Neutrino Halos in Clusters of Galaxies and their Weak Lensing Signature

We study whether non-linear gravitational effects of relic neutrinos on the development of clustering and large-scale structure may be observable by weak gravitational lensing. We compute the density profile of relic massive neutrinos in a spherical model of a cluster of galaxies, for several neutrino mass schemes and cluster masses. Relic neutrinos add a small perturbation to the mass profile, making it more extended in the outer parts. In principle, this non-linear neutrino perturbation is detectable in an all-sky weak lensing survey such as EUCLID by averaging the shear profile of a large fraction of the visible massive clusters in the universe, or from its signature in the general weak lensing power spectrum or its cross-spectrum with galaxies. However, correctly modeling the distribution of mass in baryons and cold dark matter and suppressing any systematic errors to the accuracy required for detecting this neutrino perturbation is severely challenging.Comment: 13 pages, 11 figures. Submitted to JCA

Non-linear evolution of the cosmic neutrino background

We investigate the non-linear evolution of the relic cosmic neutrino background by running large box-size, high resolution N-body simulations which incorporate cold dark matter (CDM) and neutrinos as independent particle species. Our set of simulations explore the properties of neutrinos in a reference Lambda CDM model with total neutrino masses between 0.05-0.60 eV in cold dark matter haloes of mass 10(11) ¿ 10(15) h(-1) M-circle dot, over a redshift range z = 0 ¿ 2. We compute the halo mass function and show that it is reasonably well fitted by the Sheth-Tormen formula, once the neutrino contribution to the total matter is removed. More importantly, we focus on the CDM and neutrino properties of the density and peculiar velocity fields in the cosmological volume, inside and in the outskirts of virialized haloes. The dynamical state of the neutrino particles depends strongly on their momentum: whereas neutrinos in the low velocity tail behave similarly to CDM particles, neutrinos in the high velocity tail are not affected by the clustering of the underlying CDM component. We find that the neutrino (linear) unperturbed momentum distribution is modified and mass and redshift dependent deviations from the expected Fermi-Dirac distribution are in place both in the cosmological volume and inside haloes. The neutrino density profiles around virialized haloes have been carefully investigated and a simple fitting formula is provided. The neutrino profile, unlike the cold dark matter one, is found to be cored with core size and central density that depend on the neutrino mass, redshift and mass of the halo, for halos of masses larger than similar to 10(13.5) h(-1) M-circle dot. For lower masses the neutrino profile is best fitted by a simple power-law relation in the range probed by the simulations. The results we obtain are numerically converged in terms of neutrino profiles at the 10% level for scales above similar to 200 h(-1) kpc at z = 0, and are stable with respect to box-size and starting redshift of the simulation. Our findings are particularly important in view of upcoming large-scale structure surveys, like Euclid, that are expected to probe the non-linear regime at the percent level with lensing and clustering observations

MicroRNA 101b Is Downregulated in the Prefrontal Cortex of a Genetic Model of Depression and Targets the Glutamate Transporter SLC1A1 (EAAT3) in Vitro

BACKGROUND: MicroRNAs (miRNAs) are small regulatory molecules that cause translational repression by base pairing with target mRNAs. Cumulative evidence suggests that changes in miRNA expression may in part underlie the pathophysiology and treatment of neuropsychiatric disorders, including major depressive disorder (MDD). METHODS: A miRNA expression assay that can simultaneously detect 423 rat miRNAs (miRBase v.17) was used to profile the prefrontal cortex (PFC) of a genetic rat model of MDD (the Flinders Sensitive Line [FSL]) and the controls, the Flinders Resistant Line (FRL). Gene expression data from the PFC of FSL/FRL animals (GEO accession no. GSE20388) were used to guide mRNA target selection. Luciferase reporter assays were used to verify miRNA targets in vitro. RESULTS: We identified 23 miRNAs that were downregulated in the PFC of the FSL model compared with controls. Interestingly, one of the identified miRNAs (miR-101b) is highly conserved between rat and human and was recently found to be downregulated in the PFC of depressed suicide subjects. Using a combination of in silico and in vitro analyses, we found that miR-101b targets the neuronal glutamate transporter SLC1A1 (also known as EAAC1 or EAAT3). Accordingly, both mRNA and protein levels of SLC1A1 were found to be upregulated in the PFC of the FSL model. CONCLUSIONS: Besides providing a list of novel miRNAs associated with depression-like states, this preclinical study replicated the human association of miR-101 with depression. In addition, since one of the targets of miR-101b appears to be a glutamate transporter, our preclinical data support the hypothesis of a glutamatergic dysregulation being implicated in the etiology of depression

Molecular Diversity of Midbrain Development in Mouse, Human, and Stem Cells.

