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Project description:Correct timing of neurogenesis is critical for both generating the correct number and subtypes of glia and neurons in the embryo, as well as preventing tumours and the depletion of stem cell pools in the adults. Here we analyse how the midbrain dopamine neuron (mDA) progenitors transition into cell cycle arrest (G0) and begin to mature into ependymal cells. The comparison of mDA progenitors from different embryonic stages revealed the upregulation of Nfi and Sox9 transcription factors during development. Their conditional inactivation in the early embryonic midbrain leads to delayed G0 entry and ependymal maturation, reduced gliogenesis, and increased generation of neurons, including mDA neurons. In contrast, their inactivation in late embryogenesis does not result in mitotic re-entry, suggesting that these factors are necessary for the G0 induction, but not for its maintenance. Our characterisation of mDA-progenitor-derived adult ependymal cells by single-cell RNA sequencing and histology show that they both retain several progenitor features but also secrete neuropeptides and contact neighbouring cells and blood vessels, indicating that these cells may form a novel part of the circumventricular organ system.
2025-02-27 | GSE287923 | GEO
Project description:Correct timing of neurogenesis is critical for both generating the correct number and subtypes of glia and neurons in the embryo, as well as preventing tumours and the depletion of stem cell pools in the adults. Here we analyse how the midbrain dopamine neuron (mDA) progenitors transition into cell cycle arrest (G0) and begin to mature into ependymal cells. The comparison of mDA progenitors from different embryonic stages revealed the upregulation of Nfi and Sox9 transcription factors during development. Their conditional inactivation in the early embryonic midbrain leads to delayed G0 entry and ependymal maturation, reduced gliogenesis, and increased generation of neurons, including mDA neurons. In contrast, their inactivation in late embryogenesis does not result in mitotic re-entry, suggesting that these factors are necessary for the G0 induction, but not for its maintenance. Our characterisation of mDA-progenitor-derived adult ependymal cells by single-cell RNA sequencing and histology show that they both retain several progenitor features but also secrete neuropeptides and contact neighbouring cells and blood vessels, indicating that these cells may form a novel part of the circumventricular organ system.
2025-02-27 | GSE287922 | GEO
Project description:Sox9 and Nfi transcription factors regulate the timing of neurogenesis and ependymal maturation in dopamine progenitors [scRNA]
| PRJNA1215292 | ENA
Project description:Pro-opiomelanocortin (POMC)-expressing neurons in the hypothalamic arcuate nucleus (ARC) play key roles in feeding and energy homoeostasis, hence their development is of great research interest. As the process of neurogenesis is accompanied by changes in adhesion, polarity, and migration that resemble aspects of epithelial-to-mesenchymal transitions (EMTs), we have characterised the expression and regulation within the prospective ARC of transcription factors with context-dependent abilities to regulate aspects of EMT. Informed by pseudotime meta-analysis of recent scRNA-seq data, we use immunohistochemistry and multiplex in situ hybridisation to show that SOX2, SRY-Box transcription factor 9 (SOX9), PROX1, Islet1 (ISL1), and SOX11 are sequentially expressed over the course of POMC neurogenesis in the embryonic chick. Through pharmacological studies ex vivo, we demonstrate that while inhibiting either sonic hedgehog (SHH) or Notch signalling reduces the number of SOX9+ neural progenitor cells, these treatments lead, respectively, to lesser and greater numbers of differentiating ISL1+/POMC+ neurons. These results are consistent with a model in which SHH promotes the formation of SOX9+ progenitors, and Notch acts to limit their differentiation. Both pathways are also required to maintain normal levels of proliferation and to suppress apoptosis. Together our findings demonstrate that hypothalamic neurogenesis is accompanied by dynamic expression of transcription factors (TFs) that mediate EMTs, and that SHH and Notch signalling converge to regulate hypothalamic cellular homoeostasis.
