Nerve-independent formation of a topologically complex postsynaptic apparatus

As the mammalian neuromuscular junction matures, its acetylcholine receptor (AChR)–rich postsynaptic apparatus is transformed from an oval plaque into a pretzel-shaped array of branches that precisely mirrors the branching pattern of the motor nerve terminal. Although the nerve has been believed to direct postsynaptic maturation, we report here that myotubes cultured aneurally on matrix-coated substrates form elaborately branched AChR-rich domains remarkably similar to those seen in vivo. These domains share several characteristics with the mature postsynaptic apparatus, including colocalization of multiple postsynaptic markers, clustering of subjacent myonuclei, and dependence on the muscle-specific kinase and rapsyn for their formation. Time-lapse imaging showed that branched structures arise from plaques by formation and fusion of AChR-poor perforations through a series of steps mirroring that seen in vivo. Multiple fluorophore imaging showed that growth occurs by circumferential, asymmetric addition of AChRs. Analysis in vivo revealed similar patterns of AChR addition during normal development. These results reveal the sequence of steps by which a topologically complex domain forms on a cell and suggest an unexpected nerve-independent role for the postsynaptic cell in generating this topological complexity

The dark halo of the Hydra I galaxy cluster: core, cusp, cosmological? Dynamics of NGC 3311 and its globular cluster system

NGC 3311 is the central cD galaxy of the Hydra I cluster. We use globular clusters around NGC 3311, combined with kinematical data of the galaxy itself, to investigate the dark matter distribution in the central region of Hydra I. Radial velocities of 118 bright globular clusters, based on VLT/VIMOS mask spectroscopy, are used to calculate velocity dispersions which are well defined out to 100 kpc. NGC 3311 is the most distant galaxy for which this kind of study has been performed. We also determine velocity dispersions of the stellar component from long slit spectroscopy out to 20 kpc. Moreover, we present a new photometric model for NGC 3311 in the V-band. We search for a dark halo which in the context of a spherical Jeans model. We also compare the radial velocity distributions of globular clusters and planetary nebulae. The projected stellar velocity dispersion rises from 185 km/s to 350 km/s at a radius of 20 kpc. The globular cluster dispersion rises as well from 500 km/s at 10 kpc to about 800 km/s at 100 kpc, comparable to the velocity dispersion of the cluster galaxies. A dark matter halo with a core reproduces well the velocity dispersions of stars and globular clusters simultaneously under isotropy. The central stellar velocity dispersions predicted by cosmological NFW halos are less good representations, while the globular clusters allow a wide range of halo parameters. A suspected radial anisotropy of the stellar population aggravates the deviations. However, we find discrepancies with previous kinematical data, which we cannot resolve and may indicate a more complicated velocity pattern. Although one cannot conclusively demonstrate that the dark matter halo of NGC 3311 has a core rather than a cusp, a core seems to be preferred by the present data. A more complete velocity field and an analysis of the anisotropy is required to reach firm conclusions.Comment: 8 pages, 5 figures, abstract abridged, accepted for publication in A&

Transthyretin Promotes Axon Growth via Regulation of Microtubule Dynamics and Tubulin Acetylation

Transthyretin (TTR), a plasma and cerebrospinal fluid protein, increases axon growth and organelle transport in sensory neurons. While neurons extend their axons, the microtubule (MT) cytoskeleton is crucial for the segregation of functional compartments and axonal outgrowth. Herein, we investigated whether TTR promotes axon elongation by modulating MT dynamics. We found that TTR KO mice have an intrinsic increase in dynamic MTs and reduced levels of acetylated α-tubulin in peripheral axons. In addition, they failed to modulate MT dynamics in response to sciatic nerve injury, leading to decreased regenerative capacity. Importantly, restoring acetylated α-tubulin levels of TTR KO dorsal root ganglia (DRG) neurons using an HDAC6 inhibitor is sufficient to completely revert defective MT dynamics and neurite outgrowth. In summary, our results reveal a new role for TTR in the modulation of MT dynamics by regulating α-tubulin acetylation via modulation of the acetylase ATAT1, and suggest that this activity underlies TTR neuritogenic function

A deep view on the Virgo cluster core

In this study we investigate the optical photometric properties of early-type galaxies in the Virgo cluster core region, by analysing their location on the colour magnitude relation (CMR) and the structural scaling relations down to faint magnitudes, and by constructing the luminosity function to compare it with theoretical expectations. We visually select potential cluster members based on morphology and angular size, excluding spiral galaxies. A photometric analysis has been carried out for 295 galaxies, using surface brightness profile shape and colour as further criteria to identify probable background contaminants. 216 galaxies are considered to be certain or probable Virgo cluster members. Our study reveals 77 galaxies not catalogued in the VCC (with 13 of them already found in previous studies) that are very likely Virgo cluster members because they follow the Virgo CMR and exhibit low Sersic indices. Those galaxies reach -8.7 mag in V band. The CMR shows a clear change in slope from dEs to dSphs, while the scatter of the CMR in the dSph regime does not increase significantly. Our sample might, however, be somewhat biased towards redder colours. The scaling relations given by the dEs appear to be continued by the dSphs indicating a similar origin. The observed change in the CMR slope may mark the point at which gas loss prevented significant metal enrichment. The almost constant scatter around the CMR possibly indicates a short formation period, resulting in similar stellar populations. The luminosity function shows a Schechter function's faint end slope of -1.50\pm0.17, implying a lack of galaxies related to the expected number of low-mass dark matter haloes from theoretical models. Our findings could be explained by suppressed star formation in low-mass dark matter halos or by tidal disruption of dwarfs in the dense core region of the cluster.Comment: A&A accepted, photometry of newly identified dwarf galaxies is provided in Table 3, 17 pages, 8 figure

