MBL-1/Muscleblind regulates neuronal differentiation and controls the splicing of a terminal selector in Caenorhabditis elegans
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ABSTRACT:
PROVIDER: PRJNA1146472 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR30192600_1.fastq.gz | Fastqsanger.gz | |||
| SRR30192600_2.fastq.gz | Fastqsanger.gz | |||
| SRR30192601_1.fastq.gz | Fastqsanger.gz | |||
| SRR30192601_2.fastq.gz | Fastqsanger.gz | |||
| SRR30192602_1.fastq.gz | Fastqsanger.gz |
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Project description:The muscleblind family of mRNA splicing regulators is conserved across species and regulate the development of muscles and the nervous system. However, how Muscleblind proteins regulate neuronal fate specification and neurite morphogenesis at the single-neuron level is not well understood. In this study, we found that the C. elegans Muscleblind/MBL-1 promotes axonal growth in the touch receptor neurons (TRNs) by regulating microtubule stability and polarity. Transcriptomic analysis identified dozens of MBL-1-controlled splicing events in genes related to neuronal differentiation or microtubule functions. Among the MBL- 1 targets, the LIM-domain transcription factor mec-3 is the terminal selector for the TRN fate and induces the expression of many TRN terminal differentiation genes. MBL-1 promotes the splicing of the mec-3 long isoform, which are essential for TRN fate specification, and inhibits the short isoforms that have much weaker activities in activating downstream genes. MBL-1 promotes mec-3 splicing through three “YGCU(U/G)Y” motifs located downstream of the included exon, which is similar to the mechanisms used by mammalian Muscleblind and suggests a deeply conserved context-dependency of the splicing regulation. Interestingly, the expression of mbl-1 in the TRNs is dependent on the mec-3 long isoform, indicating a positive feedback loop between the splicing regulator and the terminal selector. Finally, through a forward genetic screen, we found that MBL-1 promotes neurite growth partly by inhibiting the DLK-1/p38 MAPK pathway. In summary, our study provides mechanistic understanding of the role of Muscleblind in regulating cell fate specification and neuronal morphogenesis.
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Project description:Muscleblind-like splicing regulators (MBNLs) are RNA-binding factors that have an important role in developmental processes. Dysfunction of these factors is a key contributor of different neuromuscular degenerative disorders, including Myotonic Dystrophy type 1 (DM1). Since DM1 is a multisystemic disease characterized by symptoms resembling accelerated aging, we asked which cellular processes do MBNLs regulate that make them necessary for normal lifespan. By utilizing the model organism Caenorhabditis elegans, we found that loss of MBL-1 (the sole ortholog of mammalian MBNLs), which is known to be required for normal lifespan, shortens lifespan by decreasing the activity of p38 MAPK/PMK-1 as well as the function of transcription factors ATF-7 and SKN-1. Furthermore, we show that mitochondrial stress caused by knockdown of mitochondrial electron transport chain components promotes the longevity of mbl-1 mutants in a partially PMK-1-dependent manner. Together, the data establish a mechanism of how DM1-associated loss of muscleblind affects lifespan. Furthermore, this study suggests that mitochondrial stress could alleviate symptoms caused by the dysfunction of muscleblind splicing factor, creating a potential approach to investigate for therapy.
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Project description:We provide data showing alternative splicing regulation by Muscleblind proteins in MEFs. MEFs lacking functional Muscleblind (DKO MEFs) were stably reconstituted with Muscleblind proteins from Homo sapiens, Ciona intestinalis, Drosophila melanogaster, Caenorhabditis elegans or Trichoplax adhaerens and splicing regulation was explored using RNA-seq analysis followed by MISO (Mixture of Isoforms).
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Project description:We provide data showing alternative splicing regulation by Muscleblind proteins in MEFs. MEFs lacking functional Muscleblind (DKO MEFs) were stably reconstituted with Muscleblind proteins from Homo sapiens, Ciona intestinalis, Drosophila melanogaster, Caenorhabditis elegans or Trichoplax adhaerens and splicing regulation was explored using RNA-seq analysis followed by MISO (Mixture of Isoforms). Alternative splicing was accessed using RNA-sequencing data from five DKO MEF lines reconstituted with different GFP-tagged Muscleblind homologs or GFP alone and compared to RNA-seq data from three WT MEF lines and three control DKO MEFs (no Muscleblind reconstitution). A total of 12 samples were used for high-throughput sequencing.
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Project description:To analyzed the different mbl issoforms we pulled down RNA using probes against mbl-exon2 and performed long read sequencing
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Project description:Ozone is a common pollutant and a potent oxidant in industrialized nations. The mechanisms of ozone-induced lung injury and differential susceptibility are not fully understood. Ozone-induced lung inflammation is mediated, in part, by the innate immune system. We hypothesized that mannose binding lectin (MBL), which has a central role in the activation of the complement pathway of innate immunity, is a necessary component of the pro-inflammatory events caused by ozone-mediated activation of the innate immune system. Wild-type (Mbl+/+) and MBL deficient (Mbl-/-) mice were exposed to ozone (0.3 ppm) for 24, 48, and 72 hours, and bronchoalveolar lavage fluid (BALF) was examined for inflammatory markers. Compared to Mbl+/+ mice, significantly greater mean BALF eosinophils, neutrophils and neutrophil attractants CXCL2 (MIP-2) and CXCL5 (LIX) were found in Mbl-/- mice exposed to ozone. Using genome-wide mRNA microarray analyses, we identified significant differences in expression response profiles and networks at baseline (e.g. NRF2 mediated oxidative stress response) and after exposure (e.g. humoral immune response) between Mbl+/+ and Mbl-/- mice. The microarray data were further analyzed using a pattern recognition analysis for Extracting Patterns and Identifying co-expressed Genes (EPIG), and discovered several informative differential response patterns and subsequent gene sets, including antimicrobial response and inflammatory response. These novel findings demonstrate that targeted deletion of Mbl caused differential expression of inflammation-related gene sets basally and after exposure to ozone, and significantly reduced pulmonary inflammation thus indicating an important innate immunomodulatory role of the gene in this model.
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Project description:The large diversity of cell types in nervous systems presents a challenge in identifying the genetic mechanisms that encode it. Here, we report that nearly 200 distinct neurons in the Drosophila visual system can each be defined by unique combinations of on average 10 continuously expressed transcription factors. We show that targeted modifications of this terminal selector code induce predictable conversions of neuronal fates that appear morphologically and transcriptionally complete. Cis-regulatory analysis of open chromatin links one of these genes to an upstream patterning factor that specifies neuronal fates in stem cells. Experimentally validated network models describe the synergistic regulation of downstream effectors by terminal selectors and ecdysone signaling during brain wiring. Our results provide a generalizable framework of how specific fates are implemented in postmitotic neurons.
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