Slc22a17 governs postnatal neurogenesis by maintaining the iron homeostasis in hippocampus [RNA-Seq hippocampus]
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ABSTRACT:
PROVIDER: PRJNA1314053 | ENA |
REPOSITORIES: ENA
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Project description:Slc22a17 governs postnatal neurogenesis by maintaining the iron homeostasis in hippocampus [ATAC-Seq]
| PRJNA1314054 | ENA
Project description:Iron transporters are essential for maintaining cellular iron homeostasis. Among them, SLC22A17 mediates lipocalin-2 (LCN-2)-dependent iron transport, but its precise role in the brain remains unclear. Here, we show that Slc22a17 is critical for postnatal neurogenesis by regulating hippocampal iron balance. Conditional knockout of Slc22a17 in the murine brain causes early postnatal lethality, growth retardation, neural stem cell apoptosis, and cognitive deficits, largely due to oxidative stress from iron overload. Mechanistically, Slc22a17 interacts with p62 to modulate Nrf2 activity. Its loss aberrantly activates the Nrf2/HO-1 pathway, disrupting iron efflux and promoting accumulation of reactive oxygen species (ROS). These findings establish Slc22a17 as a key regulator of neuronal development and a potential therapeutic target for neurological disorders linked to iron dysregulation.
2025-09-08 | GSE306966 | GEO
Project description:Iron transporters are essential for maintaining cellular iron homeostasis. Among them, SLC22A17 mediates lipocalin-2 (LCN-2)-dependent iron transport, but its precise role in the brain remains unclear. Here, we show that Slc22a17 is critical for postnatal neurogenesis by regulating hippocampal iron balance. Conditional knockout of Slc22a17 in the murine brain causes early postnatal lethality, growth retardation, neural stem cell apoptosis, and cognitive deficits, largely due to oxidative stress from iron overload. Mechanistically, Slc22a17 interacts with p62 to modulate Nrf2 activity. Its loss aberrantly activates the Nrf2/HO-1 pathway, disrupting iron efflux and promoting accumulation of reactive oxygen species (ROS). These findings establish Slc22a17 as a key regulator of neuronal development and a potential therapeutic target for neurological disorders linked to iron dysregulation.
2025-09-08 | GSE306965 | GEO
Project description:Slc22a17 governs postnatal neurogenesis by maintaining the iron homeostasis in hippocampus [RNA-Seq neurosphere]
| PRJNA1314058 | ENA
Project description:Iron transporters are essential for maintaining cellular iron homeostasis. Among them, SLC22A17 mediates lipocalin-2 (LCN-2)-dependent iron transport, but its precise role in the brain remains unclear. Here, we show that Slc22a17 is critical for postnatal neurogenesis by regulating hippocampal iron balance. Conditional knockout of Slc22a17 in the murine brain causes early postnatal lethality, growth retardation, neural stem cell apoptosis, and cognitive deficits, largely due to oxidative stress from iron overload. Mechanistically, Slc22a17 interacts with p62 to modulate Nrf2 activity. Its loss aberrantly activates the Nrf2/HO-1 pathway, disrupting iron efflux and promoting accumulation of reactive oxygen species (ROS). These findings establish Slc22a17 as a key regulator of neuronal development and a potential therapeutic target for neurological disorders linked to iron dysregulation.
2025-09-08 | GSE306969 | GEO
Project description:The mechanisms underlying selective loss of dopaminergic (DAergic) neurons in substantia nigra pars compacta in Parkinson’s disease (PD) remain unclear. The NUS1 gene, encoding NgBR, has recently been identified as a novel PD risk gene. Here, we show that NgBR is highly expressed in microglia, and microglia-specific NgBR deficiency drives progressive PD-like motor deficits and DAergic neurodegeneration via lipocalin-2 (LCN2)/SLC22A17 axis-mediated iron transport. NgBR deficiency in microglia triggers endoplasmic reticulum stress and PERK-ATF4-NUPR1 pathway to selectively upregulate LCN2-mediated iron efflux rather than cytokines. Strikingly, microglia-derived iron-loaded Holo-LCN2 but not iron-free Apo-LCN2 is internalized by SLC22A17, a receptor we identified as specifically highly expressed in DAergic neurons that induces iron overload/ferroptosis. Pharmacological inhibition of the LCN2/SLC22A17 axis or ferroptosis alleviate DAergic neuron loss and PD-like symptoms caused by microglial NgBR deficiency in vitro and in vivo. Our findings establish intercellular iron homeostasis imbalance as a selective pathological driver in PD and highlight the LCN2/SLC22A17 axis for specific therapeutic targeting.
