Project description:Adult neurogenesis occurs in mammals and provides a mechanism for continuous neural plasticity in the brain.However, little is known about the molecular mechanisms regulating hippocampal neural progenitor cells (NPCs) and whether their fate can be pharmacologically modulated to improve neural plasticity and regeneration. Here, we report the characterization of a unique small molecule (KHS101) that selectively induces a neuronal differentiation phenotype. Mechanism of action studies revealed a link of KHS101 to cell cycle exit and specific binding to the TACC3 protein, whose knockdown in NPCs recapitulates the KHS101-induced phenotype. Upon systemic administration, KHS101 distributed to the brainandresulted in a significant increase in neuronal differentiation in vivo. Our findings indicate that KHS101 accelerates neuronal differentiation by interaction with TACC3 and may provide a basis for pharmacological intervention.directed at endogenous NPCs. Compare expression profile of KHS101-treated hippocampal progenitor cells (2 concentrations) vs. DMSO (negative control), retinoic acid (positive control)
Project description:Adult neurogenesis occurs in mammals and provides a mechanism for continuous neural plasticity in the brain.However, little is known about the molecular mechanisms regulating hippocampal neural progenitor cells (NPCs) and whether their fate can be pharmacologically modulated to improve neural plasticity and regeneration. Here, we report the characterization of a unique small molecule (KHS101) that selectively induces a neuronal differentiation phenotype. Mechanism of action studies revealed a link of KHS101 to cell cycle exit and specific binding to the TACC3 protein, whose knockdown in NPCs recapitulates the KHS101-induced phenotype. Upon systemic administration, KHS101 distributed to the brainandresulted in a significant increase in neuronal differentiation in vivo. Our findings indicate that KHS101 accelerates neuronal differentiation by interaction with TACC3 and may provide a basis for pharmacological intervention.directed at endogenous NPCs.
Project description:Adult neurogenesis occurs in mammals and provides a mechanism for continuous neural plasticity in the brain. However, little is known about the molecular mechanisms regulating hippocampal neural progenitor cells (NPCs) and whether their fate can be pharmacologically modulated to improve neural plasticity and regeneration. Here, we report the characterization of a small molecule (KHS101) that selectively induces a neuronal differentiation phenotype. Mechanism of action studies revealed a link of KHS101 to cell cycle exit and specific binding to the TACC3 protein, whose knockdown in NPCs recapitulates the KHS101-induced phenotype. Upon systemic administration, KHS101 distributed to the brain and resulted in a significant increase in neuronal differentiation in vivo. Our findings indicate that KHS101 accelerates neuronal differentiation by interaction with TACC3 and may provide a basis for pharmacological intervention directed at endogenous NPCs.
Project description:Forced expression of pro-neural transcription factors was shown to mediate direct neuronal conversion of human fibroblasts. Since neurons are postmitotic, the conversion efficiency represents an important parameter. Here we present a minimalist approach combining two factor neuronal programming with small molecule-based inhibition of GSK3ß and SMAD signaling, which gives rise to functional neuron-like cells (iNs) of various neurotransmitter phenotypes with an overall yield of up to >200% and a final neuronal purity of up to >80%. Timcourse of reprogramming of fibroblasts towards an neuronal phenotype in two independent fibroblast lines
Project description:This SuperSeries is composed of the following subset Series: GSE16432: MSI2 regulates hematopoiesis and accelerates leukemogenesis GSE22773: Musashi 2 regulates normal hematopoiesis and accelerates leukemogenesis (LK and MS12-inducible) GSE22774: Musashi 2 regulates normal hematopoiesis and accelerates leukemogenesis (LSK and LK) GSE22775: Musashi 2 regulates normal hematopoiesis and accelerates leukemogenesis (Leukemia cell lines) Refer to individual Series
Project description:This data series describes expression data for eight paired, control and treated cell cultures obtained on independent occasions. NG108 rat neuronal cell cultures were exposed to either 0.25% DMSO (control) or 4400 ng/ml mefloquine (treated) for two hours. Validation: Modulation of the following transcripts by mefloquine was confirmed by semi-quantitative RT-PCR: U30186, X63594cds_g_at, X63594cds_at, X17163cds_s_at, rc_AI175959 and rc_AA945867 (unpaired, unequal variance, one tailed t-test, p < 0.05). Keywords: other
Project description:Exposure to excessive glucocorticoids, which are major mediators of the stress reaction, is detrimental to brain development related to an increased risk of psychiatric disorders. However, the molecular mechanism underlying the effect of excessive glucocorticoids on the developing brain remains largely unclear. To clarify the mechanism, we examined the effects of glucocorticoids on cultured neuronal progenitor cells (NPCs) from cerebral cortices from rat embryo. We performed comparative analysis using gene expression profiling of corticosterone- or vehicle-treated NPCs. Results provide insight into the effects of glucocorticoids in regulating genetic programs important for controlling NPCs’ properties. Keywords: expression analysis, corticosterone, neuronal progenitor, cortex
Project description:Astrocytes, due to the proximity to neuronal lineage and capability to proliferate, are ideal starting cells to regenerate neurons. Human fetal astrocytes have been successfully converted into neuronal cells by small molecules, which offer a broader range of further applications than transcription factor-mediated neuronal reprogramming. Here we report human adult astrocytes could also be converted into neuronal cells by a different set with fewer small molecules. These induced neuronal cells exhibited typical neuronal morphologies, expressed neuronal markers, and displayed neuronal electrophysiological properties. Genome-wide RNA-sequencing analysis showed the gene expression profile of induced neuronal cells resembled that of human embryonic stem cell-differentiated neurons. When transplanted into postnatal mouse brains, these induced neuronal cells could survive in vivo. Altogether, our study provides a new strategy to directly generate transgene-free neurons from human adult astrocytes by small molecules.
Project description:Forced expression of pro-neural transcription factors was shown to mediate direct neuronal conversion of human fibroblasts. Since neurons are postmitotic, the conversion efficiency represents an important parameter. Here we present a minimalist approach combining two factor neuronal programming with small molecule-based inhibition of GSK3ß and SMAD signaling, which gives rise to functional neuron-like cells (iNs) of various neurotransmitter phenotypes with an overall yield of up to >200% and a final neuronal purity of up to >80%.
Project description:To unravel the gene expression changes during postnatal prefrontal cortex development, RNA-seq was performed in the rat medial prefrontal cortex at five time points from early life to adulthood (postnatal day 8, 14, 21, 35 and 70) and differential expression of protein-coding genes, lincRNAs and alternative exons was analyzed. A switch from neuronal network development to maintenance during postnatal rat prefrontal cortex development was shown.