Understanding human embryonic ventral midbrain is of major interest for Parkinson's disease. However, the cell types, their gene expression dynamics, and their relationship to commonly used rodent models remain to be defined. We performed single-cell RNA sequencing to examine ventral midbrain development in human and mouse. We found 25 molecularly defined human cell types, including five subtypes of radial glia-like cells and four progenitors. In the mouse, two mature fetal dopaminergic neuron subtypes diversified into five adult classes during postnatal development. Cell types and gene expression were generally conserved across species, but with clear differences in cell proliferation, developmental timing, and dopaminergic neuron development. Additionally, we developed a method to quantitatively assess the fidelity of dopaminergic neurons derived from human pluripotent stem cells, at a single-cell level. Thus, our study provides insight into the molecular programs controlling human midbrain development and provides a foundation for the development of cell replacement therapies.All authors were supported by EU FP7 grant DDPDGENES. S.L. was supported by European Research Council grant 261063 (BRAINCELL), Knut and Alice Wallenberg Foundation grant 2015.0041, Swedish Research Council (STARGET), and the Swedish Foundation for Strategic Research (RIF14-0057). A.Z. was supported by the Human Frontier Science Program. E.A. was supported by Swedish Research Council (VR projects: 2011-3116 and 2011-3318), Swedish Foundation for Strategic Research (SRL program), and Karolinska Institutet (SFO Thematic Center in Stem cells and Regenerative Medicine). E.A. and R.A.B. were supported by the EU FP7 grant NeuroStemcellRepair. R.A.B. was also supported by an NIHR Biomedical Research Centre award to the University of Cambridge/Addenbrookes Hospital. iCell dopaminergic neurons were a generous gift from Cellular Dynamics International. Single-cell RNA-seq servic0es were provided by the Eukaryotic Single-cell Genomics facility and the National Genomics Infrastructure at Science for Life Laboratory.This is the final version of the article. It first appeared from Elsevier via https://doi.org/10.1016/j.cell.2016.09.02

WNT5A is transported via lipoprotein particles in the cerebrospinal fluid to regulate hindbrain morphogenesis.

WNTs are lipid-modified proteins that control multiple functions in development and disease via short- and long-range signaling. However, it is unclear how these hydrophobic molecules spread over long distances in the mammalian brain. Here we show that WNT5A is produced by the choroid plexus (ChP) of the developing hindbrain, but not the telencephalon, in both mouse and human. Since the ChP produces and secretes the cerebrospinal fluid (CSF), we examine the presence of WNT5A in the CSF and find that it is associated with lipoprotein particles rather than exosomes. Moreover, since the CSF flows along the apical surface of hindbrain progenitors not expressing Wnt5a, we examined whether deletion of Wnt5a in the ChP controls their function and find that cerebellar morphogenesis is impaired. Our study thus identifies the CSF as a route and lipoprotein particles as a vehicle for long-range transport of biologically active WNT in the central nervous system.We thank Nadia Wänn for maintenance of mice colonies; the members of Bryja and Arenas lab for their help and suggestions; Martin Häring for help with in situ analysis; Johnny Söderlund and Alessandra Nanni for their technical and secretarial assistance; and the CLICK imaging facility at Karolinska Institutet for technical support. We thank MEYS CR for support to the following core facilities: Proteomics (CIISB research infrastructure project LM2015043), cellular imaging at CEITEC institution at Masaryk University (LM2015062 Czech-BioImaging) Czech Centre for Phenogenomics (LM2015040), Higher quality and capacity of transgenic model breeding (by MEYS and ERDF, OP RDI CZ.1.05/2.1.00/19.0395), Czech Centre for Phenogenomics: developing towards translation research (by MEYS and ESIF, OP RDE CZ.02.1.01/0.0/0.0/16_013/0001789). The collaboration between Masaryk University and Karolinska Institutet (KI-MU program), was co-financed by the European Social Fund and the state budget of the Czech Republic (CZ.1.07/2.3.00/20.0180). Funding to the VB lab was obtained from Neuron Fund for Support of Science (23/2016), and Czech Science Foundation (GA17-16680S). Work in the EA lab was supported by the Swedish Research Council (VR projects: DBRM, 2011-3116, 2011-3318 and 2016-01526), Swedish Foundation for Strategic Research (SRL program and SLA SB16-0065), European Commission (NeuroStemcellRepair), Karolinska Institutet (SFO Strat Regen, Senior grant 2018), Hjärnfonden (FO2015:0202 and FO2017-0059) and Cancerfonden (CAN 2016/572). Research in the JCV lab was supported by Karolinska Institutet Foundations. KK was supported by Masaryk University (MUNI/E/0965/2016). DP and ZZ were supported by the CEITEC 2020 (LQ1601) project from MEYS CR

Cxcl12/Cxcr4 signaling controls the migration and process orientation of A9-A10 dopaminergic neurons

