Axon guidance and somites

The segmental arrangement of spinal nerves in higher vertebrate embryos provides a simple system in which to study the factors that influence axon pathfinding. Developing motor and sensory axons are intimately associated with surrounding tissues that direct axon guidance. We argue that two distinct guidance mechanisms, viz. contact repulsion and chemorepulsion, act simultaneously to prescribe spinal axon trajectories by ’surround-repulsion’. Motor and sensory axons grow freely within the anterior half of each mesodermal somite, because they are excluded from posterior half-somites by contact repulsion. By contrast, the dorsoventral trajectory that bipolar sensory axons of the dorsal root ganglia follow is governed by diffusible repellents originating from the notochord medially and dermamyotome laterally. Even though spinal nerve development appears to be a simple system for elucidating axon guidance mechanisms, many distinct candidate guidance molecules have been implicated and their relative contributions remain to be evaluated. Received: 28 May 1997 / Accepted: 27 June 1997     

Axon guidance: opposing EPHects in the growth cone

Cells communicate with other cells via (trans) interaction between membrane-linked ephrins and Eph receptors. In this issue of Cell, Pfaff and colleagues (Marquardt et al., 2005) demonstrate that coexpressed ephrin-As and Ephs do not interact in cis but rather segregate into separate membrane domains, from which they signal opposing effects during motor axon guidance.     

Axon guidance: proteins turnover in turning growth cones

Accurate navigation by a neuronal growth cone requires the modulation of the growth cone's responsiveness to spatial and temporal changes in expression of guidance cues. These adaptations involve local protein synthesis and turnover in growth cones and distal axons.     

Axon guidance: growth cones make an unexpected turn

Axonal growth cones can turn in response to minute concentration differences in extracellular guidance cues. Surprising new work suggests that these cues might steer the growth cone by inducing rapid local changes in protein levels.     

Regulatory T cells and control of the germinal centre response

Germinal centres (GCs) are specialised lymphoid microenvironments that form in secondary B-cell follicles upon exposure to T-dependent antigens. In the GC, clonal expansion, selection and differentiation of GC B cells result in the production of high-affinity plasma cells and memory B cells that provide protection against subsequent infection. The GC is carefully regulated to fulfil its critical role in defence against infection and to ensure that immunological tolerance is not broken in the process. The GC response can be controlled by a number of mechanisms, one of which is by forkhead box p3 expressing regulatory T (Treg) cells, a suppressive population of CD4⁺ T cells. A specialised subset of Treg cells – follicular regulatory T (Tfr) cells – form after immunisation and are able to access the GC, where they control the size and output of the response. Our knowledge of Treg cell control of the GC is expanding. In this review we will discuss recent advances in the field, with a particular emphasis on the differentiation and function of Tfr cells in the GC.     

中脑多巴胺能神经元的轴突导向及其诱向因子

中脑多巴胺能神经元（mesodiencephalic dopamine,mdDA,neurons）由于涉及帕金森病、精神分裂症和药物成瘾等多种神经疾病的病理过程而历来受到人们的重视。研究中脑多巴胺能神经元的发育机制将给这些疾病的治疗带来希望。近来的研究表明多巴胺能神经元轴突的导向由各种诱向因子决定,诱向因子主要由相应投射部位的细胞所分泌,其中研究得最多的是ephrins,netrins,semaphorins,Slits及它们各自的受体。介绍胚胎期中脑多巴胺能神经元轴突导向过程及其主要诱向因子。     

AID-targeting and hypermutation of non-immunoglobulin genes does not correlate with proximity to immunoglobulin genes in germinal center B cells

Upon activation, B cells divide, form a germinal center, and express the activation induced deaminase (AID), an enzyme that triggers somatic hypermutation of the variable regions of immunoglobulin (Ig) loci. Recent evidence indicates that at least 25% of expressed genes in germinal center B cells are mutated or deaminated by AID. One of the most deaminated genes, c-Myc, frequently appears as a translocation partner with the Ig heavy chain gene (Igh) in mouse plasmacytomas and human Burkitt's lymphomas. This indicates that the two genes or their double-strand break ends come into close proximity at a biologically relevant frequency. However, the proximity of c-Myc and Igh has never been measured in germinal center B cells, where many such translocations are thought to occur. We hypothesized that in germinal center B cells, not only is c-Myc near Igh, but other mutating non-Ig genes are deaminated by AID because they are near Ig genes, the primary targets of AID. We tested this "collateral damage" model using 3D-fluorescence in situ hybridization (3D-FISH) to measure the distance from non-Ig genes to Ig genes in germinal center B cells. We also made mice transgenic for human MYC and measured expression and mutation of the transgenes. We found that there is no correlation between proximity to Ig genes and levels of AID targeting or gene mutation, and that c-Myc was not closer to Igh than were other non-Ig genes. In addition, the human MYC transgenes did not accumulate mutations and were not deaminated by AID. We conclude that proximity to Ig loci is unlikely to be a major determinant of AID targeting or mutation of non-Ig genes, and that the MYC transgenes are either missing important regulatory elements that allow mutation or are unable to mutate because their new nuclear position is not conducive to AID deamination.     

