mechanism forming the barrier itself has never been resolved. In general, membrane barriers can form by several mechanisms (Lasiecka et al., 2009). For example, a barrier at the axonal initial segment (AIS), which maintains axo-dendritic polarity, is formed by anchoring various transmembrane proteins to the actin-based membrane skeleton (Nakada et al., 2003; Galiano et al., 2012). In the base of the cilium, yeast bud and dendritic spines septins, proteins that are absent from AIS and tight junctions (Caudron and Barral, 2009), form high order ring-like structure that immobilize lipids in the inner membrane leaflet. In erythrocytes, direct binding of spectrin to membrane lipids forms a diffusion barrier for both proteins and lipids in the absence of actin (Sheetz et al., 2006). Interestingly, at the epithelial tight junction, the diffusion barriers for lipids and proteins are probably achieved by separate mechanisms, as targeting some junctional components results in loss of lipid but not of protein polarity (Jou et al., 1998).In the current issue, Zhang et al. succeeded to uncouple the assembly of the paranodal membrane domain from its barrier function. This was accomplished by specifically ablating βII spectrin in peripheral sensory neurons and analyzing the axonal organization of these nerves. The unique domain organization of myelinated axons allows for a simple and highly reproducible examination of the barrier function at the paranode. That is, impairment of the barrier will result in the displacement of juxtaparanodal components (i.e., Caspr2, Kv1.2, and TAG-1) into the paranodes and nodes, as observed in mutants that lack an intact paranodal junction (Bhat et al., 2001; Boyle et al., 2001). In the affected nerves of the βII spectrin mutant, the authors made the surprising observation that although the axoglial paranodal junction remained completely intact, juxtaparanodal complexes were no longer excluded from paranodes and nodes (Fig. 1). Developmental analysis of the mutant revealed a dramatic increase in the number of paranodes and nodes containing juxtaparanodal components with age, an observation suggesting that a βII spectrin–based diffusion barrier mainly contributes to the maintenance of a paranodal membrane barrier. Interestingly, these results are in line with a previous study showing that the linkage between Caspr and the adaptor protein 4.1B is crucial for the paranodal barrier (Horresh et al., 2010). Zhang et al. (2013) also observed that the absence of βII spectrin results in a significant widening of the nodes of Ranvier (Fig. 1), further supporting a role for the paranodal junction barrier in the maintenance of nodal sodium channels (Rios et al., 2003). The assembly of the nodes of Ranvier in the PNS is achieved by initial clustering of Na⁺ channels at heminodes, a process that requires binding of glial gliomedin and NrCAM to their axonal receptor Neurofascin 186, as well as by restricting the distribution of these channels to the nodal gap by the paranodal junction barrier (Feinberg et al., 2010). To examine whether the βII spectrin–based membrane barrier at the paranodal junction also participates in node formation would require additional analysis of mice lacking both βII spectrin and the glial clustering signal (i.e., gliomedin or NrCAM). Surprisingly, despite the abnormal presence of Kv1 channels at the paranodes and nodes, and in contrast to all known mutants lacking the paranodal junction, βII mutant mice exhibit normal nerve conduction. These results may indicate that the paranodal junctions that provide an intercellular sealing, similarly to epithelial tight junctions, are critical for proper nerve conduction. In contrast, an intact paranodal membrane barrier is not necessary for normal conduction.The similarity between mice lacking βII spectrin in sensory neurons and paranodal mutants lacking Caspr, NF155, and contactin uncovers a hierarchy in axonal domain organization: adhesion molecules that form the axon–glial junction independently of cytoskeletal interactions induce the formation of a βII spectrin–based membrane barrier, which in turn is responsible for maintaining axonal domain organization. Furthermore, the exact location of a barrier on the membrane can be determined by cell-intrinsic or -extrinsic factors (Katsuki et al., 2011). AISs are formed by intrinsic factors, whereas the paranodal junction is determined by axon–glia interactions. Strikingly, a previous paper from Rasband and colleagues has shown that an axonal barrier controlling the formation of the AIS is composed of the same cytoskeletal proteins as the paranodal barrier, namely ankB, βII spetrin, and αII spectrin (Galiano et al., 2012). Thus, the same membrane barrier can be localized by either external or internal cues and participate in either the formation (AIS and nodes of Ranvier) or maintenance (nodes of Ranvier and juxtaparanodal region) of axonal domains.     

Vision: the world through picket fences

Our visual system must allow us to see the form of objects in motion. Tracking objects of interest stabilises their images on the retina, but is not sufficient, as untracked images move on the retina. This problem is solved by cells tuned in both space and time, combining information about form with information about motion.     

