Biology subjects

Preussner, J.

Publications and source records attributed to Preussner, J..

4 recordsLinked to original sources

bioRxiv2018

Myh10 deficiency leads to defective extracellular matrix remodeling and pulmonary disease

Impaired alveolar formation and maintenance are features of many pulmonary diseases that are associated with significant morbidity and mortality. In a forward genetic screen for modulators of mouse lung development, we identified the non-muscle myosin II heavy chain gene, Myh10. Myh10 mutant pups exhibit cyanosis and respiratory distress, and die shortly after birth from differentiation defects in alveolar epithelium and mesenchyme. From omics analyses and follow up studies, we find decreased Thrombospondin expression accompanied with increased matrix metalloproteinase activity in both mutant lungs and cultured mutant fibroblasts, as well as disrupted extracellular matrix (ECM) remodeling. Loss of Myh10 specifically in mesenchymal cells results in ECM deposition defects and alveolar simplification. Notably, MYH10 expression is down-regulated in the lung of emphysema patients. Altogether, our findings reveal critical roles for Myh10 in alveologenesis at least in part via the regulation of ECM remodeling, which may contribute to the pathogenesis of emphysema.

developmental biology↗

bioRxiv2018

The potassium channel KCNJ13 is essential for smooth muscle cytoskeletal organization during mouse tracheal tubulogenesis

Tubulogenesis is essential for the formation and function of internal organs. One such organ is the trachea, which allows gas exchange between the external environment and the lungs. However, the cellular and molecular mechanisms underlying tracheal tube development remain poorly understood. Here, we show that the potassium channel KCNJ13 is a critical modulator of tracheal tubulogenesis. We identify Kcnj13 in an ethylnitrosourea forward genetic screen for regulators of mouse respiratory organ development. Kcnj13 mutants exhibit a shorter trachea as well as defective smooth muscle (SM) cell alignment and polarity. KCNJ13 is essential to maintain ion homeostasis in tracheal SM cells, which is required for actin polymerization. This process appears to be mediated, at least in part, through activation of the actin regulator AKT, as pharmacological increase of AKT phosphorylation ameliorates the Kcnj13 mutant trachea phenotypes. These results provide insights into the role of ion homeostasis in cytoskeletal organization during tubulogenesis.

developmental biology↗

bioRxiv2018

UROPA GUI: A web platform for genomic region annotation

The annotation of genomic ranges such as peaks resulting from ChIP-seq/ATAC-seq or other techniques represents a fundamental task of bioinformatics analysis with considerable impact on many downstream analyses. In our previous work, we introduced the Universal Robust Peak Annotator (UROPA), a flexible command line based tool which improves upon the functionality of existing annotation software. In order to reduce the complexity for biologists and clinicians, we have implemented an intuitive web-based graphical user interface (GUI) and fully functional service platform for UROPA. This extension will empower all users to generate annotations for regions of interest interactively.\n\nAvailability and ImplementationThe open source UROPA GUI server was implemented in R Shiny and Python and is available from http://loosolab.mpi-bn.mpg.de. The source code of our App can be downloaded at https://github.molgen.mpg.de/loosolab/UROPA_GUI under the MIT license.

bioinformatics↗

bioRxiv2017

Single-cell transcriptional regulations and accessible chromatin landscape of cell fate decisions in early heart development

Formation and segregation of the cell lineages forming the vertebrate heart have been studied extensively by genetic cell tracing techniques and by analysis of single marker gene expression both in embryos and differentiating ES cells. However, the underlying gene regulatory networks driving cell fate transitions during early cardiogenesis is only partially understood, in part due to limited cell numbers and substantial cellular heterogeneity within the early embryo. Here, we comprehensively characterized cardiac progenitor cells (CPC) marked by Nkx2-5 and Isl1 expression from embryonic days E7.5 to E9.5 using single-cell RNA sequencing. By leveraging on cell-to-cell heterogeneity, we identified different previously unknown cardiac sub-populations. Reconstruction of the developmental trajectory revealed that Isl1+ CPC represent a transitional cell population maintaining a prolonged multipotent state, whereas extended expression of Nkx-2.5 commits CPC to a unidirectional cardiomyocyte fate. Correlation-based analysis of cells in the unstable multipotent state uncovered underlying gene regulatory networks associated with differentiation. Furthermore, we show that CPC fate transitions are associated with distinct open chromatin states, which critically depend on Isl1 for accessibility of enhancers. In contrast, forced expression of Nkx2-5 eliminated multipotency of Isl1+ cells and established a unidirectional cardiomyocyte fate. Our data provides a transcriptional map for early cardiogenic events at single-cell resolution and establishes a general model of transcriptional and epigenetic regulations during cardiac progenitor cell fate decisions.

developmental biology↗