Molecular Regulation of Fetal Brain Development in Inbred and Congenic Mouse Strains Differing in Longevity.

The objective of this study was to investigate gene regulation of the developing fetal brain from congenic or inbred mice strains that differed in longevity. Gene expression and alternative splice variants were analyzed in a genome-wide manner in the fetal brain of C57BL/6J mice (long-lived) in comparison to B6.Cg-Cav1tm1Mls/J (congenic, short-lived) and AKR/J (inbred, short-lived) mice on day(d) 12, 15, and 17 of gestation. The analysis showed a contrasting gene expression pattern during fetal brain development in these mice. Genes related to brain development, aging, and the regulation of alternative splicing were significantly differentially regulated in the fetal brain of the short-lived compared to long-lived mice during development from d15 and d17. A significantly reduced number of splice variants was observed on d15 compared to d12 or d17 in a strain-dependent manner. An epigenetic clock analysis of d15 fetal brain identified DNA methylations that were significantly associated with single-nucleotide polymorphic sites between AKR/J and C57BL/6J strains. These methylations were associated with genes that show epigenetic changes in an age-correlated manner in mice. Together, the finding of this study suggest that fetal brain development and longevity are epigenetically linked, supporting the emerging concept of the early-life origin of longevity.

Single-Cell Transcriptional Response of the Placenta to the Ablation of Caveolin-1: Insights into the Adaptive Regulation of Brain-Placental Axis in Mice.

Caveolin-1 (Cav1) is a major plasma membrane protein that plays important functions in cellular metabolism, proliferation, and senescence. Mice lacking Cav1 show abnormal gene expression in the fetal brain. Though evidence for placental influence on brain development is emerging, whether the ablation of Cav1 affects the regulation of the brain-placental axis remains unexamined. The current study tests the hypothesis that gene expression changes in specific cells of the placenta and the fetal brain are linked to the deregulation of the brain-placental axis in Cav1-null mice. By performing single-nuclei RNA sequencing (snRNA-seq) analyses, we show that the abundance of the extravillious trophoblast (EVT) and stromal cells, but not the cytotrophoblast (CTB) or syncytiotrophoblast (STB), are significantly impacted due to Cav1 ablation in mice. Interestingly, specific genes related to brain development and neurogenesis were significantly differentially expressed in trophoblast cells due to Cav1 deletion. Comparison of single-cell gene expression between the placenta and the fetal brain further showed that specific genes such as plexin A1 (Plxna1), phosphatase and actin regulator 1 (Phactr1) and amyloid precursor-like protein 2 (Aplp2) were differentially expressed between the EVT and STB cells of the placenta, and also, between the radial glia and ependymal cells of the fetal brain. Bulk RNA-seq analysis of the whole placenta and the fetal brain further identified genes differentially expressed in a similar manner between the placenta and the fetal brain due to the absence of Cav1. The deconvolution of reference cell types from the bulk RNA-seq data further showed that the loss of Cav1 impacted the abundance of EVT cells relative to the stromal cells in the placenta, and that of the glia cells relative to the neuronal cells in the fetal brain. Together, the results of this study suggest that the ablation of Cav1 causes deregulated gene expression in specific cell types of the placenta and the fetal brain in mice.

Ablation of placental REST deregulates fetal brain metabolism and impacts gene expression of the offspring brain at the postnatal and adult stages.

In this study, the transcriptional repressor REST (Repressor Element 1 Silencing Transcription factor) was ablated in the mouse placenta to investigate molecular and cellular impacts on the offspring brain at different life stages. Ablation of placental REST deregulated several brain metabolites, including glucose and lactate that fuel brain energy, vitamin C (ascorbic acid) that functions in the epigenetic programming of the brain during postnatal development, and glutamate and creatine that help the brain to respond to stress conditions during adult life. Bulk RNA-seq analysis showed that a lack of placental REST persistently altered multiple transport genes, including those related to oxygen transportation in the offspring brain. While metabolic genes were impacted in the postnatal brain, different stress response genes were activated in the adult brain. DNA methylation was also impacted in the adult brain due to the loss of placental REST, but in a sex-biased manner. Single-nuclei RNA-seq analysis showed that specific cell types of the brain, particularly those of the choroid plexus and ependyma, which play critical roles in producing cerebrospinal fluid and maintaining metabolic homeostasis, were significantly impacted due to the loss of placental REST. These cells showed significant differential expression of genes associated with the metabotropic (G coupled protein) and ionotropic (ligand-gated ion channel) glutamate receptors, suggesting an impact of ablation of placental REST on the glutamatergic signaling of the offspring brain. The study expands our understanding of placental influences on the offspring brain.

Role of paralogs in the sex-bias transcriptional and metabolic regulation of the brain-placental axis in mice.