植物园与植物园学

随着全世界植物园数量的增加、功能和转变和我学科的综合,需要发展植物园学,以引导植物园的发展。植物园学主要包括10个方面的内容：1）植物园的性质、任务和功能;2）历史;3）规划设计;4）物种保护,尤其是迁地保护;5）活植物收集圃及其管理;6）引种驯化的理论与实践和新经济植物的发掘;7）植物展出的技术与方法;8）城市生物多样性保护和利用;9）环境教育和旅游;10）维护和管理。生物多样性是植物园的核心。美丽的外貌、科学的内涵和人与自然和谐共外的准则是植物园的基本要素。     

Training cattle to control by electric fences

Since cattle learn respect for electric fences, it may be possible to use single electric wires as permanent fences on beef-cattle properties. Two experiments are reported in this paper. The first investigated a method of training inexperienced cattle in a small yard before release to paddocks fenced with a single wire. The training yard consisted of a strong conventional fence with a single electric wire attached. It confined animals in a small area, thus encouraging them to investigate, receive shock and learn respect. After a day of such training, the animals were automatically photographed at each approach to a single wire in a test paddock and compared with an untrained group in a similar test paddock. Although no animals broke through in either group, it is clear that trained animals more quickly recognized the wire and showed respect by not touching it.The second experiment demonstrated the great respect cattle had for a single electrified wire after training, because it prevented hungry heifers from going to eat hay which they had been conditioned to eat.It is concluded that training is simple and provides a controlled learning period to give increased respect for electrified wires and to minimize the risk of animals breaking through when first released to paddocks with electrified boundaries.     

Patches, posts and fences: proteins and plasma membrane domains

Recent findings have indicated the presence of micrometre-scale protein-based domains in the membranes of several cell types. What are the implications of this organization for membrane function? Here, Michael Edidin describes the formation of protein-based domains, and discusses their possible effects on protein interactions within the bilayer.     

On the role of hypotheses in science

Scientific research progresses by the dialectic dialogue between hypothesis building and the experimental testing of these hypotheses. Microbiologists as biologists in general can rely on an increasing set of sophisticated experimental methods for hypothesis testing such that many scientists maintain that progress in biology essentially comes with new experimental tools. While this is certainly true, the importance of hypothesis building in science should not be neglected. Some scientists rely on intuition for hypothesis building. However, there is also a large body of philosophical thinking on hypothesis building whose knowledge may be of use to young scientists. The present essay presents a primer into philosophical thoughts on hypothesis building and illustrates it with two hypotheses that played a major role in the history of science (the parallel axiom and the fifth element hypothesis). It continues with philosophical concepts on hypotheses as a calculus that fits observations (Copernicus), the need for plausibility (Descartes and Gilbert) and for explicatory power imposing a strong selection on theories (Darwin, James and Dewey). Galilei introduced and James and Poincaré later justified the reductionist principle in hypothesis building. Waddington stressed the feed-forward aspect of fruitful hypothesis building, while Poincaré called for a dialogue between experiment and hypothesis and distinguished false, true, fruitful and dangerous hypotheses. Theoretical biology plays a much lesser role than theoretical physics because physical thinking strives for unification principle across the universe while biology is confronted with a breathtaking diversity of life forms and its historical development on a single planet. Knowledge of the philosophical foundations on hypothesis building in science might stimulate more hypothesis-driven experimentation that simple observation-oriented “fishing expeditions” in biological research.     

Animal behaviour at electric fences and the implications for management

Electric fences are cheaper than conventional fences and, because of this, they are being used increasingly to manage mammals. Initial investigatory behaviour at the fence, defensive reactions immediately after shock, and long-term modifications in behaviour as a result of learning, have been reviewed. This paper (i) suggests that designs of electric fences should take account of animal behaviour and (ii) reviews management solutions.     

Guanaco (Lama guanicoe) mortality by entanglement in wire fences

Wire fences are widely used in rangelands around the world and may have a negative impact on wildlife that varies among species and habitats. The guanaco (Lama guanicoe) is the largest Patagonian ungulate and though entanglement in wire fences is frequently reported, its impact on guanaco populations has not been previously evaluated. We estimated annual mortality rate of wild guanacos due to entanglement in wire fences and evaluated whether the frequency of entanglement was age-dependent in the two wire-fence designs traditionally used in Patagonian sheep ranches. We found that annual yearling mortality on fences (5.53%) was higher than adult mortality (0.84%) and was more frequent in ovine (93 cm high) than bovine (113 cm) fences. Most guanacos died entangled by their legs in the highest wire when trying to jump over the fence. Our results suggest that guanacos are more likely to die due to fence entanglement than ungulates studied in other regions. Indirect effects of wire fences should also be considered as they may act as semi-permeable barriers for guanaco populations. We suggest removal of unnecessary wire fences and replacement by guanaco-friendly fences, like high-tensile electric fences that may reduce mortality and barrier-effect on guanaco populations.     

Good fences make good neighbors: barrier elements and genomic regulation

In the genome, it is essential to maintain a physical barrier between active and inactive regions; however, the nature of this barrier has been elusive. In a recent issue of Molecular Cell, West et al. (2004) shed light on mechanisms underlying these molecular "fences."     

On the character of hygienic science

In its nature, ends and purposes, hygiene is a medical science. Consequently, it can be axiomatically accepted that the character of medicine is also the character of hygiene. Traditionally, medicine ranks among biological sciences. The author deliberates on the need to regard the current complex of medical sciences, hygiene included, as socio-biological sciences.     

Development of the renal glomerulus: good neighbors and good fences

The glomerulus of the mammalian kidney is an intricate structure that contains an unusual filtration barrier that retains higher molecular weight proteins and blood cells in the circulation. Recent studies have changed our conception of the glomerulus from a relatively static structure to a dynamic one, whose integrity depends on signaling between the three major cell lineages: podocytes, endothelial and mesangial cells. Research into the signaling pathways that control glomerular development and then maintain glomerular integrity and function has recently identified several genes, such as the nephrin and Wilms' tumor 1 genes, that are mutated in human kidney disease.