Neddylation orchestrates the complex transcriptional and post-transcriptional program that drives axonal myelination
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1007620 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR25711321_1.fastq.gz | Fastqsanger.gz | |||
| SRR25711321_2.fastq.gz | Fastqsanger.gz | |||
| SRR25711322_1.fastq.gz | Fastqsanger.gz | |||
| SRR25711322_2.fastq.gz | Fastqsanger.gz | |||
| SRR25711323_1.fastq.gz | Fastqsanger.gz |
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Project description:Myelination is essential for neuronal function and health. In peripheral nerves, >100 causative mutations have been identified that cause Charcot-Marie-Tooth disease, a disorder that can affect myelin sheaths. Among these, a number of mutations are related to essential targets of the post-translation modification neddylation, although how these lead to myelin defects is unclear. Here, we demonstrate that inhibiting neddylation leads to a striking absence of peripheral myelin and axonal loss both in developing and regenerating mouse nerves. Importantly, our data indicate that neddylation exerts a global influence on the complex transcriptional and post-transcriptional program by simultaneously regulating the expression and function of multiple essential myelination signals, including the master transcription factor EGR2 and the negative regulators c-Jun and Sox2, and inducing global secondary changes in downstream pathways, including the mTOR and YAP/TAZ signalling pathways. This places neddylation as a critical regulator of myelination and delineates the potential pathogenic mechanisms involved in CMT mutations related to neddylation.
2024-03-06 | GSE241269 | GEO
Project description:Axonal myelination is essential for neuronal function and health. In peripheral nerves, deficient myelination is responsible for the morbidity of various forms of inherited or acquired neuropathies, including Charcot-Marie-Tooth disease and diabetic neuropathy. Decades of research have uncovered a complex transcriptional and post-transcriptional program that co-ordinates the formation and maintenance of the myelin sheath. In contrast, much less is known about the functional role of post-translational modification (PTM) of proteins in this remarkable biogenic process. Neddylation, a PTM that involves the conjugation of the ubiquitin-like protein Nedd8 to protein targets, has recently emerged as a central and versatile regulator of many cellular processes, including gene transcription, metabolism, and cellular differentiation. In this study, we show that genetic and pharmacological inhibition of neddylation in vivo in developing Schwann cells lead to striking nerve defects that exhibit the classical hallmarks of a severe neuropathy, including gait abnormalities, muscle weakness, and hindlimb clasping, ultimately leading to early death. The mutant mice lack peripheral myelin and develop secondary axonal loss, and we demonstrate, at the mechanistic level, that neddylation regulates multiple critical myelination-related pathways. Together, our findings identify neddylation as a central regulatory hub of control of peripheral myelination and delineate the potential pathogenetic mechanisms in inherited human PNS disorders, characterized by mutations in genes related to the neddylation pathway.
2024-06-16 | PXD043917 | Pride
Project description:Myelination is essential for neuronal function and health. In peripheral nerves, >100 causative mutations have been identified that cause Charcot-Marie-Tooth disease, a disorder that can affect myelin sheaths. Among these, a number of mutations are related to essential targets of the posttranslational modification neddylation, although how these lead to myelin defects is unclear. Here, we demonstrate that inhibiting neddylation leads to a notable absence of peripheral myelin and axonal loss both in developing and regenerating mouse nerves. Our data indicate that neddylation exerts a global influence on the complex transcriptional and posttranscriptional program by simultaneously regulating the expression and function of multiple essential myelination signals, including the master transcription factor EGR2 and the negative regulators c-Jun and Sox2, and inducing global secondary changes in downstream pathways, including the mTOR and YAP/TAZ signaling pathways. This places neddylation as a critical regulator of myelination and delineates the potential pathogenic mechanisms involved in CMT mutations related to neddylation.
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Project description:Primary somatosensory neurons specialize in transmitting distinct types of sensory information through differences in cell size, myelination, and the expression of various receptors and ion channels, which together define their transcriptional and functional identity. By profiling sensory ganglia at single-cell resolution, we find that the different somatosensory neuronal subtypes undergo a similar transcriptional response to peripheral nerve injury that both promotes axonal regeneration and suppresses cell identity. This transcriptional reprogramming, which is not observed in non-neuronal cells from sensory ganglia, resolves over a similar time course as target reinnervation and is associated with the restoration of original cell identity. Injury-induced transcriptional reprogramming requires ATF3, a transcription factor which is induced rapidly after injury and necessary for axonal regeneration and functional recovery. Our findings suggest that the transcription factors induced early after peripheral sensory neuron injury promote their transcriptional and functional metamorphosis, analogous to their known roles in reprogramming cell fate.
