Myostatin is a negative regulator of adult neurogenesis in zebrafish
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PROVIDER: PRJNA761449 | ENA |
REPOSITORIES: ENA
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Project description:Intrinsic and extrinsic inhibition of axonal and neuronal regeneration obstruct spinal cord (SC) repair in mammals. In contrast, adult zebrafish achieve functional recovery after SC damage. While studies of innate SC regeneration have focused on axon regrowth as a primary repair mechanism, how local neurogenesis impacts functional recovery is unknown. We uncovered dynamic expression of myostatin b (mstnb) in a niche of dorsal ependymal progenitors after complete SC transection in zebrafish. Genetic loss-of-function in mstnb impaired functional recovery, although glial and axonal bridging across the lesion were unaffected. Using a series of transgenic reporter lines, we quantified the numbers of stem, progenitor, and neuronal cells in the absence of mstnb. We found neural stem cell proliferation was reduced, while newborn neurons were increased in mstnb null tissues, suggesting mstnb is a negative regulator of neurogenesis. Molecularly, neuron differentiation genes were upregulated, while the neural stem cell maintenance gene fgf1b was downregulated in mstnb mutants. Finally, we show that human FGF1 treatment rescued neuronal gene expression in mstnb mutants. These studies uncover unanticipated neurogenic functions for mstnb in adult zebrafish, and establish the importance of local neurogenesis for functional SC repair.
2022-10-20 | GSE183644 | GEO
Project description:Inhibition of myostatin signaling induces strong skeletal muscle growth making it an attractive target to treat muscle wasting and sarcopenia. However, the biological function of myostatin in the heart is barely understood. We demonstrate that conditional inactivation of myostatin in the adult murine heart leads to cardiac hypertrophy, heart failure and increased lethality. To induce cardiomyocyte specific loss of myostatin a conditionally active Mstn^fl/fl allele was generated by insertion of loxP elements upstream and downstream of exons 1 and 2 of the mouse myostatin gene. The selection cassette was removed in vivo by flp-recombination. To inactivate myostatin, mice were mated to alphaMyHC-MCM mice (Sohal, DS, et al. (2001) Circulation Research 89, 20-25). Cre-recombination was achieved by intraperitoneal administration of Tamoxifen (40 mg/kg) for 5 consecutive days. The respective control alphaMyHC-MCM animals were equally treated.
2014-05-16 | E-MEXP-3744 | biostudies-arrayexpress
Project description:Myostatin (GDF8) is a member of the TGF-beta family of proteins which is predominantly expressed in skeletal muscle and acts as a negative regulator of muscle mass. Inhibition of myostatin leads to muscle hypertrophy and has been shown to mitigate insulin resistance in mouse models of type 2 diabetes, although the mechanisms underlying this effect are unclear. We found that myostatin inhibition by AAV-mediated overexpression of the myostatin propeptide improves skeletal muscle insulin sensitivity in mice made insulin-resistant by high fat diet feeding. To gain insight into potential gene expression changes responsible for this effect, we performed microarray analysis on skeletal muscle samples from high fat diet-fed mice with and without myostatin inhibition.
2020-05-29 | GSE130622 | GEO
Project description:RNA from 5 mice with postdevelopmental knockout of myostatin and 5 mice with normal myostatin expression was analyzed with comprehensive oligonucleotide microarrays. Myostatin depletion affected the expression of several hundred genes at nominal P < 0.01, but fewer than a hundred effects were statistically significant according to a more stringent criterion (false discovery rate < 5%). Most of the effects were less than 1.5-fold in magnitude. In contrast to previously-reported effects of constitutive myostatin knockout, postdevelopmental knockout did not downregulate expression of genes encoding slow isoforms of contractile proteins or genes encoding proteins involved in energy metabolism. Several collagen genes were expressed at lower levels in the myostatin-deficient muscles, and this led to reduced tissue collagen levels as reflected by hydroxyproline content. Myostatin knockout tended to down-regulate the expression of sets of genes with promoter motifs for Smad3, Smad4, myogenin, NF-κB, serum response factor, and numerous other transcription factors. Main conclusions: in mature muscle, myostatin is a key transcriptional regulator of collagen genes, but not genes encoding contractile proteins or genes encoding proteins involved in energy metabolism.
