Conditional Deletion of LRP1 Leads to Progressive Loss of Recombined NG2-Expressing Oligodendrocyte Precursor Cells in a Novel Mouse Model

Ina Schäfer; Johannes Kaisler; Anja Scheller; Frank Kirchhoff; Aiden Haghikia; Andreas Faissner

doi:10.3390/cells8121550

Conditional Deletion of LRP1 Leads to Progressive Loss of Recombined NG2-Expressing Oligodendrocyte Precursor Cells in a Novel Mouse Model

Cells. 2019 Nov 30;8(12):1550. doi: 10.3390/cells8121550.

Authors

Ina Schäfer¹, Johannes Kaisler², Anja Scheller³, Frank Kirchhoff³, Aiden Haghikia², Andreas Faissner¹

Affiliations

¹ Department of Cell Morphology and Molecular Neurobiology, Ruhr University Bochum, Universitätsstr. 150, 44801 Bochum, Germany.
² Research Center Neuroimmunology, Department of Neurology, Ruhr-University Bochum, Universitätsstr. 150, 44801 Bochum, Germany.
³ Department of Molecular Physiology, Center for Integrative Physiology and Molecular Medicine (CIPMM), University of Saarland, Building 48, 66421 Homburg, Germany.

Abstract

The low-density lipoprotein receptor-related protein 1 (LRP1) is a transmembrane receptor, mediating endocytosis and activating intracellular signaling cascades. LRP1 is highly expressed in the central nervous system (CNS), especially in oligodendrocyte precursor cells (OPCs). Previous studies have suggested LRP1 as a regulator in early oligodendrocyte development, repair of chemically induced white matter lesions, and cholesterol homeostasis. To circumvent embryonic lethality observed in the case of global LRP1 deletion, we generated a new inducible conditional knockout (KO) mouse model, which enabled an NG2-restricted LRP1 deficiency (NG2-CreERT2^ct2/wtxR26eGFP^flox/floxxLRP1^flox/flox). When characterizing our triple transgenic mouse model, we noticed a substantial and progressive loss of recombined LRP1-deficient cells in the oligodendrocyte lineage. On the other hand, we found comparable distributions and fractions of oligodendroglia within the Corpus callosum of the KO and control animals, indicating a compensation of these deficits. An initial study on experimental autoimmune encephalomyelitis (EAE) was performed in triple transgenic and control mice and the cell biology of oligodendrocytes obtained from the animals was studied in an in vitro myelination assay. Differences could be observed in these assays, which, however, did not achieve statistical significance, presumably because the majority of recombined LRP1-deficient cells has been replaced by non-recombined cells. Thus, the analysis of the role of LRP1 in EAE will require the induction of acute recombination in the context of the disease process. As LRP1 is necessary for the survival of OPCs in vivo, we assume that it will play an important role in myelin repair.

Keywords: cre-recombinase; demyelination; experimental autoimmune encephalomyelitis (EAE); glial progenitor cells; myelin; tamoxifen.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cells, Cultured
Disease Models, Animal
Encephalomyelitis, Autoimmune, Experimental
Fluorescent Antibody Technique
Gene Deletion*
Gene Expression
Low Density Lipoprotein Receptor-Related Protein-1 / genetics*
Low Density Lipoprotein Receptor-Related Protein-1 / metabolism
Mice
Mice, Knockout
Oligodendrocyte Precursor Cells / metabolism*

Substances

Low Density Lipoprotein Receptor-Related Protein-1
Lrp1 protein, mouse