Axon guidance: receptor complexes and signaling mechanisms

The generation of a functional neuronal network requires that axons navigate precisely to their appropriate targets. Molecules that specify guidance decisions have been identified, and the signaling events that occur downstream of guidance receptors are beginning to be understood. New research shows that guidance receptor signaling can be hierarchical -- one receptor silencing the other -- thereby allowing navigating growth cones to interpret opposing guidance cues. Among the known intracellular signaling molecules shared by all guidance receptor families, Rho GTPases appear to be primary regulators of actin dynamics and growth cone guidance. Novel effector molecules complete the picture and suggest additional signaling mechanisms.     

Follicular dendritic cells and apoptosis: Life and death in the germinal centre

Summary The germinal centre forms a specialized microenvironment thought to play a key role in the induction of antibody synthesis, affinity maturation of B cells and memory B cell formation. Clonal-expanded follicular B lymphocytes with mutated antigen receptors (centrocytes) have to be selected on the basis of their capacity to compete for binding to antigen held in limited amounts on the follicular dendritic cells. In this way, only high-affinity B cells are selected. Binding to a follicular dendritic cell is an unconditional prerequisite for centrocytes to survive. Cells that do not succeed in binding to a follicular dendritic cell die rapidly by apoptosis. Apoptosis is a common form of cell death characterized by the activation of an endonuclease culminating in nuclear destruction. The pathway by which apoptosis is triggered varies from cell type to cell type. However, for germinal centre B cells this process is still poorly understood.     

Axon guidance receptors direct growth cone pathfinding: rivalry at the leading edge

One of the earliest steps in the development of the central and peripheral nervous systems is the initiation of axon outgrowth from newly born neurons. Nascent axons then navigate towards their specific targets to establish the intricate network of axon projections found within the mature central nervous system. In doing so, the projecting axons must continually reassess their spatial environment and accurately select the correct pathways among the maze of possible routes. A variety of molecular navigational systems governing axon pathfinding have now been identified. Understanding how these individual molecular guidance systems operate at the level of a single axon, and, how these different systems work in concert to initiate and steer axonal migration is a major goal in developmental neurobiology.     

Axon guidance: starting and stopping with slit.

As developing axons navigate, they exhibit various behaviours: extending and branching, pausing, changing direction, retracting. Now, the Slit protein has been discovered to have striking positive and negative effects on axon growth and guidance.     

Shining a light on germinal center B cells

The mechanisms of B cell selection in lymphoid tissues are poorly understood. In this issue, Victora et?al. (2010) use imaging of photoactivatable green fluorescent protein to define the movements of B?cells in germinal centers and provide evidence that antibody affinity maturation is driven by competition for T?cell help.     

Axon guidance: mice and men need Rig and Robo

For many growing axons, navigating across the midline of the nervous system is a crucial stage of their development. New studies on mice and humans show that the axon guidance receptor Robo3/Rig1 is indispensable for axons to accomplish this task.     

Axon guidance: push and pull with ephrins and GDNF

The pathfinding of motor axons is an important model system for understanding binary axon guidance decisions. Recent work has shown that GDNF attracts motor neuron growth cones, and interacts synergistically with ephrinAs on growth cone directionality.     

Functional properties of human germinal center B cells.

Germinal centers (GCs) are histologically defined areas where B cells undergo extensive proliferation and maturation, or die of apoptosis. GC B cells isolated from human tonsils can be phenotypically identified by expression of peanut agglutinin (PNA)-binding sites and can be further divided into subpopulations based on their expression of CD77. To assess the functional potential of GC B cells, we studied CD77+ PNA+ B cells isolated from tonsils by examining their differentiation status and their ability to proliferate in vitro to various cytokines and costimulants. We found that CD77+ GC B cells are less differentiated than CD77- GC B cells; GC B cells less frequently express cytoplasmic IgG and IgM, and spontaneously secrete less Ig compared to CD77- GC B cells. To identify conditions capable of inducing GC B cell proliferation, we examined IL-4, IL-2, IFN-gamma, low molecular weight BCGF (LMW-BCGF), and an MLR supernatant along with costimulants such as anti-IgM antibody, Staphylococcus aureus Cowan I (SAC), PMA, and pokeweed mitogen (PWM). While non-GC B cells proliferate strongly in response to these stimuli, GC B cells did not proliferate. However, CD77+ as well as CD77- GC B cells mounted a rapid and strong proliferative response upon stimulation with IL-4, but only in the presence of anti-CD40 antibody. Moreover, although nine additional cytokines were examined, only IL-4 was capable of supporting CD77+ GC B cell proliferation in the presence of anti-CD40 antibody. When cells were stimulated with IL-4 and anti-CD40 antibody, we also found that IFN-gamma consistently decreased the proliferative response of CD77+ GC B cells without affecting the response of non-GC B cells. Taken together, these data indicate that GC B cells have characteristic growth requirements and that IL-4 may be important for GC B cell growth in vivo.