Brief Studies

Theses on Principles Governing Co-operation Between Churches Not in Church Fellowshi

Theological Observer

Theological Observe

Sonic Hedgehog Is a Chemoattractant for Midbrain Dopaminergic Axons

Midbrain dopaminergic axons project from the substantia nigra (SN) and the ventral tegmental area (VTA) to rostral target tissues, including the striatum, pallidum, and hypothalamus. The axons from the medially located VTA project primarily to more medial target tissues in the forebrain, whereas the more lateral SN axons project to lateral targets including the dorsolateral striatum. This structural diversity underlies the distinct functions of these pathways. Although a number of guidance cues have been implicated in the formation of the distinct axonal projections of the SN and VTA, the molecular basis of their diversity remains unclear. Here we investigate the molecular basis of structural diversity in mDN axonal projections. We find that Sonic Hedgehog (Shh) is expressed at a choice point in the course of the rostral dopaminergic projections. Furthermore, in midbrain explants, dopaminergic projections are attracted to a Shh source. Finally, in mice in which Shh signaling is inactivated during late neuronal development, the most medial dopaminergic projections are deficient

The transcription factor BCL11A defines distinct subsets of midbrain dopaminergic neurons.

Midbrain dopaminergic (mDA) neurons are diverse in their projection targets, effect on behavior, and susceptibility to neurodegeneration. Little is known about the molecular mechanisms establishing this diversity during development. We show that the transcription factor BCL11A is expressed in a subset of mDA neurons in the developing and adult murine brain and in a subpopulation of pluripotent-stem-cell-derived human mDA neurons. By combining intersectional labeling and viral-mediated tracing, we demonstrate that Bcl11a-expressing mDA neurons form a highly specific subcircuit within the murine dopaminergic system. In the substantia nigra, the Bcl11a-expressing mDA subset is particularly vulnerable to neurodegeneration upon α-synuclein overexpression or oxidative stress. Inactivation of Bcl11a in murine mDA neurons increases this susceptibility further, alters the distribution of mDA neurons, and results in deficits in skilled motor behavior. In summary, BCL11A defines mDA subpopulations with highly distinctive characteristics and is required for establishing and maintaining their normal physiology

BMP/SMAD pathway promotes neurogenesis of midbrain dopaminergic neurons in vivo and in human induced pluripotent and neural stem cells

The embryonic formation of midbrain dopaminergic (mDA) neurons in vivo provides critical guidelines for the in vitro differentiation of mDA neurons from stem cells, which are currently being developed for Parkinson’s disease cell replacement therapy. Bone morphogenetic protein (BMP)/SMAD inhibition is routinely used during early steps of stem cell differentiation protocols, including for the generation of mDA neurons. However, the function of the BMP/SMAD pathway for in vivo specification of mammalian mDA neurons is virtually unknown. Here, we report that BMP5/7-deficient mice (Bmp5 -/- ; Bmp7 -/- ) lackmDAneurons due to reduced neurogenesis in the mDA progenitor domain. As molecular mechanisms accounting for these alterations in Bmp5 -/- ; Bmp7 -/- mutants, we have identified expression changes of the BMP/SMAD target genes MSX1/2 (msh homeobox 1/2) and SHH (sonic hedgehog). Conditionally inactivatingSMAD1in neural stem cells of mice in vivo (Smad1 Nes ) hampered the differentiation of progenitor cells intomDAneurons by preventing cell cycle exit, especially of TH + SOX6 + (tyrosine hydroxylase, SRY-box 6) and TH + GIRK2 + (potassium voltage-gated channel subfamily-J member-6) substantia nigra neurons. BMP5/7 robustly increased the in vitro differentiation of human induced pluripotent stem cells and induced neural stem cells to mDA neurons by up to threefold. In conclusion, we have identified BMP/SMAD signaling as a novel critical pathway orchestrating essential steps of mammalian mDA neurogenesis in vivo that balances progenitor proliferation and differentiation. Moreover, we demonstrate the potential of BMPs to improve the generation of stem-cell-derived mDA neurons in vitro, highlighting the importance of sequential BMP/SMAD inhibition and activation in this process

Ectopic Wnt/Beta–Catenin Signaling Induces Neurogenesis in the Spinal Cord and Hindbrain Floor Plate

