Brn3a regulates neuronal subtype specification in the trigeminal ganglion by promoting Runx expression during sensory differentiation

The transcription factor Brn3a, product of the pou4f1 gene, is expressed in most sensory neurons throughout embryogenesis. Prior work has demonstrated a role for Brn3a in the repression of early neurogenic genes; here we describe a second major role for Brn3a in the specification of sensory subtypes in the trigeminal ganglion (TG). Sensory neurons initially co-express multiple Trk-family neurotrophin receptors, but are later marked by the unique expression of TrkA, TrkB or TrkC. Maturation of these sensory subtypes is known to depend on the expression of Runx transcription factors. Newborn Brn3a knockout mice fail to express TrkC, which is associated in the TG with mechanoreceptors, plus a set of functional genes associated with nociceptor subtypes. In embryonic Brn3a-/- ganglia, the normal expression of Runx3 is never initiated in TrkC+ neurons, and Runx1 expression is greatly attenuated in TrkA+ nociceptors. These changes are accompanied by expanded expression of TrkB in neurons that abnormally express multiple Trks, followed by the loss of TrkC and TrkA expression. In transgenic embryos expressing a Brn3a-VP16 dominant transactivator, Runx3 mRNA expression is increased, suggesting that it is a direct regulatory target of Brn3a. Chromatin immunoprecipitation confirms that Brn3a binds in vivo to a conserved upstream enhancer element within histone H3-acetylated chromatin in the Runx3 locus. Together these data show that Brn3a acts upstream of the Runx factors, which then repress TrkB expression to allow establishment of the non-overlapping Trk receptor profiles and correct terminally differentiated phenotypes

POU-domain factor Brn3a regulates both distinct and common programs of gene expression in the spinal and trigeminal sensory ganglia

BACKGROUND: General somatic sensation is conveyed to the central nervous system at cranial levels by the trigeminal ganglion (TG), and at spinal levels by the dorsal root ganglia (DRG). Although these ganglia have similar functions, they have distinct embryological origins, in that both contain neurons originating from the neural crest, while only the TG includes cells derived from the placodal ectoderm. RESULTS: Here we use microarray analysis of E13.5 embryos to demonstrate that the developing DRG and TG have very similar overall patterns of gene expression. In mice lacking the POU-domain transcription factor Brn3a, the DRG and TG exhibit many common changes in gene expression, but a subset of Brn3a target genes show increased expression only in the TG. In the wild-type TG these Brn3a-repressed genes are silent, yet their promoter regions exhibit histone H3-acetylation levels similar to constitutively transcribed gene loci. This increased H3-acetylation is not observed in the DRG, suggesting that chromatin modifications play a role in cell-specific target gene regulation by Brn3a. CONCLUSION: These results demonstrate that one developmental role of Brn3a is to repress potential differences in gene expression between sensory neurons generated at different axial levels, and to regulate a convergent program of developmental gene expression, in which functionally similar populations of neurons are generated from different embryological substrates

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Correction to: Cluster identification, selection, and description in Cluster randomized crossover trials: the PREP-IT trials

An amendment to this paper has been published and can be accessed via the original article

Why we must move beyond LCOE for renewable energy design

The inherent intermittency of wind and solar energy challenges the relevance of Levelized Cost of Energy (LCOE) for their future design since LCOE neglects the time-varying price of electricity. The Cost of Valued Energy (COVE) is an improved valuation metric that takes into account time-dependent electricity prices. In particular, it integrates short-term (e.g., hourly) wind and solar energy “generation devaluation”, whereby high wind and/or solar energy generation can lead to low, and even negative, energy prices for grids with high renewable penetration. These aspects are demonstrated and quantified with examples of two large grids with high renewable shares using three approaches to model hourly price: (1) residual demand, (2) wind and solar generation, and (3) statistical price-generation correlation. All three approaches indicate significant generation devaluation. The residual demand approach provides the most accurate price information while statistical correlations show that generation devaluation is most pronounced for the Variable Renewable Energy (VRE) that dominates market share (e.g., solar for California and wind for Germany). In some cases, the cost of valued energy relative to levelized cost can be 43% higher for solar (CAISO) and 129% higher for wind (ERCOT). This indicates that COVE is a much more relevant metric than LCOE in such markets. This is because COVE is based on the annualized system costs relative to the annualized spot market revenue, and thus considers economic effects of costs vs. revenue as well as those of supply vs. demand. As such, COVE (instead of LCOE) is recommended to design and value next-generation renewable energy systems, including storage integration tradeoffs. However, more work is needed to develop generation devaluation models for projected grids and markets and to better classify grid characteristics as we head to a carbon-neutral energy future