Inducible knockout of Mef2a, -c, and -d from nestin-expressing stem/progenitor cells and their progeny unexpectedly uncouples neurogenesis and dendritogenesis in vivo

Myocyte enhancer factor (Mef)‐2 transcription factors are implicated in activity‐dependent neuronal processes during development, but the role of MEF2 in neural stem/progenitor cells (NSPCs) in the adult brain is unknown. We used a transgenic mouse in which Mef2a, ‐c, and ‐d were inducibly deleted in adult nestin‐expressing NSPCs and their progeny. Recombined cells in the hippocampal granule cell layer were visualized and quantified by yellow fluorescent protein (YFP) expression. In control mice, postmitotic neurons expressed Mef2a, ‐c, and ‐d, whereas type 1 stem cells and proliferating progenitors did not Based on this expression, we hypothesized that Mef2a, ‐c, and ‐d deletion in adult nestin‐expressing NSPCs and their progeny would result in fewer mature neurons. Control mice revealed an increase in YFP+ neurons and dendrite formation over time. Contrary to our hypothesis, inducible Mef2 KO mice also displayed an increase in YFP+ neurons over time—but with significantly stunted dendrites—suggesting an uncoupling of neuron survival and dendritogenesis. We also found non‐cell‐autonomous effects after Mef2a, ‐c, and ‐d deletion. These in vivo findings indicate a surprising functional role for Mef2a, ‐c, and ‐d in cell‐ and non‐cell‐autonomous control of adult hippocampal neurogenesis that is distinct from its role during development.—Latchney, S. E., Jiang, Y., Petrik, D. P., Eisch, A. J., Hsieh, J. Inducible knockout of Mef2a, ‐c, and ‐d from nestin‐expressing stem/progenitor cells and their progeny unexpectedly uncouples neurogenesis and dendritogenesis in vivo

Spatial Identification and Change Analysis of Production-Living-Ecological Space Using Multi-Source Geospatial Data: A Case Study in Jiaodong Peninsula, China

The significant heterogeneity in the spatial distribution of point of interest (POI) data, the absence of human socio-economic activity information in remote sensing images (RSI), and the high cost of land use (LU) data acquisition restrict their application in PLES spatial identification. Utilizing easily accessible data for detailed spatial identification of PLES remains an urgent challenge, especially when selecting a study area that encompasses both urban built-up areas (UBUA) and non-urban built-up areas (NUBUA). To address this issue, we proposed a PLES spatial identification method that combines POI data and land cover (LC) data in this paper. The proposed method first classified spatial analysis units (SAUs) into agricultural production space (APS), ecological space (ES), and ambiguous space (AS) based on the rich surface physical information from LC data. Subsequently, the AS was further classified into living space (LS) and non-agricultural production space (NAPS) based on the rich human socioeconomic information from POI data. For the AS that contains no POI, a simple rule was established to differentiate it into LS or NAPS. The effectiveness of the method was verified by accuracy evaluation and visual comparison. Applying the method to the Jiaodong Peninsula, we identified the PLES of the Jiaodong Peninsula for 2018 and 2022, further explored their spatial distribution characteristics, and analyzed their changes. Finally, we conducted a discussion on the real-world situations and driving mechanisms of the PLES changes and proposed several policy insights. The results indicated that both the spatial distribution characteristics of PLES and PLES change in the Jiaodong Peninsula were obvious and showed significant differentiation between UBUA and NUBUA. Climatic and natural resource conditions, geographic location, macro-policies, and governmental behaviors drove the PLES changes

Inducible knockout of Mef2a, -c, and -d from nestin-expressing stem/progenitor cells and their progeny unexpectedly uncouples neurogenesis and dendritogenesis in vivo

Myocyte enhancer factor (Mef)‐2 transcription factors are implicated in activity‐dependent neuronal processes during development, but the role of MEF2 in neural stem/progenitor cells (NSPCs) in the adult brain is unknown. We used a transgenic mouse in which Mef2a, ‐c, and ‐d were inducibly deleted in adult nestin‐expressing NSPCs and their progeny. Recombined cells in the hippocampal granule cell layer were visualized and quantified by yellow fluorescent protein (YFP) expression. In control mice, postmitotic neurons expressed Mef2a, ‐c, and ‐d, whereas type 1 stem cells and proliferating progenitors did not Based on this expression, we hypothesized that Mef2a, ‐c, and ‐d deletion in adult nestin‐expressing NSPCs and their progeny would result in fewer mature neurons. Control mice revealed an increase in YFP+ neurons and dendrite formation over time. Contrary to our hypothesis, inducible Mef2 KO mice also displayed an increase in YFP+ neurons over time—but with significantly stunted dendrites—suggesting an uncoupling of neuron survival and dendritogenesis. We also found non‐cell‐autonomous effects after Mef2a, ‐c, and ‐d deletion. These in vivo findings indicate a surprising functional role for Mef2a, ‐c, and ‐d in cell‐ and non‐cell‐autonomous control of adult hippocampal neurogenesis that is distinct from its role during development.—Latchney, S. E., Jiang, Y., Petrik, D. P., Eisch, A. J., Hsieh, J. Inducible knockout of Mef2a, ‐c, and ‐d from nestin‐expressing stem/progenitor cells and their progeny unexpectedly uncouples neurogenesis and dendritogenesis in vivo

