NeuroD1-based in situ neural regeneration for the treatment of radiation-induced brain injury
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE273938 | GEO | 2026/07/22
REPOSITORIES: GEO
Similar Datasets
Project description:Astrocytes, the most abundant glial cells in the central nervous system (CNS), play a critical role in brain injury responses. While NeuroD1 overexpression in astrocytes has been shown to reverse glial scar formation and promote tissue repair in mouse models of traumatic brain injury (TBI), the underlying molecular mechanisms remain incompletely understood. To address this, we performed single-cell transcriptomic analysis on a controlled cortical impact (CCI) mouse model using recombinant adeno-associated virus (rAAV)-mediated astrocyte-specific NeuroD1 overexpression.Our findings demonstrate that NeuroD1 overexpression suppresses microglial activation and mitigates brain damage post-TBI. Single-cell RNA sequencing revealed significant shifts in astrocyte subtypes, with upregulated neuroinflammatory pathways and downregulated oxygen metabolism in TBI mice. Conversely, NeuroD1 overexpression reshaped astrocyte subpopulation dynamics, enhanced oxygen metabolism-related gene expression, and attenuated neuroinflammatory signaling. This study provides a comprehensive transcriptomic dataset detailing cellular and astrocyte subtype-specific changes following NeuroD1-mediated brain repair. These insights advance our understanding of cell fate modulation in TBI and support the development of NeuroD1-based gene therapies, offering a valuable resource for future TBI research and therapeutic strategies.
2025-11-01 | GSE305371 | GEO
Project description:Small cell lung carcinoma (SCLC) and large cell neuroendocrine carcinoma (LCNEC) are high-grade pulmonary neuroendocrine tumors. The neural basic helix-loop-helix (bHLH) transcription factors ASCL1 and NEUROD1 have been shown to play crucial roles in promoting the malignant behavior and survival of human SCLC cell lines. In this study, we find ASCL1 and NEUROD1 identify distinct neuroendocrine tumors, bind distinct genomic loci, and regulate mostly distinct genes. ASCL1 and NEUROD1 are often bound in super-enhancers that are associated with highly expressed genes in their respective SCLC cell lines suggesting different cell lineage of origin for these tumors. ASCL1 targets oncogenic genes such as MYCL1, RET, and NFIB, while NEUROD1 targets the oncogenic gene MYC. Although ASCL1 and NEUROD1 regulate different genes, many of these gene targets commonly contribute to neuroendocrine and cell migration function. ASCL1 in particular also regulates genes in the NOTCH pathway and genes important in cell-cycle dynamics. Finally, we demonstrate ASCL1 but not NEUROD1 is required for SCLC and LCNEC tumor formation in current in vivo genetic mouse models of pulmonary neuroendocrine tumors RNA-seq analysis performed on two ASCL1high and two NEUROD1high human SCLC cell lines to identify gene expression patterns in these cells. Also, we performed RNA-seq in mouse neuroendocrine lung tumors obtained from Trp53;Rb1;Rbl2 triple knockout model mice treated with Adeno-CMVCRE intratracheally.
2016-07-21 | E-GEOD-69393 | biostudies-arrayexpress
Project description:Small cell lung carcinoma (SCLC) and large cell neuroendocrine carcinoma (LCNEC) are high-grade pulmonary neuroendocrine tumors. The neural basic helix-loop-helix (bHLH) transcription factors ASCL1 and NEUROD1 have been shown to play crucial roles in promoting the malignant behavior and survival of human SCLC cell lines. In this study, we find ASCL1 and NEUROD1 identify distinct neuroendocrine tumors, bind distinct genomic loci, and regulate mostly distinct genes. ASCL1 and NEUROD1 are often bound in super-enhancers that are associated with highly expressed genes in their respective SCLC cell lines suggesting different cell lineage of origin for these tumors. ASCL1 targets oncogenic genes such as MYCL1, RET, and NFIB, while NEUROD1 targets the oncogenic gene MYC. Although ASCL1 and NEUROD1 regulate different genes, many of these gene targets commonly contribute to neuroendocrine and cell migration function. ASCL1 in particular also regulates genes in the NOTCH pathway and genes important in cell-cycle dynamics. Finally, we demonstrate ASCL1 but not NEUROD1 is required for SCLC and LCNEC tumor formation in current in vivo genetic mouse models of pulmonary neuroendocrine tumors ChIP-seq analysis performed on three ASCL1high and two NEUROD1high human SCLC cell lines to identify ASCL1 and/or NEUROD1 binding sites in these two types of cells. Also, we performed ChIP-seq for Ascl1 binding sites in mouse neuroendocrine lung tumors obtained from Trp53;Rb1;Rbl2 triple knockout model mice treated with Adeno-CMVCRE intratracheally.
