The mRNA decay factor CAR-1 regulates axon regeneration via mitochondrial calcium dynamics
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA513199 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:mRNA decay factors regulate mRNA turnover by recruiting non-translating mRNAs and targeting them for degradation, yet it remains poorly understood how mRNA decay factors function in vivo to regulate specific cellular processes. Here we show that mRNA decay factors form cytoplasmic puncta in C. elegans neurons and have opposing roles in axon maintenance and regrowth. While the decapping enzymes DCAP-1/DCP1 and DCAP-2/DCP2 regulate developmental axon guidance and promote axon regrowth upon injury, the translational repressors CAR-1/LSM14 and CGH-1/DDX6 regulate axon maintenance and inhibit axon regrowth in adult animals. We identified mRNA targets of CAR-1 in neurons and found that the mitochondrial calcium uptake regulator micu-1 is repressed by CAR-1. We show that axon injury triggers a transient mitochondrial calcium influx via the MCU-1 uniporter that is more sustained in car-1 loss of function mutants. The enhanced axon regrowth and defective axon maintenance of car-1 mutants are dependent on MICU-1 function. Our results uncover specific roles for mRNA decay regulators in neurons and reveal a novel pathway that controls axon regrowth through mitochondrial calcium uptake.
2020-01-23 | GSE124714 | GEO
Project description: Not available
| S-EPMC7147385 | biostudies-literature
Project description:Purpose: Injuries to the adult central nervous system (CNS) often result in permanent disabilities because neurons lose the ability to regenerate their axon during development. Although the developmental transition from a growing to a transmitting phase may represent one of the first steps in the gradual loss of axon growth and regeneration ability, the molecular mechanisms regulating this process has yet to be identified. The main goal of this study was to dissect the molecular mechanisms mediating the decline in axon growth ability and its relationship with regeneration failure in the adult CNS. To this end, we sequenced the whole transcriptome of dorsal root ganglia (DRG) neurons in both growth competent and incompetent states at different developmental stages, in diverse culture and in vivo experimental conditions.
2016-09-17 | GSE66128 | GEO
Project description:N6-methyladenosine (m6A) affects multiple aspects of mRNA metabolism and regulates developmental transitions by promoting mRNA decay. Little is known about the role of m6A in the adult mammalian nervous system. Here we report that sciatic nerve lesion elevates levels of m6A-tagged transcripts encoding many regeneration-associated genes and protein translation machinery components in the adult mouse dorsal root ganglion (DRG). Single base resolution m6A-CLIP mapping further reveals a dynamic m6A landscape in the adult DRG upon injury. Loss of either m6A methyltransferase complex component Mettl14 or m6A-binding protein Ythdf1 globally attenuates injury induced protein translation in adult DRGs and reduces functional axon regeneration in the peripheral nervous system in vivo. Furthermore, Pten deletion-induced axon regeneration of retinal ganglion neurons in the adult central nervous system is attenuated upon Mettl14 knockdown. Our study reveals a critical epitranscriptomic mechanism in promoting injury-induced protein synthesis and axon regeneration in the adult mammalian nervous system.
2018-01-17 | GSE106423 | GEO
Project description:Muscle LIM Protein is a Regeneration Associated Protein and promotes Axon Regeneration
| PRJEB29357 | ENA
Project description:Chimeric antigen receptor (CAR) T cells are known to be potent in recognizing and eliminating tumor elimination, and effector functions. They induce marked responses in patients with refractory leukemia and lymphoma, but dysfunction of T cells is an inevitable obstacle for persistent curative effect. Extending the persistence of these cells without compromising their potency is supposed to improve treatment outcomes. We demonstrated that the SOCE (Store-Operated Calcium Entry) inhibitor BTP-2, rather than calcium chelator BAPTA-AM, diminished exhaustion and terminal differentiation of CAR-T cells both in tonic signaling and tumor antigen exposure models. And BTP-2 pretreated CAR-T cells showed improved antitumor potency and prolonged survival in NSG mice. To further investigate the biological impact of calcium signaling at the molecular level, we performed RNA-seq on CAR-T cells and CAR-T cells exposed to Nalm6 stimulation followed by treatment with DMSO, BAPTA and BTP-2.The high-throughput RNA sequencing (RNA-Seq) revealed that treatment with BTP-2 downregulates glycolysis pathway.
