Developmental programs that generate the astonishing neuronal diversity of the nervous system are not completely understood and thus present a significant challenge for clinical applications of guided cell differentiation strategies. Using direct neuronal programming of embryonic stem cells, we found that two main vertebrate proneural factors, Ascl1 and Neurog2, induce different neuronal fates by binding to largely different sets of genomic sites. Their divergent binding patterns are not determined by the previous chromatin state but are distinguished by enrichment of specific E-box sequences which reflect the binding preferences of the DNA-binding domains. The divergent Ascl1 and Neurog2 binding patterns result in distinct chromatin accessibility and enhancer activity profiles that differentially shape the binding of downstream transcription factors during neuronal differentiation. This study provides a mechanistic understanding of how transcription factors constrain terminal cell fates, and it delineates the importance of choosing the right proneural factor in neuronal reprogramming strategies.
Background: Arrestin recruitment to the -opioid receptor (KOR) has been linked to several adverse effects of analgesics, such as dysphoria and tolerance. Results: We identified 6Ј-guanidinonaltrindole (6Ј-GNTI) as a potent KOR agonist for G protein activation that fails to recruit arrestin. Conclusion: 6Ј-GNTI is an extreme G protein-biased KOR ligand. Significance: 6Ј-GNTI is a lead toward analgesics with fewer arrestin-mediated adverse effects.-Opioid receptor (KOR) agonists do not activate the reward pathway stimulated by morphine-like -opioid receptor (MOR) agonists and thus have been considered to be promising nonaddictive analgesics. However, KOR agonists produce other adverse effects, including dysphoria, diuresis, and constipation. The therapeutic promise of KOR agonists has nonetheless recently been revived by studies showing that their dysphoric effects require arrestin recruitment, whereas their analgesic effects do not. Moreover, KOR agonist-induced antinociceptive tolerance observed in vivo has also been proposed to be correlated to the ability to induce arrestin-dependent phosphorylation, desensitization, and internalization of the receptor. The discovery of functionally selective drugs that are therapeutically effective without the adverse effects triggered by the arrestin pathway is thus an important goal. We have identified such an extreme G protein-biased KOR compound, 6-guanidinonaltrindole (6-GNTI), a potent partial agonist at the KOR receptor for the G protein activation pathway that does not recruit arrestin. Indeed, 6-GNTI functions as an antagonist to block the arrestin recruitment and KOR internalization induced by other nonbiased agonists. As an extremely G protein-biased KOR agonist, 6-GNTI represents a promising lead compound in the search for nonaddictive opioid analgesic as its signaling profile suggests that it will be without the dysphoria and other adverse effects promoted by arrestin recruitment and its downstream signaling.-Opioid receptors (KOR) 2 are widely expressed in the periphery, the dorsal root ganglia, the spinal cord, and the supraspinal regions associated with pain modulation. KOR agonists have been shown to activate pain inhibitory pathways in the central nervous system, and peripherally restricted KOR agonists have been developed to target KOR located on visceral and somatic afferent nerves for relief of inflammatory, visceral, and neuropathic chronic pain (1, 2). The analgesic properties of KOR agonists are attributed to their ability to activate G proteins in the G i/o family (3, 4) as the subsequent inhibition of cAMP production (5), as well as the activation of inward rectifier potassium channels (6) and blockade of calcium channels (7), has an inhibitory effect in neurons. In contrast to MOR agonists, KOR agonists are unable to activate the reward pathway and have therefore attracted considerable attention for their ability to exert potent analgesic effects without high abuse potential (1,8).Unfortunately, KOR agonists have been found to produce other signif...
The sensory nervous system of C. elegans comprises cells with varied molecular and functional characteristics, and is, therefore, a powerful model for understanding mechanisms that generate neuronal diversity. We report here that VAB-3, a C. elegans homolog of the homeodomain-containing protein Pax6, has opposing functions in regulating expression of a specific chemosensory fate. A homeodomain-only short isoform of VAB-3 is expressed in BAG chemosensory neurons, where it promotes gene expression and cell function. In other cells, a long isoform of VAB-3, comprising a Paired homology domain and a homeodomain, represses expression of ETS-5, a transcription factor required for expression of BAG fate. Repression of ets-5 requires the Eyes Absent homolog EYA-1 and the Six-class homeodomain protein CEH-32. We determined sequences that mediate high-affinity binding of ETS-5, VAB-3 and CEH-32. The ets-5 locus is enriched for ETS-5-binding sites but lacks sequences that bind VAB-3 and CEH-32, suggesting that these factors do not directly repress ets-5 expression. We propose that a promoterselection system together with lineage-specific expression of accessory factors allows VAB-3/Pax6 to either promote or repress expression of specific cell fates in a context-dependent manner.This article has an associated 'The people behind the papers' interview.
During development, the nervous system generates neurons that serve highly specialized roles and, accordingly, possess unique functional attributes. The chemosensory BAG neurons of C. elegans are striking exemplars of this. BAGs sense the respiratory gas carbon dioxide (CO 2 ) and, in a context-dependent manner, switch from mediating avoidance of CO 2 to supporting CO 2 attraction. To determine mechanisms that support the physiology and plasticity of BAG neurons, we used tandem ChIP-seq and cell targeted RNA-seq to identify gene targets of the transcription factor ETS-5, which is required for BAG development. A functional screen of ETS-5 targets revealed that NHR-6, the sole C. elegans NR4A-type nuclear receptor, is required for BAG-mediated avoidance of CO 2 and regulates expression of a subset of BAG-specific genes. Unlike ets-5 mutants, which are defective for both attraction to and avoidance of CO 2 , nhr-6 mutants are fully competent for attraction. These data indicate that the remarkable ability of BAGs to adaptively assign positive or negative valence to a chemosensory stimulus requires a gene-regulatory program supported by an evolutionarily conserved type of nuclear receptor. We suggest that NHR-6 might be an example of a developmental mechanism for modular encoding of functional plasticity in the nervous system.
ELISA kit, Abcam). Patients completed the Beck Depression Inventory (BDI) and the Female Sexual Functioning Index (FSFI), which includes domains for desire, arousal, lubrication, orgasm, satisfaction, and pain, at study initiation and at 6 months. Pearson correlation was used to determine associations between total Vit D levels, BDI, and FSFI scores and paired T-Tests were used to determine change over time.RESULTS: Forty-seven women were initially evaluated; 5 were excluded with severe depression.
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