Axon or dendrite? cell biology and molecular pathways for neuronal cell asymmetry

Young neurons polarize by specializing axons and dendrites from immature neurites. After synapse formations, they transmit electrical activity along the axon-dendrite axis, thereby working as functional units of the neural circuits. This axon-dendrite asymmetry is referred to as neuronal polarity. Although a great number of cell biological studies in vitro had been performed, little was known about the molecular events that establish the polarity. In the last several years, rapid advancement in molecular and genetic studies has unraveled the multiple signaling pathways. This paper summarizes current perspectives on the cell and molecular biological mechanisms of the neuronal polarization, to clarify future directions in this growing research field.     

Increased cell–cell adhesion, a novel effect of R-(−)-deprenyl

Summary. The neuroprotective effect of the antiparkinsonian monoamine oxidase (MAO)-B inhibitor, R-(−)-deprenyl has been under investigation for years. Cytoskeleton, a main component of cell adhesion, is involved in the development of R-(−)-deprenyl-responsive diseases, the effect of the drug on cell adhesion, however, is not known. We examined the effect of R-(−)-deprenyl on cell–cell adhesion of neuronal and non-neuronal cells. R-(−)-deprenyl treatment resulted in a cell type- and concentration-dependent increase in cell–cell adhesion of PC12 and NIH3T3 cells at concentrations lower than those required for MAO-B inhibition, while S-(+)-deprenyl was not effective. This acitvity of R-(−)-deprenyl was not prevented by the cytochrome P-450 inhibitor, SKF525A, while deprenyl-N-oxide, a newly described metabolite, also induced an increase in cell–cell adhesion. The effect of R-(−)-deprenyl was not reversible during a 24-hour recovery period. In summary, we described a new, MAO-B independent effect of R-(−)-deprenyl on cell–cell adhesion which can contribute to its neuroprotective function.     

Cell birth, cell death, cell diversity and DNA breaks: how do they all fit together?

Substantial death of migrating and differentiating neurons occurs within the developing CNS of mice that are deficient in genes required for repair of double-stranded DNA breaks. These findings suggest that large-scale, yet previously unrecognized, double-stranded DNA breaks occur normally in early postmitotic and differentiating neurons. Moreover, they imply that cell death occurs if the breaks are not repaired. The cause and natural function of such breaks remains a mystery; however, their occurrence has significant implications. They might be detected by histological methods that are sensitive to DNA fragmentation and mistakenly interpreted to indicate cell death when no relationship exists. In a broader context, there is now renewed speculation that DNA recombination might be occurring during neuronal development, similar to DNA recombination in developing lymphocytes. If this is true, the target gene(s) of recombination and their significance remain to be determined.     

Demyelination: a failure of cell communication?

A hypothesis is proposed that demyelination in both the CNS and PNS involves a failure of cell communication between the axon and oligodendrocyte/Schwann cell, as a primary event. The site of communication is assumed to be the paranodal myelin loop-axolemma membrane complex. It is postulated that "cross-talk" between the two cell types can be interrupted, and hence demyelination initiated, by pathophysiological changes in either the axon or myelinating cell. Experimental evidence in support of the hypothesis is cited in so far as it exists.     

Müller cell differentiation in the zebrafish neural retina: evidence of distinct early and late stages in cell maturation

The vertebrate neural retina is mainly composed of cells of neuroectodermal origin. The primary cell types found in all vertebrate retinas are several categories of neurons and the archetypical retina glial cell the Müller cell. Although the neurons and the single glial cell type of the retina are specialized for very distinct functions, they all have a common developmental origin within the tissue. How the distinctions between cell types, in particular between neurons and glia, arise during embryonic development remains a central issue in neurobiology. In this report, we examine the genesis of Müller glial cells during zebrafish (Danio rerio) eye development. Particular emphasis is placed on the expression of the Müller cell maturation markers carbonic anhydrase and glutamine synthetase. In addition, we report that the HNK-1 monoclonal antibody, which identifies a particular glycoconjugate frequently found on cell surface recognition molecules, also identifies zebrafish retina Müller cells early in development. The expression patterns of these three markers clearly show that the Müller cells mature in stages: HNK-1 labeling and glutamine synthetase arise earlier than carbonic anhydrase expression. In addition, the embryonic zebrafish neural retina is characterized by the presence of amoeboid, carbonic anhydrase-positive microglial cells even before the genesis of retinal neuroectodermal glia. The stepwise maturation of the glia is likely to be indicative of an overall retinal maturational program in which cell differentiation and the expression of certain phenotype-defining gene products may be separately regulated.     