2021-11-19 | GSE178998 | GEO
Project description:Axon regeneration of dorsal root ganglia (DRG) neurons after peripheral axotomy involves epigenetic reconfigurations that rewire gene regulatory circuits to establish regenerative gene program. However, the mechanisms and transcriptional regulators remain poorly understood. Here, we conducted an unbiased survey of DNA differentially hydroxymethylated regions (DhMRs) in DRG after peripheral lesion, which identified enriched binding motif for Bmal1, a transcription factor and a central regulator of the circadian clock. Through applying conditional deletion of Bmal1, in vitro and in vivo models of axon regrowth, and transcriptomic profiling, we showed that Bmal1 inhibits axon regeneration in part through Tet3-dependent manner. Mechanistically, Bmal1 functions as a gatekeeper of neuroepigenetic injury responses by limiting Tet3 expression and restricting 5hmC modifications. Notably, Bmal1-regulated genes after axotomy not only concern axon guidance and axon regrowth, but also stress responses, energy homeostasis, and neuroinflammation. Furthermore, we uncovered diurnal oscillation of Tet3 and 5hmC in DRG neurons, and this epigenetic rhythm corresponded to time-of-day effect on axon growth potential. Collectively, our studies showed that Bmal1 deletion mimics the conditioning lesion in lifting epigenetic barriers to enhance axon regeneration.
2023-08-02 | GSE233367 | GEO
Project description:Rhabdomyosarcoma (RMS), the most common paediatric soft-tissue sarcoma, is characterized by cells of skeletal muscle origin that fail to both irreversibly exit the cell cycle and complete skeletal muscle differentiation. Embryonal rhabdomyosarcoma (ERMS) is the most prevalent subtype of RMS and its molecular signatures has been associated with metabolism defects and increased oxidative stress. However, the details of the contributing factors or molecules have not been studied. Both metabolism and oxidative stress are associated with mitochondrial functions and an important molecule that regulates mitochondrial functions is calcium. Till date, there has been no studies that examine the role of mitochondrial calcium in ERMS. In addition, the molecular component of mitochondrial calcium uniporter complex, which is responsible for the uptake of mitochondrial calcium was only discovered in 2012. Since then, there has been an increasing interest in investigating the role of mitochondrial calcium and mitochondrial calcium uniporter complex in various cancers. Mitochondrial calcium uniporter (MCU), the main channel forming protein is often found to be dysregulated in various cancers. Our preliminary data has shown that mitochondrial calcium is dysregulated in ERMS due to overexpression of MCU. This dysregulation of mitochondrial calcium has led to multiple mitochondrial dysfunctions and oncogenic phenotypes. Hence, we would like to investigate the downstream targets of MCU in order to identify the mechanism through which MCU regulates oncogenic phenotypes in ERMS.
2022-05-04 | GSE173200 | GEO
Project description:Injured peripheral neurons successfully activate a pro-regenerative transcriptional program to enable axon regeneration and functional recovery. How transcriptional regulators coordinate the expression of such programs remains unclear. Here we show that hypoxia-inducible factor 1α (HIF-1α) controls multiple injury-induced genes in sensory neurons and contribute to the pre-conditioning lesion effect. Knockdown of HIF-1α in vitro or conditional knockout in vivo impairs sensory axon regeneration. The HIF-1α target gene Vascular Endothelial Growth Factor A (VEGFA) is expressed in injured neurons and contributes to stimulate axon regeneration. Induction of HIF-1α using hypoxia enhances axon regeneration in vitro and in vivo in sensory neurons. Hypoxia also stimulates motor neuron regeneration and accelerates neuromuscular junction reinnervation. This study demonstrates that HIF-1α represents a critical transcriptional regulator in regenerating neurons and suggests hypoxia as a tool to stimulate axon regeneration.
2016-01-21 | GSE73415 | GEO
Project description:Gene repression by DNA methylation promotes axon regeneration
| PRJNA354787 | ENA