A transcriptomics resource reveals a transcriptional transition during ordered sarcomere morphogenesis in flight muscle
Abstract
Muscles organise pseudo-crystalline arrays of actin, myosin and titin filaments to build force-producing sarcomeres. To study sarcomerogenesis, we have generated a transcriptomics resource of developing Drosophila flight muscles and identified 40 distinct expression profile clusters. Strikingly, most sarcomeric components group in two clusters, which are strongly induced after all myofibrils have been assembled, indicating a transcriptional transition during myofibrillogenesis. Following myofibril assembly, many short sarcomeres are added to each myofibril. Subsequently, all sarcomeres mature, reaching 1.5 µm diameter and 3.2 µm length and acquiring stretch-sensitivity. The efficient induction of the transcriptional transition during myofibrillogenesis, including the transcriptional boost of sarcomeric components, requires in part the transcriptional regulator Spalt major. As a consequence of Spalt knock-down, sarcomere maturation is defective and fibers fail to gain stretch-sensitivity. Together, this defines an ordered sarcomere morphogenesis process under precise transcriptional control - a concept that may also apply to vertebrate muscle or heart development.
Data availability
Processed data from DESeq2, Mfuzz and GO-Elite are available in Supplementary Files 1, 2, 4. mRNA-Seq data are publicly available from NCBI's Gene Expression Omnibus (GEO) under accession number GSE107247. Fiji scripts for analysis of sarcomere length, myofibril width and myofibril diameter are available from https://imagej.net/MyofibrilJ. Raw data used to generate all plots presented in figure panels are available in the source data files for Figures 1, 5, 6, 7 and 8. Data on statistical test results are presented in Supplementary File 5.
-
Systematic transcriptomics reveals a biphasic mode of sarcomere morphogenesis in flight muscles regulated by SpaltPublicly available at the NCBI Gene Expression Omnibus (accession no: GSE107247).
-
The RNA binding protein Arrest (Aret) regulates myofibril maturation in Drosophila flight musclePublicly available at the NCBI Gene Expression Omnibus (accession no: GSE63707).
Article and author information
Author details
Funding
Max-Planck-Gesellschaft
- Maria L Spletter
- Christiane Barz
- Assa Yeroslaviz
- Xu Zhang
- Sandra B Lemke
- Bianca H Habermann
- Frank Schnorrer
Agence Nationale de la Recherche (ANR-10-INBS-04- 01)
- Frank Schnorrer
Agence Nationale de la Recherche (ANR ACHN)
- Frank Schnorrer
Centre National de la Recherche Scientifique
- Xu Zhang
- Adrien Bonnard
- Bianca H Habermann
- Frank Schnorrer
European Molecular Biology Organization (EMBO-LTR 688-2011)
- Maria L Spletter
Alexander von Humboldt-Stiftung
- Maria L Spletter
National Institute for Health Research (5F32AR062477)
- Maria L Spletter
H2020 European Research Council (ERC Grant 310939)
- Frank Schnorrer
Aix-Marseille Université (ANR-11-IDEX-0001-02)
- Bianca H Habermann
- Frank Schnorrer
Agence Nationale de la Recherche (ANR-11- LABX-0054)
- Frank Schnorrer
European Molecular Biology Organization (EMBO-YIP)
- Frank Schnorrer
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- K VijayRaghavan, National Centre for Biological Sciences, Tata Institute of Fundamental Research, India
Version history
- Received: December 4, 2017
- Accepted: May 26, 2018
- Accepted Manuscript published: May 30, 2018 (version 1)
- Version of Record published: June 18, 2018 (version 2)
Copyright
© 2018, Spletter et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 4,193
- views
-
- 526
- downloads
-
- 70
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Further reading
-
- Cancer Biology
- Cell Biology
Immune checkpoint inhibitors have produced encouraging results in cancer patients. However, the majority of ß-catenin-mutated tumors have been described as lacking immune infiltrates and resistant to immunotherapy. The mechanisms by which oncogenic ß-catenin affects immune surveillance remain unclear. Herein, we highlighted the involvement of ß-catenin in the regulation of the exosomal pathway and, by extension, in immune/cancer cell communication in hepatocellular carcinoma (HCC). We showed that mutated ß-catenin represses expression of SDC4 and RAB27A, two main actors in exosome biogenesis, in both liver cancer cell lines and HCC patient samples. Using nanoparticle tracking analysis and live-cell imaging, we further demonstrated that activated ß-catenin represses exosome release. Then, we demonstrated in 3D spheroid models that activation of β-catenin promotes a decrease in immune cell infiltration through a defect in exosome secretion. Taken together, our results provide the first evidence that oncogenic ß-catenin plays a key role in exosome biogenesis. Our study gives new insight into the impact of ß-catenin mutations on tumor microenvironment remodeling, which could lead to the development of new strategies to enhance immunotherapeutic response.
-
- Cell Biology
Asymmetric cell divisions (ACDs) generate two daughter cells with identical genetic information but distinct cell fates through epigenetic mechanisms. However, the process of partitioning different epigenetic information into daughter cells remains unclear. Here, we demonstrate that the nucleosome remodeling and deacetylase (NuRD) complex is asymmetrically segregated into the surviving daughter cell rather than the apoptotic one during ACDs in Caenorhabditis elegans. The absence of NuRD triggers apoptosis via the EGL-1-CED-9-CED-4-CED-3 pathway, while an ectopic gain of NuRD enables apoptotic daughter cells to survive. We identify the vacuolar H+–adenosine triphosphatase (V-ATPase) complex as a crucial regulator of NuRD’s asymmetric segregation. V-ATPase interacts with NuRD and is asymmetrically segregated into the surviving daughter cell. Inhibition of V-ATPase disrupts cytosolic pH asymmetry and NuRD asymmetry. We suggest that asymmetric segregation of V-ATPase may cause distinct acidification levels in the two daughter cells, enabling asymmetric epigenetic inheritance that specifies their respective life-versus-death fates.