Upregulation of AKT attenuates amyloid-β-induced cell apoptosis

Overproduction and accumulation of amyloid-β (Aβ) have been proposed to be an initiating factor of neuron loss in Alzheimer's disease (AD). AKT is a pivotal molecule in regulating neuronal survival, however, it is still not known whether upregulation of AKT can protect the cells from the Aβ-induced apoptosis. By using cell viability assay and flow cytometry, we demonstrated in the present study that overexpression of AKT could significantly attenuate the cell apoptosis induced by Aβ1-42, whereas simultaneous inhibition of PI3 K, the immediate upstream stimulator of AKT, abolished the protective effect of AKT in HEK293 cells. Upregulation of AKT restored the Aβ-induced alterations of the mitochondria-related Bcl-2 family members (including Bcl-xL, Bcl-w, Bad, and Bax) and suppressed the activation of caspase-3 and JNK. Our data suggest that upregulation of AKT could be a promising therapeutic strategy for arresting Aβ toxicity in AD patients.     

Does hair cell differentiation predate the vertebrate appearance?

It is generally accepted that the three main chordate groups (tunicates, cephalochordates and vertebrates) originated from a common ancestor having the basic features of the chordate body plan, i.e. a neural tube and a notochord flanked by striated musculature. There is now increasing evidence that tunicates, rather than cephalochordates, are the vertebrate sister-group. Correlated with this, tunicates have sensory structures similar to those derived from placodes or neural crest in vertebrates. In this context, we discuss here whether the precursors of vertebrate hair cells, which are placodal in origin, were present in ancestral chordates. The ascidian tunicates possess a coronal organ, consisting of a row of mechanosensory cells that runs around the base of the oral siphon. Its function is to monitor the incoming water flow. The cells are secondary sensory cells, i.e. they lack axons and synapse with neurons whose somata lie in the cerebral ganglion. They are accompanied by supporting cells and, as in vertebrates, have varying morphologies in the species so far examined: in one order (Enterogona), they are multiciliate; in the other (Pleurogona), they may possess an apical apparatus, consisting of one or two cilia accompanied by stereovilli, that are graded in length. Coronal cells thus resemble vertebrate hair cells closely in their morphology, embryonic origin and arrangement, which suggests they originated early in ancestral chordates. We are continuing our study of the coronal organ in other ascidian species, and report new data here on Botrylloides leachi, which conforms with the pattern of Pleurogona and, in particular, with previously published results on other botryllid ascidians.     

Complex rectification of Müller cell Kir currents

Although Kir4.1 channels are the major inwardly rectifying channels in glial cells and are widely accepted to support K+- and glutamate-uptake in the nervous system, the properties of Kir4.1 channels during vital changes of K+ and polyamines remain poorly understood. Therefore, the present study examined the voltage-dependence of K+ conductance with varying physiological and pathophysiological external [K+] and intrapipette spermine ([SP]) concentrations in Müller glial cells and in tsA201 cells expressing recombinant Kir4.1 channels. Two different types of [SP] block were characterized: "fast" and "slow." Fast block was steeply voltage-dependent, with only a low sensitivity to spermine and strong dependence on extracellular potassium concentration, [K+]o. Slow block had a strong voltage sensitivity that begins closer to resting membrane potential and was essentially [K+]o-independent, but with a higher spermine- and [K+]i-sensitivity. Using a modified Woodhull model and fitting i/V curves from whole cell recordings, we have calculated free [SP](in) in Müller glial cells as 0.81 +/- 0.24 mM. This is much higher than has been estimated previously in neurons. Biphasic block properties underlie a significantly varying extent of rectification with [K+] and [SP]. While confirming similar properties of glial Kir and recombinant Kir4.1, the results also suggest mechanisms underlying K+ buffering in glial cells: When [K+]o is rapidly increased, as would occur during neuronal excitation, "fast block" would be relieved, promoting potassium influx to glial cells. Increase in [K+]in would then lead to relief of "slow block," further promoting K+-influx.     

Beneficial effects of BV2 cell on proliferation and neuron-differentiating of mesenchymal stem cells in the circumstance of injured PC12 cell supernatant

1 Introduction The injury of nervous system leads to the irreversible death of neurons. The application of stem cells has shed light on the reconstruction and function recovery of in- jured nervous tissues[1].The proliferation and neuron-dif- ferentiating potential of stem cells bring approaches to the issue that “injured neurons are not able to be revitalized”. People have realized that the proliferation and dif- ferentiation of stem cells are closely related to the micro- environment they …     