CXCL12/CXCR4 signaling has been reported to regulate three essential processes for the establishment of neural networks in different neuronal systems: neuronal migration, cell positioning and axon wiring. However, it is not known whether it regulates the development of A9-A10 tyrosine hydroxylase positive (TH+) midbrain dopaminergic (mDA) neurons. We report here that Cxcl12 is expressed in the meninges surrounding the ventral midbrain (VM), whereas CXCR4 is present in NURR1+ mDA precursors and mDA neurons from E10.5 to E14.5. CXCR4 is activated in NURR1+ cells as they migrate towards the meninges. Accordingly, VM meninges and CXCL12 promoted migration and neuritogenesis of TH+ cells in VM explants in a CXCR4-dependent manner. Moreover, in vivo electroporation of Cxcl12 at E12.5 in the basal plate resulted in lateral migration, whereas expression in the midline resulted in retention of TH+ cells in the IZ close to the midline. Analysis of Cxcr4-/- mice revealed the presence of VM TH+ cells with disoriented processes in the intermediate zone (IZ) at E11.5 and marginal zone (MZ) at E14. Consistently, pharmacological blockade of CXCR4 or genetic deletion of Cxcr4 resulted in an accumulation of TH+ cells in the lateral aspect of the IZ at E14, indicating that CXCR4 is required for the radial migration of mDA neurons in vivo. Altogether, our findings demonstrate that CXCL12/CXCR4 regulates the migration and orientation of processes in A9-A10 mDA neurons.This work was funded by the Swedish Research Council [VR projects: DBRM, 2008:2811, 2011-3116 and 2011-3318]; by the Swedish Foundation for Strategic Research (SRL program); by the Knut and Alice Wallenberg Foundation (CLICK); by the European Commission (NeuroStemcell and DDPD-Genes) and Karolinska Institutet (SFO Thematic Center in Stem cells and Regenerative Medicine) to E.A.; and by the European Commission [mdDANeurodev 222999] to O.M. S.Y. was supported by grants from KID and Chinese Scholarship Council.Peer reviewe

An integrative proteomics method identifies a regulator of translation during stem cell maintenance and differentiation

To characterize molecular changes during cell type transitions, the authors develop a method to simultaneously measure protein expression and thermal stability changes. They apply this approach to study differences between human pluripotent stem cells, their progenies, parental and allogeneic cells. Detailed characterization of cell type transitions is essential for cell biology in general and particularly for the development of stem cell-based therapies in regenerative medicine. To systematically study such transitions, we introduce a method that simultaneously measures protein expression and thermal stability changes in cells and provide the web-based visualization tool ProteoTracker. We apply our method to study differences between human pluripotent stem cells and several cell types including their parental cell line and differentiated progeny. We detect alterations of protein properties in numerous cellular pathways and components including ribosome biogenesis and demonstrate that modulation of ribosome maturation through SBDS protein can be helpful for manipulating cell stemness in vitro. Using our integrative proteomics approach and the web-based tool, we uncover a molecular basis for the uncoupling of robust transcription from parsimonious translation in stem cells and propose a method for maintaining pluripotency in vitro

Cytoplasmic Prep1 Interacts with 4EHP Inhibiting Hoxb4 Translation

embryo development. Interestingly, Prep1 contains a putative binding motif for 4EHP, which may reflect a novel unknown function. development effect. mRNA to the 5′ cap structure. This is the first demonstration that a mammalian homeodomain transcription factor regulates translation, and that this function can be possibly essential for the development of female germ cells and involved in mammalian zygote development

Cxcl12/Cxcr4 signaling controls the migration and process orientation of A9-A10 dopaminergic neurons

CXCL12/CXCR4 signaling has been reported to regulate three essential processes for the establishment of neural networks in different neuronal systems: neuronal migration, cell positioning and axon wiring. However, it is not known whether it regulates the development of A9-A10 tyrosine hydroxylase positive (TH + ) midbrain dopaminergic (mDA) neurons. We report here that Cxcl12 is expressed in the meninges surrounding the ventral midbrain (VM), whereas CXCR4 is present in NURR1 + mDA precursors and mDA neurons from E10.5 to E14.5. CXCR4 is activated in NURR1 + cells as they migrate towards the meninges. Accordingly, VM meninges and CXCL12 promoted migration and neuritogenesis of TH + cells in VM explants in a CXCR4-dependent manner. Moreover, in vivo electroporation of Cxcl12 at E12.5 in the basal plate resulted in lateral migration, whereas expression in the midline resulted in retention of TH + cells in the IZ close to the midline. Analysis of Cxcr4 − / − mice revealed the presence of VM TH + cells with disoriented processes in the intermediate zone (IZ) at E11.5 and marginal zone (MZ) at E14. Consistently, pharmacological blockade of CXCR4 or genetic deletion of Cxcr4 resulted in an accumulation of TH + cells in the lateral aspect of the IZ at E14, indicating that CXCR4 is required for the radial migration of mDA neurons in vivo . Altogether, our findings demonstrate that CXCL12/CXCR4 regulates the migration and orientation of processes in A9-A10 mDA neurons.14.976 JCR (2013) Q1, 6/251 Neuroscience