Epigenetic regulation of axon and dendrite growth

Neuroregenerative therapies for central nervous system (CNS) injury, neurodegenerative disease, or stroke require axons of damaged neurons to grow and re-innervate their targets. However, mature mammalian CNS neurons do not regenerate their axons, limiting recovery in these diseases. Although neurons' intrinsic capacity for axon growth may depend in part on the panoply of expressed transcription factors, epigenetic factors such as the accessibility of DNA and organization of chromatin are required for downstream genes to be transcribed. Thus, a potential approach to overcoming regenerative failure focuses on the epigenetic mechanisms regulating regenerative gene expression in the CNS. Here we review molecular mechanisms regulating the epigenetic state of DNA through chromatin modifications, their implications for regulating axon and dendrite growth, and important new directions for this field of study

Isoform-specific subcellular localization and function of protein kinase A identified by mosaic imaging of mouse brain.

Protein kinase A (PKA) plays critical roles in neuronal function that are mediated by different regulatory (R) subunits. Deficiency in either the RIβ or the RIIβ subunit results in distinct neuronal phenotypes. Although RIβ contributes to synaptic plasticity, it is the least studied isoform. Using isoform-specific antibodies, we generated high-resolution large-scale immunohistochemical mosaic images of mouse brain that provided global views of several brain regions, including the hippocampus and cerebellum. The isoforms concentrate in discrete brain regions, and we were able to zoom-in to show distinct patterns of subcellular localization. RIβ is enriched in dendrites and co-localizes with MAP2, whereas RIIβ is concentrated in axons. Using correlated light and electron microscopy, we confirmed the mitochondrial and nuclear localization of RIβ in cultured neurons. To show the functional significance of nuclear localization, we demonstrated that downregulation of RIβ, but not of RIIβ, decreased CREB phosphorylation. Our study reveals how PKA isoform specificity is defined by precise localization

KLF9 and JNK3 Interact to Suppress Axon Regeneration in the Adult CNS

Neurons in the adult mammalian CNS decrease in intrinsic axon growth capacity during development in concert with changes in Krüppel-like transcription factors (KLFs). KLFs regulate axon growth in CNS neurons including retinal ganglion cells (RGCs). Here, we found that knock-down of KLF9, an axon growth suppressor that is normally upregulated 250-fold in RGC development, promotes long-distance optic nerve regeneration in adult rats of both sexes. We identified a novel binding partner, MAPK10/JNK3 kinase, and found that JNK3 (c-Jun N-terminal kinase 3) is critical for KLF9\u27s axon-growth-suppressive activity. Interfering with a JNK3-binding domain or mutating two newly discovered serine phosphorylation acceptor sites, Ser106 and Ser110, effectively abolished KLF9\u27s neurite growth suppression in vitro and promoted axon regeneration in vivo. These findings demonstrate a novel, physiologic role for the interaction of KLF9 and JNK3 in regenerative failure in the optic nerve and suggest new therapeutic strategies to promote axon regeneration in the adult CNS

Prevalence of filarioid nematodes and trypanosomes in American robins and house sparrows, Chicago USA

AbstractHosts are commonly infected with a suite of parasites, and interactions among these parasites can affect the size, structure, and behavior of host–parasite communities. As an important step to understanding the significance of co-circulating parasites, we describe prevalence of co-circulating hemoparasites in two important avian amplification hosts for West Nile virus (WNV), the American robin (Turdus migratorius) and house sparrow (Passer domesticus), during the 2010–2011 in Chicago, Illinois, USA. Rates of nematode microfilariemia were 1.5% of the robins (n=70) and 4.2% of the house sparrows (n=72) collected during the day and 11.1% of the roosting robins (n=63) and 0% of the house sparrows (n=11) collected at night. Phylogenetic analysis of nucleotide sequences of the 18S rRNA and cytochrome oxidase subunit I (COI) genes from these parasites resolved two clades of filarioid nematodes. Microscopy revealed that 18.0% of American robins (n=133) and 16.9% of house sparrows (n=83) hosted trypanosomes in the blood. Phylogenetic analysis of nucleotide sequences from the 18s rRNA gene revealed that the trypanosomes fall within previously described avian trypanosome clades. These results document hemoparasites in the blood of WNV hosts in a center of endemic WNV transmission, suggesting a potential for direct or indirect interactions with the virus

Evaluation of the efficacy and safety of bempedoic acid in women and men: Pooled analyses from phase 3 trials

