Retrotransposon-induced mosaicism in the neural genome

Over the past decade, major discoveries in retrotransposon biology have depicted the neural genome as a dynamic structure during life. In particular, the retrotransposon LINE-1 (L1) has been shown to be transcribed and mobilized in the brain. Retrotransposition in the developing brain, as well as during adult neurogenesis, provides a milieu in which neural diversity can arise. Dysregulation of retrotransposon activity may also contribute to neurological disease. Here, we review recent reports of retrotransposon activity in the brain, and discuss the temporal nature of retrotransposition and its regulation in neural cells in response to stimuli. We also put forward hypotheses regarding the significance of retrotransposons for brain development and neurological function, and consider the potential implications of this phenomenon for neuropsychiatric and neurodegenerative conditions

Temporal-spatial changes in Sonic Hedgehog expression and signaling reveal different potentials of ventral mesencephalic progenitors to populate distinct ventral midbrain nuclei

<p>Abstract</p> <p>Background</p> <p>The ventral midbrain contains a diverse array of neurons, including dopaminergic neurons of the ventral tegmental area (VTA) and substantia nigra (SN) and neurons of the red nucleus (RN). Dopaminergic and RN neurons have been shown to arise from ventral mesencephalic precursors that express <it>Sonic Hedgehog </it>(<it>Shh</it>). However, <it>Shh </it>expression, which is initially confined to the mesencephalic ventral midline, expands laterally and is then downregulated in the ventral midline. In contrast, expression of the Hedgehog target gene <it>Gli1 </it>initiates in the ventral midline prior to <it>Shh </it>expression, but after the onset of <it>Shh </it>expression it is expressed in precursors lateral to <it>Shh</it>-positive cells. Given these dynamic gene expression patterns, <it>Shh </it>and <it>Gli1 </it>expression could delineate different progenitor populations at distinct embryonic time points.</p> <p>Results</p> <p>We employed genetic inducible fate mapping (GIFM) to investigate whether precursors that express <it>Shh </it>(Shh-GIFM) or transduce Shh signaling (Gli1-GIFM) at different time points give rise to different ventral midbrain cell types. We find that precursors restricted to the ventral midline are labeled at embryonic day (E)7.5 with Gli1-GIFM, and with Shh-GIFM at E8.5. These precursors give rise to all subtypes of midbrain dopaminergic neurons and the anterior RN. A broader domain of progenitors that includes the ventral midline is marked with Gli1-GIFM at E8.5 and with Shh-GIFM at E9.5; these fate-mapped cells also contribute to all midbrain dopaminergic subtypes and to the entire RN. In contrast, a lateral progenitor domain that is labeled with Gli1-GIFM at E9.5 and with Shh-GIFM at E11.5 has a markedly reduced potential to give rise to the RN and to SN dopaminergic neurons, and preferentially gives rise to the ventral-medial VTA. In addition, cells derived from <it>Shh</it>- and <it>Gli1</it>-expressing progenitors located outside of the ventral midline give rise to astrocytes.</p> <p>Conclusions</p> <p>We define a ventral midbrain precursor map based on the timing of <it>Gli1 </it>and <it>Shh </it>expression, and suggest that the diversity of midbrain dopaminergic neurons is at least partially determined during their precursor stage when their medial-lateral position, differential gene expression and the time when they leave the ventricular zone influence their fate decisions.</p

Effect of Nuclear Quadrupole Interaction on the Relaxation in Amorphous Solids

Recently it has been experimentally demonstrated that certain glasses display an unexpected magnetic field dependence of the dielectric constant. In particular, the echo technique experiments have shown that the echo amplitude depends on the magnetic field. The analysis of these experiments results in the conclusion that the effect seems to be related to the nuclear degrees of freedom of tunneling systems. The interactions of a nuclear quadrupole electrical moment with the crystal field and of a nuclear magnetic moment with magnetic field transform the two-level tunneling systems inherent in amorphous dielectrics into many-level tunneling systems. The fact that these features show up at temperatures $T<100mK$, where the properties of amorphous materials are governed by the long-range $R^{-3}$ interaction between tunneling systems, suggests that this interaction is responsible for the magnetic field dependent relaxation. We have developed a theory of many-body relaxation in an ensemble of interacting many-level tunneling systems and show that the relaxation rate is controlled by the magnetic field. The results obtained correlate with the available experimental data. Our approach strongly supports the idea that the nuclear quadrupole interaction is just the key for understanding the unusual behavior of glasses in a magnetic field.Comment: 18 pages, 9 figure

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

Taxing times: taxation, divided societies and the informal economy in Northern Nigeria

This paper challenges the notion that taxing the informal economy provides a mechanism for increasing popular political voice and rebuilding the social contract. It contends that current arguments for taxing the informal economy suffer from a Eurocentric understanding of taxation and state formation, and a fiscally essentialist and undifferentiated notion of the informal economy. Drawing on fieldwork in northern Nigeria, this paper shows that history, gender, wealth and ethno-religious identity influence how taxing the informal economy shapes governance outcomes. Evidence from Nigeria suggests an inverse relationship between informal economy taxation and political voice, posing the risk that increased taxation will exacerbate social divisions rather than rebuild the social contract

The Pathway Coexpression Network: Revealing pathway relationships.

A goal of genomics is to understand the relationships between biological processes. Pathways contribute to functional interplay within biological processes through complex but poorly understood interactions. However, limited functional references for global pathway relationships exist. Pathways from databases such as KEGG and Reactome provide discrete annotations of biological processes. Their relationships are currently either inferred from gene set enrichment within specific experiments, or by simple overlap, linking pathway annotations that have genes in common. Here, we provide a unifying interpretation of functional interaction between pathways by systematically quantifying coexpression between 1,330 canonical pathways from the Molecular Signatures Database (MSigDB) to establish the Pathway Coexpression Network (PCxN). We estimated the correlation between canonical pathways valid in a broad context using a curated collection of 3,207 microarrays from 72 normal human tissues. PCxN accounts for shared genes between annotations to estimate significant correlations between pathways with related functions rather than with similar annotations. We demonstrate that PCxN provides novel insight into mechanisms of complex diseases using an Alzheimer's Disease (AD) case study. PCxN retrieved pathways significantly correlated with an expert curated AD gene list. These pathways have known associations with AD and were significantly enriched for genes independently associated with AD. As a further step, we show how PCxN complements the results of gene set enrichment methods by revealing relationships between enriched pathways, and by identifying additional highly correlated pathways. PCxN revealed that correlated pathways from an AD expression profiling study include functional clusters involved in cell adhesion and oxidative stress. PCxN provides expanded connections to pathways from the extracellular matrix. PCxN provides a powerful new framework for interrogation of global pathway relationships. Comprehensive exploration of PCxN can be performed at http://pcxn.org/