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Project description:Elucidating the genes regulated during cell-cell communication remains fascinating considering the importance of cell recognition and downstream signaling through development and in many diseases. In the peripheral nervous system, the interaction between Schwann cells (SCs) and axons is crucial as it allows their survival and induces SCs to differentiate and engage a process of myelination. To get further insight the molecular mechanisms resulting from this cell interaction, comparative gene analysis between SCs and SCs co-cultured with DRG neurons were performed and led us to identify a set of 32 genes regulated in SCs in the early stage of neuron-SC contact. Expression of several candidates were analyzed by QPCR during development and we demonstrate using a blocking antibody approach in an in vitro myelination assay that one candidate was not only upregulated in response to axonal contact but also controls peripheral myelination. Three biological replicates each in dye swap for 22k slides and two biological replicates each in dye swap for NeuroDev2
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Project description:STAG2 promotes the myelination transcriptional program in oligodendrocytes
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Project description:The transcriptional regulatory network governing the differentiation and functionality of oligodendrocytes is essential for the formation and maintenance of the myelin sheath, and hence for the proper function of the nervous system. Perturbations in the intricate interplay of transcriptional effectors within this network can lead to a variety of nervous system pathologies. In this study, we have identified Gtf2i-encoded general transcription factor II-I (Tfii-i) as a regulator of key myelination-related genes. To assess how Tfii-i absence from oligodendrocytes alters myelin properties on a molecular level, we compared the biochemically-enriched myelin fraction purified from brains of Gtf2i-KO and control mice by label-free quantitative mass spectrometry using the MSE-type data-independent acquisition (DIA) mode. We found an increased protein abundance of several key myelin proteins such as Mbp and Mog, while the abundance of Gpr37 was decreased, overall indicating a molecular hypermyelination phenotype in the absence of Tfii-i. These results, together with findings from - among others - structural, electrophysiological and behavioral approaches, show that Gtf2i deletion from myelinating glia cells in mice led to functional alterations in CNS myelin, which resulted in faster axonal conduction and improved motor coordination.
2025-07-14 | PXD054341 | Pride
Project description:Myelination is essential for nervous system function. Schwann cells interact with neurons and with the basal lamina to sort and myelinate axons, using known receptors and signaling pathways. In contrast, the transcriptional control of axonal sorting and the role of mechano-transduction in myelination are largely unknown. Yap and Taz are effectors of the Hippo pathway that integrate chemical and mechanical signals in cells. Here, we describe a previously unknown role for the Hippo pathway in myelination. Using conditional mutagenesis in mice we show that Taz is required in Schwann cells for radial sorting and myelination. Yap is redundant with Taz as ablation of both Yap and Taz abolishes radial sorting. Yap/Taz regulate Schwann cell proliferation and transcription of basal lamina receptors, both necessary for proper radial sorting of axons, and subsequent myelination. These data link transcriptional effectors of the Hippo pathway and of mechanotransduction to myelin formation in Schwann cells.
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Project description:Understanding the regulation of oligodendrocyte development and myelination in the central nervous system (CNS) is essential, not only to facilitate myelin repair but also to define the role of oligodendrocytes in maintaining axonal integrity. In vitro studies have implicated astrocytes in influencing multiple aspects of oligodendrocytes and their precursors, however the in vivo role of astrocytes in myelination and myelin repair remain poorly defined. We show that astrocyte ablation during postnatal spinal cord development resulted in a concomitant delay in myelination, demonstrating a critical role for astrocytes in promoting developmental myelination. By contrast, in the adult CNS, localized ablation of astrocytes 2 days after a demyelinating insult resulted in increased numbers of oligodendrocytes and accelerated remyelination in both the spinal cord and the corpus callosum. Microarray analysis reveals astrocytic NF-kB signaling pathway as a major contributor to pathological events occurring after demyelination. We suggest that the localized functions of astrocytes are fundamentally different during developmental myelination and myelin repair. Astrocytes are critical for developmental myelination, however in a demyelinating environment they are detrimental to myelin repair.
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Project description:The heart undergoes significant structural, metabolic, gene expression and functional alterations during the perinatal to postnatal transition. While recent studies have identified multiple epigenetic and transcriptional regulators of cardiac maturation, post-transcriptional mechanisms regulating this process remain poorly understood. Neddylation is a post-translational modification that conjugates a small ubiquitin-like protein, NEDD8, to protein substrates via an E1-E2-E3 enzymatic cascade. The goal of this study was to define the role of neddylation in perinatal cardiac development and cardiac maturation. Neddylation was inhibited in adult mouse hearts by cardiac-specific deletion of NAE1 gene, a regulatory subunit of NEDD8 E1 enzyme, or in neonatal cardiomyocytes (CMs) with a pharmacological neddylation inhibitor, MLN4924. The impact on cardiac transcriptome, metabolism, maturation and function was assessed. Mosaic deletion of NAE1 in ~40% neonatal CMs disrupted aspects of maturation, including transverse-tubule formation, cellular hypertrophy and fetal/adult isoform switching, whereas deletion of NAE1 in over 80% CMs led to rapid development of cardiomyopathy and heart failure. Transcriptome analysis demonstrated an association of metabolic derangement with immature cardiomyocyte signature. Biochemical, ultrastructural and metabolomics analyses confirmed downregulation of fatty acid and oxidative phosphorylation genes, deficits in fatty acid utilization, mitochondrial dysfunction, and significantly altered metabolic profiles in NAE1-deficient hearts or MLN4924-treated neonatal CMs. Mechanistically, we found that HIF1α, a transcription factor known to promote glycolysis and suppress oxidative metabolism, is a putative NEDD8 target. Inhibition of neddylation resulted in HIF1α accumulation and activation, which contributed to diminished fatty acid utilization. Taken together, we conclude that neddylation plays a crucial role in CM maturation and postnatal cardiac development through sustaining the glycolytic to oxidative metabolic switch in perinatal hearts.
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