INTRODUCTION: Duplicated genes or paralogs play important roles in the adaptive function of eukaryotic genomes. Animal studies have shown evidence for the functional role of paralogs in pregnancy, but our knowledge about the role of paralogs in the fetoplacental regulation remains limited. In particular, if fetoplacental metabolic regulation is modulated by differential expression of paralogs remains unexamined. METHODS: In this study, gene expression profiles of day-15 placenta and fetal brain were compared to identify families or groups of paralogous genes expressed in the placenta and brain of male versus female fetuses in mice. A Bayesian modeling was applied to infer directional relationship of transcriptional variation of the paralogs relative to the phylogenetic variation of the genes in each family. Gas chromatography-mass spectrometry (GC-MS) was used to perform untargeted metabolomics analysis of day-15 placenta and fetal brain of both sexes. RESULTS: We identified paralog groups that were expressed in a sex and/or tissue biased manner between the placenta and fetal brain. Bayesian modeling showed evidence for directional relationship between expression and phylogeny of specific paralogs. These relationships were sex specific. GC-MS analysis identified metabolites that were expressed in a sex-bias manner between the placenta and fetal brain. By performing integrative analysis of the metabolomics and gene expression data, we showed that specific groups of metabolites and paralogous genes were expressed in a coordinated manner between the placenta and fetal brain. DISCUSSION: The findings of this study collectively suggest that paralogs play an influential role in the regulation of the brain-placental axis in mice.

Role of caveolin-1 in metabolic programming of fetal brain.

Mice lacking caveolin-1 (Cav1), a key protein of plasma membrane, exhibit brain aging at an early adult stage. Here, integrative analyses of metabolomics, transcriptomics, epigenetics, and single-cell data were performed to test the hypothesis that metabolic deregulation of fetal brain due to the ablation of Cav1 is linked to brain aging in these mice. The results of this study show that lack of Cav1 caused deregulation in the lipid and amino acid metabolism in the fetal brain, and genes associated with these deregulated metabolites were significantly altered in the brain upon aging. Moreover, ablation of Cav1 deregulated several metabolic genes in specific cell types of the fetal brain and impacted DNA methylation of those genes in coordination with mouse epigenetic clock. The findings of this study suggest that the aging program of brain is confounded by metabolic abnormalities in the fetal stage due to the absence of Cav1.

Efficiency improvement of thin film solar cell using silver pyramids array and antireflective layer.

In recent years, plasmonics has been widely employed to improve light trapping in solar cells. Silver nanospheres have been used in several research works to improve the capability of solar absorption. In this paper, we use silver pyramid-shaped nanoparticles, a noble plasmonic nanoparticle, inside thin-film silicon and InP solar cells to increase light absorption compared to previously published topologies. The proposed structure consists of a TiO2 pyramid structure placed at the top of the surface working as an anti-reflective layer, silicon/indium phosphate as an absorption layer, silver pyramid-shaped nanoparticles incorporated inside the absorption layer, and an aluminum reflecting layer at the bottom. In this research, we used finite difference time domain (FDTD) simulation to model the thin-film solar cell (TFSC). Optimizing the shape and placement of the silver pyramids, we have achieved an efficiency of 17.08% and 18.58% using silicon and InP as the absorbing layers respectively, which is significantly better than previously reported studies. The open-circuit voltages are 0.58 V and 0.92 V respectively, which is the highest among other configurations. To conclude, the findings of this study laid the foundation to create an efficient thin-film solar cell utilizing the light-trapping mechanism of noble plasmonic nanoparticles.

Fetal origin of sex-bias brain aging.

DNA methylation plays crucial roles during fetal development as well as aging. Whether the aging of the brain is programmed at the fetal stage remains untested. To test this hypothesis, mouse epigenetic clock (epiclock) was profiled in fetal (gestation day 15), postnatal (day 5), and aging (week 70) brain of male and female C57BL/6J inbred mice. Data analysis showed that on week 70, the female brain was epigenetically younger than the male brain. Predictive modeling by neural network identified specific methylations in the brain at the developing stages that were predictive of epigenetic state of the brain during aging. Transcriptomic analysis showed coordinated changes in the expression of epiclock genes in the fetal brain relative to the placenta. Whole-genome bisulfite sequencing identified sites that were methylated both in the placenta and fetal brain in a sex-specific manner. Epiclock genes and genes associated with specific signaling pathways, primarily the gonadotropin-releasing hormone receptor (GnRHR) pathway, were associated with the sex-bias methylations in the placenta as well as the fetal brain. Transcriptional crosstalk among the epiclock and GnRHR pathway genes was evident in the placenta that was maintained in the brain during development as well as aging. Collectively, these findings suggest that sex differences in the aging of the brain are of fetal origin and epigenetically linked to the placenta.