The most ventral structure of the developing neural tube, the floor plate (FP), differs in neurogenic capacity along the neuraxis. The FP is largely non-neurogenic at the hindbrain and spinal cord levels, but generates large numbers of dopamine (mDA) neurons at the midbrain levels. Wnt1, and other Wnts are expressed in the ventral midbrain, and Wnt/beta catenin signaling can at least in part account for the difference in neurogenic capacity of the FP between midbrain and hindbrain levels. To further develop the hypothesis that canonical Wnt signaling promotes mDA specification and FP neurogenesis, we have generated a model wherein beta–catenin is conditionally stabilized throughout the FP. Here, we unambiguously show by fate mapping FP cells in this mutant, that the hindbrain and spinal cord FP are rendered highly neurogenic, producing large numbers of neurons. We reveal that a neurogenic hindbrain FP results in the altered settling pattern of neighboring precerebellar neuronal clusters. Moreover, in this mutant, mDA progenitor markers are induced throughout the rostrocaudal axis of the hindbrain FP, although TH+ mDA neurons are produced only in the rostral aspect of rhombomere (r)1. This is, at least in part, due to depressed Lmx1b levels by Wnt/beta catenin signaling; indeed, when Lmx1b levels are restored in this mutant, mDA are observed not only in rostral r1, but also at more caudal axial levels in the hindbrain, but not in the spinal cord. Taken together, these data elucidate both patterning and neurogenic functions of Wnt/beta catenin signaling in the FP, and thereby add to our understanding of the molecular logic of mDA specification and neurogenesis

Large-scale Cosmic-Ray Anisotropies above 4 EeV Measured by the Pierre Auger Observatory

We present a detailed study of the large-scale anisotropies of cosmic rays with energies above 4 EeV measured using the Pierre Auger Observatory. For the energy bins [4, 8] EeV and E ≥ 8 EeV, the most significant signal is a dipolar modulation in R.A. at energies above 8 EeV, as previously reported. In this paper we further scrutinize the highest-energy bin by splitting it into three energy ranges. We find that the amplitude of the dipole increases with energy above 4 EeV. The growth can be fitted with a power law with index β = 0.79 ± 0.19. The directions of the dipoles are consistent with an extragalactic origin of these anisotropies at all the energies considered. Additionally, we have estimated the quadrupolar components of the anisotropy: they are not statistically significant. We discuss the results in the context of the predictions from different models for the distribution of ultrahigh-energy sources and cosmic magnetic fields

Azimuthal asymmetry in the risetime of the surface detector signals of the Pierre Auger Observatory

The azimuthal asymmetry in the risetime of signals in Auger surface detector stations is a source of information on shower development. The azimuthal asymmetry is due to a combination of the longitudinal evolution of the shower and geometrical effects related to the angles of incidence of the particles into the detectors. The magnitude of the effect depends upon the zenith angle and state of development of the shower and thus provides a novel observable, $(\sec \theta)_\mathrm{max}$, sensitive to the mass composition of cosmic rays above $3 \times 10^{18}$ eV. By comparing measurements with predictions from shower simulations, we find for both of our adopted models of hadronic physics (QGSJETII-04 and EPOS-LHC) an indication that the mean cosmic-ray mass increases slowly with energy, as has been inferred from other studies. However, the mass estimates are dependent on the shower model and on the range of distance from the shower core selected. Thus the method has uncovered further deficiencies in our understanding of shower modelling that must be resolved before the mass composition can be inferred from $(\sec \theta)_\mathrm{max}$.Comment: Replaced with published version. Added journal reference and DO

Ultrahigh-energy neutrino follow-up of Gravitational Wave events GW150914 and GW151226 with the Pierre Auger Observatory

On September 14, 2015 the Advanced LIGO detectors observed their first gravitational-wave (GW) transient GW150914. This was followed by a second GW event observed on December 26, 2015. Both events were inferred to have arisen from the merger of black holes in binary systems. Such a system may emit neutrinos if there are magnetic fields and disk debris remaining from the formation of the two black holes. With the surface detector array of the Pierre Auger Observatory we can search for neutrinos with energy above 100 PeV from point-like sources across the sky with equatorial declination from about -65 deg. to +60 deg., and in particular from a fraction of the 90% confidence-level (CL) inferred positions in the sky of GW150914 and GW151226. A targeted search for highly-inclined extensive air showers, produced either by interactions of downward-going neutrinos of all flavors in the atmosphere or by the decays of tau leptons originating from tau-neutrino interactions in the Earth's crust (Earth-skimming neutrinos), yielded no candidates in the Auger data collected within $\pm 500$ s around or 1 day after the coordinated universal time (UTC) of GW150914 and GW151226, as well as in the same search periods relative to the UTC time of the GW candidate event LVT151012. From the non-observation we constrain the amount of energy radiated in ultrahigh-energy neutrinos from such remarkable events.Comment: Published version. Added journal reference and DOI. Added Report Numbe