Developmental Coordination of Gene Expression between Synaptic Partners During GABAergic Circuit Assembly in Cerebellar Cortex

The assembly of neural circuits involves multiple sequential steps such as the specification of cell-types, their migration to proper brain locations, morphological and physiological differentiation, and the formation and maturation of synaptic connections. This intricate and often prolonged process is guided by elaborate genetic mechanisms that regulate each step. Evidence from numerous systems suggests that each cell-type, once specified, is endowed with a genetic program that unfolds in response to, and is regulated by, extrinsic signals, including cell–cell and synaptic interactions. To a large extent, the execution of this intrinsic program is achieved by the expression of specific sets of genes that support distinct developmental processes. Therefore, a comprehensive analysis of the developmental progression of gene expression in synaptic partners of neurons may provide a basis for exploring the genetic mechanisms regulating circuit assembly. Here we examined the developmental gene expression profiles of well-defined cell-types in a stereotyped microcircuit of the cerebellar cortex. We found that the transcriptomes of Purkinje cell and stellate/basket cells are highly dynamic throughout postnatal development. We revealed “phasic expression” of transcription factors, ion channels, receptors, cell adhesion molecules, gap junction proteins, and identified distinct molecular pathways that might contribute to sequential steps of cerebellar inhibitory circuit formation. We further revealed a correlation between genomic clustering and developmental co-expression of hundreds of transcripts, suggesting the involvement of chromatin level gene regulation during circuit formation

Coordinate to Guard: Crosstalk of Phosphorylation, Sumoylation, and Ubiquitylation in DNA Damage Response

Small ubiquitin-like modifier-1/2/3 (SUMO-1/2/3) and ubiquitin share similar structure and utilize analogous machinery for protein lysine conjugation. Although sumoylation and ubiquitylation have distinct functions, they are often tightly associated with each other to fine-tune protein fate in transducing signals to regulate a wide variety of cellular functions, including DNA damage response, cell proliferation, DNA replication, embryonic development, and cell differentiation. In this Perspective, we specifically highlight the role of sumoylation and ubiquitylation in ataxia-telangiectasia mutated (ATM) signaling in response to DNA double-strand breaks and hypothesize that ATM-induced phosphorylation is a unique node in regulating SUMO-targeted ubiquitylation in mammalian cells to combat DNA damage and to maintain genome integrity. A potential role for the coordination of three types of post-translational modification in dictating the tempo and extent of cellular response to genotoxic stress is speculated

Effect of polybrominated diphenyl ether (PBDE) treatment on the composition and function of the bacterial community in the sponge Haliclona cymaeformis

Marine sponges play important roles in benthic environments and are sensitive to environmental stresses. Polybrominated diphenyl ethers (PBDEs) have been widely used as flame retardants since the 1970s and are cytotoxic and genotoxic to organisms. In the present study, we studied the short-period effect of PBDE-47 (2,2',4,4'-tetrabromodiphenyl ether) treatment on the community structure and functional gene composition of the bacterial community inhabiting the marine sponge Haliclona cymaeformis. Our results showed that the bacterial community shifted from an autotrophic bacteria-dominated community to a heterotrophic bacteria-dominated community in response to PBDE-47 in a time- and concentration-dependent manner. A potentially symbiotic sulfur-oxidizing bacterium (SOB) was dominant (>80% in abundance) in the untreated sponge. However, exposure to a high concentration (1 µg/L) of PBDE-47 caused a substantial decrease in the potential symbiont and an enrichment of heterotrophic bacteria like Clostridium. A metagenomic analysis showed a selective effect of the high concentration treatment on the functional gene composition of the enriched heterotrophic bacteria, revealing an enrichment for the functions responsible for DNA repair, multidrug efflux pumping, and bacterial chemotaxis and motility. This study demonstrated that PBDE-47 induced a shift in the composition of the community and functional genes in the sponge-associated bacterial community, revealing the selective effect of PBDE-47 treatment on the functions of the bacterial community in the microenvironment of the sponge

Early life environmental and pharmacological stressors result in persistent dysregulations of the serotonergic system

Dysregulations in the brain serotonergic system and exposure to environmental stressors have been implicated in the development of major depressive disorder. Here, we investigate the interactions between the stress and serotonergic systems by characterizing the behavioral and biochemical effects of chronic stress applied during early-life or adulthood in wild type (WT) mice and mice with deficient tryptophan hydroxylase 2 (TPH2) function. We showed that chronic mild stress applied in adulthood did not affect the behaviors and serotonin levels of WT and TPH2 knock-in (KI) mice. Whereas, maternal separation (MS) stress increased anxiety- and depressive-like behaviors of WT mice, with no detectable behavioral changes in TPH2 KI mice. Biochemically, we found that MS WT mice had reduced brain serotonin levels, which was attributed to increased expression of monoamine oxidase A (MAO A). The increased MAO A expression was detected in MS WT mice at 4 weeks old and adulthood. No change in TPH2 expression was detected. To determine whether a pharmacological stressor, dexamethasone (Dex), will result in similar biochemical results obtained from MS, we used an in vitro system, SH-SY5Y cells, and found that Dex treatment resulted in increased MAO A expression levels. We then treated WT mice with Dex for 5 days, either during postnatal days 7-11 or adulthood. Both groups of Dex treated WT mice had reduced basal corticosterone and glucocorticoid receptors expression levels. However, only Dex treatment during PND7-11 resulted in reduced serotonin levels and increased MAO A expression. Just as with MS WT mice, TPH2 expression in PND7-11 Dex-treated WT mice was unaffected. Taken together, our findings suggest that both environmental and pharmacological stressors affect the expression of MAO A, and not TPH2, when applied during the critical postnatal period. This leads to long-lasting perturbations in the serotonergic system, and results in anxiety- and depressive-like behaviors