Functional and mechanistic exploration of an adult neurogenesis-promoting small molecule

Adult neurogenesis occurs throughout life in the mammalian hippocampus and is essential for memory and mood control. There is significant interest in identifying ways to promote neurogenesis and ensure maintenance of these hippocampal functions. Previous work with a synthetic small molecule, isoxazole 9 (Isx-9), highlighted its neuronal-differentiating properties in vitro. However, the ability of Isx-9 to drive neurogenesis in vivo or improve hippocampal function was unknown. Here we show that Isx-9 promotes neurogenesis in vivo, enhancing the proliferation and differentiation of hippocampal subgranular zone (SGZ) neuroblasts, and the dendritic arborization of adult-generated dentate gyrus neurons. Isx-9 also improves hippocampal function, enhancing memory in the Morris water maze. Notably, Isx-9 enhances neurogenesis and memory without detectable increases in cellular or animal activity or vascularization. Molecular exploration of Isx-9-induced regulation of neurogenesis (via FACS and microarray of SGZ stem and progenitor cells) suggested the involvement of the myocyte-enhancer family of proteins (Mef2). Indeed, transgenic-mediated inducible knockout of all brain-enriched Mef2 isoforms (Mef2a/c/d) specifically from neural stem cells and their progeny confirmed Mef2's requirement for Isx-9-induced increase in hippocampal neurogenesis. Thus, Isx-9 enhances hippocampal neurogenesis and memory in vivo, and its effects are reliant on Mef2, revealing a novel cell-intrinsic molecular pathway regulating adult neurogenesis.—Petrik, D., Jiang, Y., Birnbaum, S. G., Powell, C. M., Kim, M.-S., Hsieh, J., Eisch, A. J. Functional and mechanistic exploration of an adult neurogenesis-promoting small molecule

Colibactin assembly line enzymes use S-adenosylmethionine to build a cyclopropane ring

Despite containing an α-amino acid, the versatile cofactor S-adenosylmethionine (SAM) is not a known building block for non-ribosomal peptide synthetase (NRPS) assembly lines. Here we report an unusual NRPS module from colibactin biosynthesis that uses SAM for amide bond formation and subsequent cyclopropanation. Our findings showcase a new use for SAM and reveal a novel biosynthetic route to a functional group that likely mediates colibactin’s genotoxicity

Phylogeny-Aware Chemoinformatic Analysis of Chemical Diversity in Lamiaceae Enables Iridoid Pathway Assembly and Discovery of Aucubin Synthase

Countless reports describe the isolation and structural characterization of natural products, yet this information remains disconnected and underutilized. Using a cheminformatics approach, we leverage the reported observations of iridoid glucosides with the known phylogeny of a large iridoid producing plant family (Lamiaceae) to generate a set of biosynthetic pathways that best explain the extant iridoid chemical diversity. We developed a pathway reconstruction algorithm that connects iridoid reports via reactions and prunes this solution space by considering phylogenetic relationships between genera. We formulate a model that emulates the evolution of iridoid glucosides to create a synthetic data set, used to select the parameters that would best reconstruct the pathways, and apply them to the iridoid data set to generate pathway hypotheses. These computationally generated pathways were then used as the basis by which to select and screen biosynthetic enzyme candidates. Our model was successfully applied to discover a cytochrome P450 enzyme from Callicarpa americana that catalyzes the oxidation of bartsioside to aucubin, predicted by our model despite neither molecule having been observed in the genus. We also demonstrate aucubin synthase activity in orthologues of Vitex agnus-castus, and the outgroup Paulownia tomentosa, further strengthening the hypothesis, enabled by our model, that the reaction was present in the ancestral biosynthetic pathway. This is the first systematic hypothesis on the epi-iridoid glucosides biosynthesis in 25 years and sets the stage for streamlined work on the iridoid pathway. This work highlights how curation and computational analysis of widely available structural data can facilitate hypothesis-based gene discovery