2009-03-24 | GSE15349 | GEO
Project description:ABSTRACT Stimulating the commitment of implanted dystrophin+ muscle derived stem cells (MDSC) into myogenic, as opposed to lipofibrogenic, lineages is a promising therapeutic strategy for Duchenne muscular dystrophy (DMD). To examine whether counteracting myostatin, a negative regulator of muscle mass and a pro-lipofibrotic factor, would help this process, we compared the in vitro myogenic and fibrogenic capacity of MDSC from wild type (WT), myostatin knockout (Mst KO), and mdx (DMD model) (mdx) young mice under various modulators, the expression of key stem cell and myogenic genes, and the capacity of these MDSC to repair the injured gastrocnemius in aged mdx mice with exacerbated lipofibrosis. Surprisingly, the potent in vitro myotube formation by WT MDSC was refractory to modulators of myostatin expression or activity, and the Mst KO and mdx MDSC failed to form myotubes under any condition, despite all MDSC expressed Oct-4 and various stem cell genes and differentiated into other lineages. The genetic inactivation of myostatin or dystrophin in MDSC was associated with silencing of critical genes for early myogenesis (Actc1, Acta1, and MyoD). WT MDSC implanted into the injured gastrocnemius of old mdx mice significantly improved myofiber repair and reduced fat deposition and, to a lesser extent, fibrosis. In contrast to their in vitro behavior, Mst KO MDSC in vivo also significantly improved myofiber repair, but had no significant effects on lipofibrotic degeneration. In conclusion, while WT MDSC are considerably myogenic in culture and stimulate muscle repair after injury in the aged mdx mouse, myostatin genetic inactivation blocks myotube formation in vitro but the myogenic capacity is recovered in vivo under the influence of the host tissue environment, presumably by reactivation of key genes originally silenced in the Mst KO MDSC. Key words: dystrophin, mdx mouse, Duchenne, fibrosis, dystrophy One sample each of mouse wild type (WT), myostatin knockout (KO), muscular dystrophy model mdx, and the transgenic OCT4 promoter plus reporter were grown, RNA was isolated, and subjected to the SABiosciences mouse stem cell oligo array.
2012-09-30 | E-GEOD-28986 | biostudies-arrayexpress
Project description:RNA from 5 mice with postdevelopmental knockout of myostatin and 5 mice with normal myostatin expression was analyzed with comprehensive oligonucleotide microarrays. Myostatin depletion affected the expression of several hundred genes at nominal P < 0.01, but fewer than a hundred effects were statistically significant according to a more stringent criterion (false discovery rate < 5%). Most of the effects were less than 1.5-fold in magnitude. In contrast to previously-reported effects of constitutive myostatin knockout, postdevelopmental knockout did not downregulate expression of genes encoding slow isoforms of contractile proteins or genes encoding proteins involved in energy metabolism. Several collagen genes were expressed at lower levels in the myostatin-deficient muscles, and this led to reduced tissue collagen levels as reflected by hydroxyproline content. Myostatin knockout tended to down-regulate the expression of sets of genes with promoter motifs for Smad3, Smad4, myogenin, NF-κB, serum response factor, and numerous other transcription factors. Main conclusions: in mature muscle, myostatin is a key transcriptional regulator of collagen genes, but not genes encoding contractile proteins or genes encoding proteins involved in energy metabolism. Experiment Overall Design: Comparison of muscle gene expression in 5 mice with postdevelopmental myostatin knockout and 5 control mice
2009-03-28 | E-GEOD-15349 | biostudies-arrayexpress