Review: ‘Gimme five’: future challenges in multiple sclerosis. ECTRIMS Lecture 2009

This article is based on the ECTRIMS lecture given at the 25th ECTRIMS meeting which was held in Düsseldorf, Germany, from 9 to 12 September 2009. Five challenges have been identified: (1) safeguarding the principles of medical ethics; (2) optimizing the risk/benefit ratio; (3) bridging the gap between multiple sclerosis and experimental autoimmune encephalitis; (4) promoting neuroprotection and repair; and (5) tailoring multiple sclerosis therapy to the individual patient. Each of these challenges will be discussed and placed in the context of current research into the pathogenesis and treatment of multiple sclerosis

A large population of ultra-compact dwarf galaxies in the Hydra I cluster

We performed a large spectroscopic survey of compact, unresolved objects in the core of the Hydra I galaxy cluster (Abell 1060), with the aim of identifying ultra-compact dwarf galaxies (UCDs), and investigating the properties of the globular cluster (GC) system around the central cD galaxy NGC 3311. We obtained VIMOS medium resolution spectra of about 1200 candidate objects with apparent magnitudes 18.5 < V < 24.0 mag, covering both the bright end of the GC luminosity function and the luminosity range of all known UCDs. By means of spectroscopic redshift measurements, we identified 118 cluster members, from which 52 are brighter than M_V = -11.0 mag, and can therefore be termed UCDs. The brightest UCD in our sample has an absolute magnitude of M_V = -13.4 mag (corresponding to a mass of > 5 x 10^7 M_sun) and a half-light radius of 25 pc. This places it among the brightest and most massive UCDs ever discovered. Most of the GCs/UCDs are both spatially and dynamically associated to the central cD galaxy. The overall velocity dispersion of the GCs/UCDs is comparable to what is found for the cluster galaxies. However, when splitting the sample into a bright and a faint part, we observe a lower velocity dispersion for the bright UCDs/GCs than for the fainter objects. At a dividing magnitude of M_V = -10.75 mag, the dispersions differ by more than 200 km/s, and up to 300 km/s for objects within 5 arcmin around NGC 3311. We interpret these results in the context of different UCD formation channels, and conclude that interaction driven formation seems to play an important role in the centre of Hydra I.Comment: 18 pages, 17 figures, accepted for publication in A&

Two adhesive systems cooperatively regulate axon ensheathment and myelin growth in the CNS

Central nervous system myelin is a multilayered membrane produced by oligodendrocytes to increase neural processing speed and efficiency, but the molecular mechanisms underlying axonal selection and myelin wrapping are unknown. Here, using combined morphological and molecular analyses in mice and zebrafish, we show that adhesion molecules of the paranodal and the internodal segment work synergistically using overlapping functions to regulate axonal interaction and myelin wrapping. In the absence of these adhesive systems, axonal recognition by myelin is impaired with myelin growing on top of previously myelinated fibers, around neuronal cell bodies and above nodes of Ranvier. In addition, myelin wrapping is disturbed with the leading edge moving away from the axon and in between previously formed layers. These data show how two adhesive systems function together to guide axonal ensheathment and myelin wrapping, and provide a mechanistic understanding of how the spatial organization of myelin is achieved

Considerations for a European animal welfare standard to evaluate adverse phenotypes in teleost fish

No abstract available

Profound functional and molecular diversity of mitochondria revealed by cell type-specific profiling in vivo

Mitochondria vary in morphology and function in different tissues, however little is known about their molecular diversity among cell types. To investigate mitochondrial diversity in vivo, we developed an efficient protocol to isolate cell type-specific mitochondria based on a new MitoTag mouse. We profiled the mitochondrial proteome of three major neural cell types in cerebellum and identified a substantial number of differential mitochondrial markers for these cell types in mice and humans. Based on predictions from these proteomes, we demonstrate that astrocytic mitochondria metabolize long-chain fatty acids more efficiently than neurons. Moreover, we identified Rmdn3 as a major determinant of ER-mitochondria proximity in Purkinje cells. Our novel approach enables exploring mitochondrial diversity on the functional and molecular level in many in vivo contexts

Ketogenic diet uncovers differential metabolic plasticity of brain cells

To maintain homeostasis, the body, including the brain, reprograms its metabolism in response to altered nutrition or disease. However, the consequences of these challenges for the energy metabolism of the different brain cell types remain unknown. Here, we generated a proteome atlas of the major central nervous system (CNS) cell types from young and adult mice, after feeding the therapeutically relevant low-carbohydrate, high-fat ketogenic diet (KD) and during neuroinflammation. Under steady-state conditions, CNS cell types prefer distinct modes of energy metabolism. Unexpectedly, the comparison with KD revealed distinct cell type–specific strategies to manage the altered availability of energy metabolites. Astrocytes and neurons but not oligodendrocytes demonstrated metabolic plasticity. Moreover, inflammatory demyelinating disease changed the neuronal metabolic signature in a similar direction as KD. Together, these findings highlight the importance of the metabolic cross-talk between CNS cells and between the periphery and the brain to manage altered nutrition and neurological disease