| S-EPMC9404380 | biostudies-literature
Project description:Androgen receptor (AR) action throughout prostate development and in maintenance of the prostatic epithelium is partly controlled by interactions between AR and forkhead box (FOX) transcription factors, particularly FOXA1. We sought to identity additional FOXA1 binding partners that may mediate prostate-specific gene expression. Here we identify the nuclear factor I (NFI) family of transcription factors as novel FOXA1 binding proteins. All four family members (NFIA, NFIB, NFIC, and NFIX) can interact with FOXA1, and knockdown studies in androgen-dependent LNCaP cells determined that modulating expression of NFI family members results in changes in AR target gene expression. This effect is probably mediated by binding of NFI family members to AR target gene promoters, because chromatin immunoprecipitation (ChIP) studies found that NFIB bound to the prostate-specific antigen enhancer. Förster resonance energy transfer studies revealed that FOXA1 is capable of bringing AR and NFIX into proximity, indicating that FOXA1 facilitates the AR and NFI interaction by bridging the complex. To determine the extent to which NFI family members regulate AR/FOXA1 target genes, motif analysis of publicly available data for ChIP followed by sequencing was undertaken. This analysis revealed that 34.4% of peaks bound by AR and FOXA1 contain NFI binding sites. Validation of 8 of these peaks by ChIP revealed that NFI family members can bind 6 of these predicted genomic elements, and 4 of the 8 associated genes undergo gene expression changes as a result of individual NFI knockdown. These observations suggest that NFI regulation of FOXA1/AR action is a frequent event, with individual family members playing distinct roles in AR target gene expression.
| S-EPMC4042066 | biostudies-literature
Project description:Degeneration of dopamine neurons in the midbrain causes symptoms of the movement disorder, Parkinson disease. Dopamine neurons are generated from proliferating progenitor cells localized in the embryonic ventral midbrain. However, it remains unclear for how long cells with dopamine progenitor character are retained and if there is any potential for reactivation of such cells after cessation of normal dopamine neurogenesis. We show here that cells expressing Lmx1a and other progenitor markers remain in the midbrain aqueductal zone beyond the major dopamine neurogenic period. These cells express dopamine receptors, are located in regions heavily innervated by midbrain dopamine fibres and their proliferation can be stimulated by antagonizing dopamine receptors, ultimately leading to increased neurogenesis in vivo. Furthermore, treatment with dopamine receptor antagonists enhances neurogenesis in vitro, both from embryonic midbrain progenitors as well as from embryonic stem cells. Altogether our results indicate a potential for reactivation of resident midbrain cells with dopamine progenitor potential beyond the normal period of dopamine neurogenesis.
| S-EPMC4887985 | biostudies-literature
Project description:Expression of one out of > 1000 olfactory receptor (OR) genes is stochastic, yet organized into anatomic "zones" along the dorsoventral axis of the olfactory epithelium. Here we profile the gene expression, chromatin state and nuclear architecture of olfactory sensory neurons and olfactory progenitors of different zones. We discovered that zonal OR expression is specified by two processes: low-level polygenic transcription of OR genes in olfactory progenitors, as wells as the chromatin structure and nuclear architecture during olfactory differentiation. Specifically, in cells of any zonal segment, polygenic transcription in olfactory progenitors defines the OR repertoire eligible for OR choice as the cells mature, while an increased level of heterochromatin and chromatin compaction represses ectopic more dorsally expressed ORs. We find that this process is regulated by the NFI family of transcription factors that are expressed in a graded fashion in the olfactory epithelium. Conditional deletion of NFI A, B, and X results in a transformation of the chromatin state and nucellar architecture and an accompanying shift in the preferred OR repertoire.