2016-07-21 | E-GEOD-69394 | biostudies-arrayexpress
Project description:Direct astrocyte-to-neuron conversion holds promise for in situ neuroregeneration to treat neurodegenerative diseases. However, commonly-used adeno-associated vectors carrying GFAP mini-promoters drive leaky expression of neurogenic factors in endogenous neurons, raising concerns about trans-differentiation validity. Developing inducible, lineage-traceable transgenic mice, we evaluate NeuroD1 effects on astrocyte-to-neuron conversion in spinal cord and brain injury models. Lineage-tracing and single-cell transcriptomics reveal that ectopic NeuroD1 expression promotes robust conversion of reactive astrocytes in lesion cores to neurons at the acute phase of injury, but not in peri-injury astrocytes.
2025-06-18 | GSE290098 | GEO
Project description:The experiment evaluates the therapeutic effect brain injected AAV9-IDS (Adeno-associated virus 9 encoding IDS enzyme) treatment in a mouse model of Mucopolysaccharidosis Type II (MPSII). Microarrays were performed in order to compare the transcriptional profiling after the treatment. Three groups were analyzed, wild type (WT) mice, MPSII mice treated with AAV-NULL (AAV vector alone) and MPSII mice treated with AAV-IDS (vector encoding IDS enzyme). Four months after vector administration (at 6 months of age), animals were sacrificed and tissues were harvested and processed. RNA isolated from the encephalon of three groups of mice was analysed using the Affimetrix® microarray platform
2019-05-20 | E-MTAB-4728 | biostudies-arrayexpress
Project description:NeuroD1 encodes a basic helix-loop-helix transcription factor involved in the development of neural and endocrine structures. NeuroD1 mRNA is highly abundant in the adult mammalian pineal gland and exhibits a developmental expression pattern similar to the retina. This is consistent with the common evolutionary origin of pinealocytes and retinal photoreceptors. Pinealocytes and retinal photoreceptors express a shared set of phototransduction genes and submammalian pinealocytes are photosensitive. In contrast to the retina, the pineal gland is a relatively homogeneous structure, composed 95% of pinealocytes. This makes the pineal gland a particularly useful model for understanding photoreceptor cell biology. The loss of NeuroD1 in the retina results in progressive photoreceptor degeneration and the molecular mechanisms underlying this retinal degeneration phenotype remain unknown. Similarly, the role that NeuroD1 plays in the pineal gland is unknown. To determine the function of NeuroD1 in the pineal gland and retina, a Cre/loxP recombination strategy was used to selectively target a NeuroD1 floxed allele and generate NeuroD1 conditional knockout (cKO) mice. Tissue specificity was conferred using Cre recombinase expressed under the control of the promoter of Crx, a transcription factor selectively expressed in the pineal gland and retina. Pineal and retinal tissues from two-month-old NeuroD1 cKO and control animals were used in microarray studies to identify candidate genes responsible for the photoreceptor degeneration phenotype. The Cre/loxP recombination strategy was used to target a NeuroD1 floxed allele and generate NeuroD1 conditional knockout mice (NeuroD1floxed::Crx-Cre+/-). NeuroD1 floxed mice (NeuroD1floxed::Crx-Cre-/-) served as the controls. Pineal glands and retinas from two-month-old control and conditional knockout mice were collected at ZT6 and ZT20. 3 pools of 6 pineal glands per genotype and respective time of day were collected for each sample. Similarly, 3 pools of 6 retinas each were also collected. RNA from each pool was extracted and hybridized on the Affymetrix Mouse 430 2.0 array.
2012-07-25 | E-GEOD-35396 | biostudies-arrayexpress
Project description:Apolipoprotein A-I mimetic peptides are amphipathic alpha-helix peptides that display similar functions to apolipoprotein A-I. Preclinical and clinical studies have demonstrated the safety and efficacy of apolipoprotein A-I mimetic peptides in multiple indications associated with inflammatory processes. In this study, we evaluated the effect of the long-term expression of L37pA in the liver by an adeno-associated virus (AAV-L37pA) on the expression of an adeno-associated virus encoding interferon-alpha (AAV-IFNα). Long-term IFNα expression in the liver leads to lethal hematological toxicity one month after AAV administration. Concomitant administration of AAV-L37pA prevented the lethal toxicity since the IFNα expression was reduced one month after AAV administration by decreasing the expression of IFNα. To identify the mechanism of action of L37pA, a genomic and proteomic analysis was performed fifteen days after AAV administration when a similar level of IFNα and interferon-stimulated genes were observed in mice treated with AAV-IFNα alone and in mice treated with AAV-IFNα and AAV-L37pA. The coexpression of the apolipoprotein A-I mimetic peptide L37pA with IFNα modulated the gene expression program of IFNα, inducing a significant reduction in inflammatory pathways affecting pathogen-associated molecular patterns receptor, dendritic cells, NK cells and Th1 immune response. The proteomic analysis confirmed the impact of the L37pA activity on several inflammatory pathways and indicated an activation of LXR/RXR and PPPARα/γ nuclear receptors. Thus, long-term expression of L37pA induces an anti-inflammatory effect in the liver that allows silencing of IFNα expression mediated by an adeno-associated virus.