Hydrogen sulfide protects amyloid-β induced cell toxicity in microglia

Alzheimer's disease (AD) is pathologically characterized by the accumulation of senile plaques, containing activated microglia and amyloid-β peptides (Aβ). We found that aggregated Aβ1-40 peptide (25 μM, 24 h) significantly decreased viability of BV-2 microglial cells. This was concentration-dependently attenuated by NaHS (a hydrogen sulfide (H2S) donor, 25-500 μM). NaHS also significantly attenuated Aβ-induced LDH release and the up-regulation of protein expression of growth arrest DNA damage (GADD 153). These data suggest that H2S may attenuate Aβ-induced cell toxicity and cell cycle re-entry. Pretreatment with NaHS also suppressed the release of nitric oxide and the upregulation of inducible nitric oxide synthase. These effects were attenuated by exogenous application of NaHS or stimulation of endogenous generation of H2S with S-adenosyl-L-methionine, a cystathionine β synthase activator. NaHS also decreased the releases of TNF-α and suppressed the up-regulation of protein expression of cyclooxygenase 2, which were mimicked by blockade of p38 and JNK-MAPK. In addition, Aβ induced loss of mitochondrial member potential (ΔΨm) and activation of p38-, JNK-, and ERK-MAPKs. Application of NaHS attenuated these effects but failed to affect the activation of ERK. In conclusion, we demonstrated for the first time that H2S may protect cell against Aβ-induced cell injury by inhibition of inflammation, promotion of cell growth and preservation of mitochondrial function in a p38- and JNK-MAPK dependent manner. Our results suggest that H2S may have potential therapeutic value for treatment of AD.     

Are sparse-coding simple cell receptive field models physiologically plausible?

Olshausen and Field (1996) developed a simple cell receptive field model for natural scene processing in V1, based on unsupervised learning and non-orthogonal basis function optimization of an overcomplete representation of visual space. The model was originally tested with an ensemble of whitened natural scenes, simulating pre-cortical filtering in the retinal ganglia and lateral geniculate nucleus, and the basis functions qualitatively resembled the orientation-specific responses of V1 simple cells in the spatial domain. In this study, the quantitative tuning responses of the basis functions in the spectral domain are estimated using a Gaussian model, to determine their goodness-of-fit to the known bandwidths of simple cells in primate V1. Five simulation experiments which examined key features of the model are reported: changing the size of the basis functions; using a complete versus over-complete representation; changing the sparseness factor; using a variable learning rate; and mapping the basis functions with a whitening spatial function. The key finding of this study is that across all image themes, basis function sizes, number of basis functions, sparseness factors and learning rates, the spatial-frequency tuning did not closely resemble that of primate area 17 -- the model results more closely resembled the unclassified cat neurones of area 19 with a single exception, and not area 17 as predicted.     

The cell biology of alpha-synuclein: a sticky problem?

Parkinson’s disease (PD) is the most common neurodegenerative motor disorder, marked by chronic progressive loss of neurons in the substantia nigra, thereby damaging purposeful control of movement. For decades, it was believed that PD was caused solely by environmental causes. However, the discovery of genetic factors involved in PD has revolutionized our attempts to understand the disease’s pathology. PD now appears to be more polygenetic than previously thought and is most likely caused by a complex interaction of genetic risks and environmental exposures. The first gene found to be mutated in PD encodes for the presynaptic protein α-synuclein, which is also a major component of Lewy bodies and Lewy neurites, the neuropathological hallmarks of the disease. While these findings provide a classic example of how rare genetic mutations in disease can point to important pathways in idiopathic disease pathologies, much of the study of α-synuclein has focused on understanding how this protein undergoes the transition from an unfolded monomer to amorphous aggregates or Lewy body-like filaments rather than addressing what its fundamental function might be. Since alterations in synuclein function may predispose to the disease pathology of PD, regardless of the presence of genetic mutations, a more thorough understanding of the cellular regulation and function of α-synuclein may be of crucial importance to our understanding of this degenerating disorder.     

Is the AMPA receptor subunit GluR2 mRNA an early indicator of cell fate after ischemia? A quantitative single cell RT-PCR study

After a moderate global cerebral ischemia, two hypothetical populations of pyramidal neurons are present among the hippocampal CA1 pyramidal neurons: one that will die and another one that will survive. Prior analysis of dissected hippocampal CA1 regions has shown a reduction of the GluR1-3 mRNA following ischemia. In order to identify these changes in single neurons, quantitative single cell RT-PCR was used to analyze the expression of GluR1-4 mRNA in rats 24 h after ischemia and also in rats after tolerance inducing ischemia. Control CA1 cells had a median copy-number of 290, 247, 207 and 16 GluR1-4, respectively. The tolerant cells showed small significant up-regulations of GluR1, 3 and 4 mRNA, while the GluR2 mRNA showed a more than 4-fold up-regulation compared to control cells. All the cells from ischemic animals displayed down-regulations of GluR1-3 mRNA. The GluR4 mRNA was not detectable in the ischemic animals. Our results thus show that the CA1 neurons react uniformly 24 h after a moderate ischemia independent of the fate of the neuron: thus two neuron populations with different GluR2 profiles cannot be identified in post-ischemic animals at 24 h. It seems however that an increased level of GluR2 can be used as an indicator of tolerance to ischemia.     

Editor's Choice——Retinal ganglion cell damage and regeneration

Retinal ganglion cell damage and regeneration Retinal ganglion cell apoptosis is considered to be the main cause of loss of vision in glaucoma patients.Microglia cells are phagocytic cells present in the retina.In the retinaof glaucoma rat models,microglia cells become activated,which suggests a role for microglia in the