2023-06-14 | GSE158730 | GEO
Project description:The regulation of adult neurogenesis by opiates has been implicated in modulating different addiction cycles. At which neurogenesis stage opiates exert their action remains unresolved. We attempt to define the temporal window of morphine's inhibition effect on adult neurogenesis by using the POMC-EGFP mouse model, in which newborn granular cells (GCs) can be visualized between days 3-28 post-mitotic. The POMC-EGFP mice were trained under the 3-chambers conditioned place preference (CPP) paradigm with either saline or morphine. We observed after 4 days of CPP training with saline, the number of EGFP-labeled newborn GCs in sub-granular zone (SGZ) hippocampus significantly increased compared to mice injected with saline in their homecage. CPP training with morphine significantly decreased the number of EGFP-labeled GCs, whereas no significant difference in the number of EGFP-labeled GCs was observed with the homecage mice injected with the same dose of morphine. Using cell-type selective markers, we observed that morphine reduced the number of late stage progenitors and immature neurons such as Doublecortin (DCX) and ?III Tubulin (TuJ1) positive cells in the SGZ but did not reduce the number of early progenitors such as Nestin, SOX2, or neurogenic differentiation-1 (NeuroD1) positive cells. Analysis of co-localization between different cell markers shows that morphine reduced the number of adult-born GCs by interfering with differentiation of early progenitors, but not by inducing apoptosis. In addition, when NeuroD1 was over-expressed in DG by stereotaxic injection of lentivirus, it rescued the loss of immature neurons and prolonged the extinction of morphine-trained CPP. These results suggest that under the condition of CPP training paradigm, morphine affects the transition of neural progenitor/stem cells to immature neurons via a mechanism involving NeuroD1.
| S-EPMC4831694 | biostudies-literature
Project description:Ependymal cells are part of the neurogenic niche in the adult subventricular zone of the lateral ventricles, where they regulate neurogenesis and neuroblast migration. Ependymal cells are generated from radial glia cells during embryonic brain development and acquire their final characteristics postnatally. The homeobox gene Six3 is expressed in ependymal cells during the formation of the lateral wall of the lateral ventricles in the brain. Here, we show that Six3 is necessary for ependymal cell maturation during postnatal stages of brain development. In its absence, ependymal cells fail to suppress radial glia characteristics, resulting in a defective lateral wall, abnormal neuroblast migration and differentiation, and hydrocephaly.
| S-EPMC3222208 | biostudies-literature
Project description:Endothelial to mesenchymal transition (EndMT) is a leading cause of fibrosis and disease, however its mechanism has yet to be elucidated. The endothelium possesses a profound regenerative capacity to adapt and reorganize that is attributed to a population of vessel-resident endovascular progenitors (EVP) governing an endothelial hierarchy. Here, using fate analysis, we show that two transcription factors SOX9 and RBPJ specifically affect the murine EVP numbers and regulate lineage specification. Conditional knock-out of Sox9 from the vasculature (Sox9fl/fl/Cdh5-CreER RosaYFP) depletes EVP while enhancing Rbpj expression and canonical Notch signalling. Additionally, skin wound analysis from Sox9 conditional knock-out mice demonstrates a significant reduction in pathological EndMT resulting in reduced scar area. The converse is observed with Rbpj conditionally knocked-out from the murine vasculature (Rbpjfl/fl/Cdh5-CreER RosaYFP) or inhibition of Notch signaling in human endothelial colony forming cells, resulting in enhanced Sox9 and EndMT related gene (Snail, Slug, Twist1, Twist2, TGF-β) expression. Similarly, increased endothelial hedgehog signaling (Ptch1fl/fl/Cdh5-CreER RosaYFP), that upregulates the expression of Sox9 in cells undergoing pathological EndMT, also results in excess fibrosis. Endothelial cells transitioning to a mesenchymal fate express increased Sox9, reduced Rbpj and enhanced EndMT. Importantly, using topical administration of siRNA against Sox9 on skin wounds can substantially reduce scar area by blocking pathological EndMT. Overall, here we report distinct fates of EVPs according to the relative expression of Rbpj or Notch signalling and Sox9, highlighting their potential plasticity and opening exciting avenues for more effective therapies in fibrotic diseases.
| S-EPMC8105340 | biostudies-literature