2021-09-09 | PXD023281 | Pride
Project description:Adeno-associated virus (AAV) is a defective mono-stranded DNA virus, endemic in human population (35-80%). Recurrent clonal AAV2 insertions are associated with the pathogenesis of rare human hepatocellular carcinoma (HCC) developed on normal liver. This study aimed to characterize the natural history of AAV infection in the liver and its consequence in tumor development.
In silico analyses using viral capture data explored viral variants and new clonal insertions. Clonal AAV insertions were positive selected during HCC development on non-cirrhotic liver challenging the notion of AAV as a non-pathogenic virus.
| EGAD00001004484 | EGA
Project description:Neuroblastoma, derived from the sympathetic neural crest, represents the most prevalent extracranial solid tumor in children. Amplification of MYCN is widely recognized as a key indicator of unfavorable prognosis in neuroblastoma. However, the structural properties of the N-Myc protein encoded by MYCN have hindered the development of direct inhibitors with favorable drug-like properties. Therefore, uncovering the upstream regulatory mechanisms of N-Myc offers promising new targets for therapeutic intervention in MYCN-amplified neuroblastoma. In this study, we identified NeuroD1 as a critical regulator closely associated with MYCN amplification. NeuroD1 was shown to drive the proliferation of MYCN-amplified neuroblastoma cells both in vitro and in vivo. Mechanistically, NeuroD1 knockdown led to increased K48-linked polyubiquitination of N-Myc, resulting in its proteasomal degradation. Through transcriptional target screening, USP1 was identified as a key downstream effector of NeuroD1. Further investigation revealed that USP1 interacts with N-Myc, removing K48-linked polyubiquitin chains and stabilizing the protein. Importantly, Pimozide, an FDA-approved USP1 inhibitor, was found to effectively suppress USP1 expression, reduce N-Myc levels, and inhibit neuroblastoma cell proliferation. These findings highlight a novel oncogenic axis in MYCN-amplified neuroblastoma, where NeuroD1 transcriptionally upregulates USP1, facilitating N-Myc stabilization and tumor progression. Additionally, our results underscore the therapeutic potential of repurposing Pimozide as a viable treatment strategy for this aggressive tumor subtype.
2025-05-01 | GSE285630 | GEO
Project description:Neuroblastoma, derived from the sympathetic neural crest, represents the most prevalent extracranial solid tumor in children. Amplification of MYCN is widely recognized as a key indicator of unfavorable prognosis in neuroblastoma. However, the structural properties of the N-Myc protein encoded by MYCN have hindered the development of direct inhibitors with favorable drug-like properties. Therefore, uncovering the upstream regulatory mechanisms of N-Myc offers promising new targets for therapeutic intervention in MYCN-amplified neuroblastoma. In this study, we identified NeuroD1 as a critical regulator closely associated with MYCN amplification. NeuroD1 was shown to drive the proliferation of MYCN-amplified neuroblastoma cells both in vitro and in vivo. Mechanistically, NeuroD1 knockdown led to increased K48-linked polyubiquitination of N-Myc, resulting in its proteasomal degradation. Through transcriptional target screening, USP1 was identified as a key downstream effector of NeuroD1. Further investigation revealed that USP1 interacts with N-Myc, removing K48-linked polyubiquitin chains and stabilizing the protein. Importantly, Pimozide, an FDA-approved USP1 inhibitor, was found to effectively suppress USP1 expression, reduce N-Myc levels, and inhibit neuroblastoma cell proliferation. These findings highlight a novel oncogenic axis in MYCN-amplified neuroblastoma, where NeuroD1 transcriptionally upregulates USP1, facilitating N-Myc stabilization and tumor progression. Additionally, our results underscore the therapeutic potential of repurposing Pimozide as a viable treatment strategy for this aggressive tumor subtype.
2025-05-01 | GSE285627 | GEO