Project description:ABSTRACT Stimulating the commitment of implanted dystrophin+ muscle derived stem cells (MDSC) into myogenic, as opposed to lipofibrogenic, lineages is a promising therapeutic strategy for Duchenne muscular dystrophy (DMD). To examine whether counteracting myostatin, a negative regulator of muscle mass and a pro-lipofibrotic factor, would help this process, we compared the in vitro myogenic and fibrogenic capacity of MDSC from wild type (WT), myostatin knockout (Mst KO), and mdx (DMD model) (mdx) young mice under various modulators, the expression of key stem cell and myogenic genes, and the capacity of these MDSC to repair the injured gastrocnemius in aged mdx mice with exacerbated lipofibrosis. Surprisingly, the potent in vitro myotube formation by WT MDSC was refractory to modulators of myostatin expression or activity, and the Mst KO and mdx MDSC failed to form myotubes under any condition, despite all MDSC expressed Oct-4 and various stem cell genes and differentiated into other lineages. The genetic inactivation of myostatin or dystrophin in MDSC was associated with silencing of critical genes for early myogenesis (Actc1, Acta1, and MyoD). WT MDSC implanted into the injured gastrocnemius of old mdx mice significantly improved myofiber repair and reduced fat deposition and, to a lesser extent, fibrosis. In contrast to their in vitro behavior, Mst KO MDSC in vivo also significantly improved myofiber repair, but had no significant effects on lipofibrotic degeneration. In conclusion, while WT MDSC are considerably myogenic in culture and stimulate muscle repair after injury in the aged mdx mouse, myostatin genetic inactivation blocks myotube formation in vitro but the myogenic capacity is recovered in vivo under the influence of the host tissue environment, presumably by reactivation of key genes originally silenced in the Mst KO MDSC. Key words: dystrophin, mdx mouse, Duchenne, fibrosis, dystrophy
2012-09-30 | GSE28986 | GEO
Project description:To identify microRNAs involved in myostatin-deficient muscular hypertrophy, we compared miRNA expression in wild-type and myostatin knockout mice.
2013-12-17 | GSE49523 | GEO
Project description:To identify microRNAs involved in myostatin-deficient muscular hypertrophy, we compared miRNA expression in wild-type and myostatin knockout mice. Total RNA, isolated from three wild-type or myostatin knockout mice, was pooled and then used for microarray analysis.
2013-12-17 | E-GEOD-49523 | biostudies-arrayexpress
Project description:Neural development is tightly controlled at multiple levels to orchestrate appropriate choices of cell fate and differentiation. While more attention has been paid to the roles of neural-restricted factors, broadly-expressed factors can have compelling impacts on tissue-specific development. Here, we describe in vivo genetic analysis of Ars2, which has mostly been studied as a general RNA processing factor in yeast and cultured cells. Ars2 protein exhibits a dynamic expression pattern during neural lineage progression, and conditional knockout analyses demonstrated that Ars2 is required for proliferation of embryonic neural stem cells (NSCs). In addition, Ars2 null neural stem cells can still transition into post-mitotic neurons, but fail to undergo terminal differentiation. Ars2 is similarly required for neurogenesis in the adult brain. We next generated Ars2 ChIP-seq data to broaden evidence for a distinct role for Ars2 as a transcriptional regulator in neural development. Notably, Ars2 preferentially occupies DNA enhancers in NSCs, and broadly colocalizes with the NSC regulator SOX2, but exhibits markedly reduced association with chromatin following differentiation. Finally, we demonstrate a continuous requirement for Ars2 during adult neurogenesis, since adult-specific deletion of Ars2 compromises hippocampal neurogenesis and results in specific behavioral defects. Together, we provide evidence for Ars2 as an essential neural regulator that interacts dynamically with DNA and controls neural lineage development.
2020-01-13 | GSE134106 | GEO