BACKGROUND AND AIMS: Sex-specific differences in the response to lipid-lowering therapies have been reported. Here, we assessed the effect of bempedoic acid in women and men using pooled, patient-level data from four phase 3 clinical trials of bempedoic acid. METHODS: Patients were grouped into two pools: 1) atherosclerotic cardiovascular disease (ASCVD) and/or heterozygous familial hypercholesterolemia (HeFH) on statins and 2) low-dose or no statin . Percent changes from baseline to at least week 12 in low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol (non-HDL-C), total cholesterol (TC), apolipoprotein B (Apo B), and high-sensitivity C-reactive protein (hsCRP), as well as safety, were analyzed by statin pool and sex. RESULTS: Overall, 3623 patients were included (bempedoic acid, 2425; placebo, 1198). Significant reductions in lipid parameters and hsCRP were observed with bempedoic acid vs. placebo in both sexes in the ASCVD and/or HeFH on statins (n = 3009) and the low-dose or no statin (n = 614) pools (p ≤ 0.002). Compared with men, women had significantly greater placebo-corrected reductions in LDL-C (-21.2% vs. -17.4%; p = 0.044), non-HDL-C (-17.3% vs. -12.1%; p = 0.003), TC (-13.8% vs. -10.5%; p = 0.012), and Apo B (-16.0% vs. -11.3%; p = 0.004) in the ASCVD and/or HeFH on statins pool. Women had similar reductions to men in lipid parameters in the low-dose or no statin pool and hsCRP in both pools. The safety of bempedoic acid was comparable between sexes. CONCLUSIONS: In this pooled analysis, women experienced significant improvements in levels of LDL-C and other lipid parameters with bempedoic acid

Gene Expression Profiling of Purified Rat Retinal Ganglion Cells

PURPOSE. The phenotype of specialized cells arises, in part, from their characteristic gene expression patterns. Retinal ganglion cells (RGCs) are of wide interest in neuroscience and die in glaucoma and other optic neuropathies. In this study the genes expressed by RGCs were profiled by expressed sequence tag (EST) analysis. METHODS. ESTs were generated from a cDNA library constructed from RGCs isolated by immunopanning. The RGC genes were compared with published microarray expression profiles from 13 different neural regions. Immunohistochemistry was performed by standard methods. RESULTS. Clustering of 4791 RGC ESTs identified 2360 unique gene clusters. Of these, 60% represented known genes, 27% uncharacterized genes/ESTs, and 13% novel sequence. Unexpectedly, one of the largest RGC clusters, RESP18, corresponded to a neuroendocrine-specific gene preferentially expressed in the hypothalamus. RESP18 immunoreactivity within the retina was found mainly in the RGC layer. DDAH1, a gene involved in nitric oxide metabolism, was localized to RGC and amacrine layers. Comparison of gene expression patterns across neuronal regions revealed a prominent subset of RGC genes that were overexpressed in dorsal root and trigeminal ganglia. To narrow the search for candidate disease-related genes, RGC genes were mapped to known disease loci for optic neuropathies. CONCLUSIONS. This work is one of the first efforts to profile gene expression in a purified population of retinal neurons, the RGCs. The profiling, in addition to revealing both known and novel genes underlying the RGC phenotype, also uncovered common patterns of gene expression between RGCs and other sensory ganglia. (Invest Ophthalmol Vis Sci

International Network of Twin Registries (INTR): Building a Platform for International Collaboration

This publication is with permission of the rights owner freely accessible due to an Alliance licence and a national licence (funded by the DFG, German Research Foundation) respectively.The International Network of Twin Registries (INTR) aims to foster scientific collaboration and promote twin research on a global scale by working to expand the resources of twin registries around the world and make them available to researchers who adhere to established guidelines for international collaboration. Our vision is to create an unprecedented scientific network of twin registries that will advance knowledge in ways that are impossible for individual registries, and includes the harmonization of data. INTR will also promote a broad range of activities, including the development of a website, formulation of data harmonization protocols, creation of a library of software tools for twin studies, design of a search engine to identify research partners, establishment of searchable inventories of data and biospecimens, development of templates for informed consent and data sharing, organization of symposia at International Society of Twin Studies conferences, support for scholar exchanges, and writing grant proposals.Peer Reviewe

Dispersal of Adult Culex Mosquitoes in an Urban West Nile Virus Hotspot: A Mark-Capture Study Incorporating Stable Isotope Enrichment of Natural Larval Habitats

Dispersal is a critical life history behavior for mosquitoes and is important for the spread of mosquito-borne disease. We implemented the first stable isotope mark-capture study to measure mosquito dispersal, focusing on Culex pipiens in southwest suburban Chicago, Illinois, a hotspot of West Nile virus (WNV) transmission. We enriched nine catch basins in 2010 and 2011 with 15N-potassium nitrate and detected dispersal of enriched adult females emerging from these catch basins using CDC light and gravid traps to distances as far as 3 km. We detected 12 isotopically enriched pools of mosquitoes out of 2,442 tested during the two years and calculated a mean dispersal distance of 1.15 km and maximum flight range of 2.48 km. According to a logistic distribution function, 90% of the female Culex mosquitoes stayed within 3 km of their larval habitat, which corresponds with the distance-limited genetic variation of WNV observed in this study region. This study provides new insights on the dispersal of the most important vector of WNV in the eastern United States and demonstrates the utility of stable isotope enrichment for studying the biology of mosquitoes in other disease systems.The open access fee for this work was funded through the Texas A&M University Open Access to Knowledge (OAK) Fund