2026-03-11 | GSE301569 | GEO
Project description:The mechanisms underlying selective loss of dopaminergic (DAergic) neurons in substantia nigra pars compacta in Parkinson’s disease (PD) remain unclear. The NUS1 gene, encoding NgBR, has recently been identified as a novel PD risk gene. Here, we show that NgBR is highly expressed in microglia, and microglia-specific NgBR deficiency drives progressive PD-like motor deficits and DAergic neurodegeneration via lipocalin-2 (LCN2)/SLC22A17 axis-mediated iron transport. NgBR deficiency in microglia triggers endoplasmic reticulum stress and PERK-ATF4-NUPR1 pathway to selectively upregulate LCN2-mediated iron efflux rather than cytokines. Strikingly, microglia-derived iron-loaded Holo-LCN2 but not iron-free Apo-LCN2 is internalized by SLC22A17, a receptor we identified as specifically highly expressed in DAergic neurons that induces iron overload/ferroptosis. Pharmacological inhibition of the LCN2/SLC22A17 axis or ferroptosis alleviate DAergic neuron loss and PD-like symptoms caused by microglial NgBR deficiency in vitro and in vivo. Our findings establish intercellular iron homeostasis imbalance as a selective pathological driver in PD and highlight the LCN2/SLC22A17 axis for specific therapeutic targeting.
2026-03-11 | GSE318178 | GEO
Project description:Physical exercise stimulates adult hippocampal neurogenesis in mammals, and is considered a relevant strategy for preventing age-related cognitive decline in aging humans. However, its mechanism is controversial. Here, by investigating microRNAs (miRNAs) and their downstream pathways, we uncover that downregulation of miR-135a-5p mediates exercise-induced proliferation of adult NPCs in adult neurogenesis in the mouse hippocampus, likely by activation of phosphatidylinositol (IP3) signaling. Specifically, while overexpression of miR-135 prevents exercise-induced proliferation in the adult mouse hippocampus in vivo and in NPCs in vitro, its inhibition activates NPCs proliferation in resting and aged mice. Label free proteomics and bioinformatics analysis identifies 11 potential targets of miR-135 in NPCs, several of them involved in phosphatidylinositol signaling. Thus, miR-135a is key in mediating exercise-induced adult neurogenesis and opens intriguing perspectives toward the therapeutic exploitation of miR-135 to delay or prevent pathological brain ageing.Physical exercise stimulates adult hippocampal neurogenesis in mammals, and is considered a relevant strategy for preventing age-related cognitive decline in aging humans. However, its mechanism is controversial. Here, by investigating microRNAs (miRNAs) and their downstream pathways, we uncover that downregulation of miR-135a-5p mediates exercise-induced proliferation of adult NPCs in adult neurogenesis in the mouse hippocampus, likely by activation of phosphatidylinositol (IP3) signaling. Specifically, while overexpression of miR-135 prevents exercise-induced proliferation in the adult mouse hippocampus in vivo and in NPCs in vitro, its inhibition activates NPCs proliferation in resting and aged mice. Label free proteomics and bioinformatics analysis identifies 11 potential targets of miR-135 in NPCs, several of them involved in phosphatidylinositol signaling. Thus, miR-135a is key in mediating exercise-induced adult neurogenesis and opens intriguing perspectives toward the therapeutic exploitation of miR-135 to delay or prevent pathological brain ageing.
2019-11-12 | PXD009845 | Pride
Project description:Experience governs neurogenesis from radial-glial neural stem cells (RGLs) in the adult hippocampus to support memory. Transcription factors in RGLs integrate physiological signals to dictate quiescence-activation decisions and self-renewal divisions. Whereas asymmetric RGL self-renewal drives neurogenesis during favorable conditions, symmetric divisions prevent premature neurogenesis during unfavorable conditions while amplifying RGLs to anticipate neurogenic demands when conditions become favorable. Here, we show that the transcription factor Kruppel-like factor 9 (Klf9) is enriched in quiescent RGLs and inducible, bidirectional modulation of Klf9 biases RGL quiescence-activation decisions. Clonal lineage tracing and longitudinal intravital two-photon imaging of RGLs following cell-autonomous Klf9 deletion directly demonstrated increased symmetric self-renewal. In vivo translational profiling of RGLs identified a Klf9-dependent blueprint for genetic and metabolic programs instructing RGL quiescence and expansion. Thus, experience dependent regulation of Klf9 in RGLs may ensure self-preservation of neural stem cells while anticipating future demands for neurogenesis and astrogenesis to support hippocampal functions.
2022-01-06 | GSE164889 | GEO
Project description:Neural progenitor cells (aNPCs) ensure lifelong neurogenesis in the mammalian hippocampus. Proper regulation of aNPC fate entails important implications for brain plasticity and healthy aging. Piwi proteins and the small noncoding RNAs interacting with them (piRNAs) are best known in gonads as repressors of transposons. Here, we show that Piwil2 (Mili) and piRNAs are abundant in aNPCs of the postnatal mouse hippocampus and demonstrate that this pathway is essential for proper neurogenesis. Particularly, depleting the piRNA pathway in aNPCs impaired neurogenesis while increasing senescence and the generation of reactive glia. Moreover, depletion of the piRNA pathway primarily elevated 5S ribosomal RNA, SINEB1 and mRNAs encoding ribosomal proteins and regulators of translation, resulting in higher polysome density and protein synthesis upon differentiation. Our results provide evidence of an essential role for the piRNA pathway in maintaining homeostasis to sustain neural stem cell fate, underpinning its possible involvement in brain plasticity and successful aging.
2021-08-30 | GSE182848 | GEO