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

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-CreERT2ct2/wtxR26eGFPflox/floxxLRP1flox/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did not achieve statistical significance, presumably because the majority of recombined LRP1-deficient cells has been replaced by non-recombined cells.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.

Lipoprotein receptor loss in forebrain radial glia results in neurological deficits and severe seizures

“…Despite no changes in the astrocyte lineage embryonically, we did detect a mild increase in Sox9‐Olig2 double positive cells at the investigated stage. This interesting finding may indicate that the oligodendrocytic lineage is impacted by our in vivo KO as it is upon in vitro Lrp1 deletion in NSPCs (Safina et al, 2016), as well as in NG2‐positive glia in vivo (Schafer et al, 2019) and should be therefore studied further.…”

“…In our recent work, we unraveled that the elimination of Lrp1 in cortical neural stem precursor cells (NSPCs) in vitro leads to their altered differentiation properties including an impaired neurogenesis and reduced oligodendrocyte numbers, whereas differentiation toward astrocytes is enhanced (Hennen et al, 2013; Safina et al, 2016; Schafer et al, 2019). This raises the until now unanswered key question concerning the specific impact of Lrp1 deletion from the radial glia stem cell compartment in the living animal.…”

Low-Density Lipoprotein Receptor-Related Protein 1 (LRP1) as a Novel Regulator of Early Astroglial Differentiation

“…Cryosections of 14 μm were prepared. The cryosections were stained as previously described ( Schäfer et al, 2019 ; Ulc et al, 2019 ). Shortly, cryosections were transferred to citric acid buffer (solution A: 0.1 M citric acid-1-hydrate, solution B: 0.1 M Na-citrate-dihydrate; 1 mM of solution A and 4 mM of solution B in aqua dest .)…”

Deletion of LRP1 From Astrocytes Modifies Neuronal Network Activity in an in vitro Model of the Tripartite Synapse

“…In general, LRP1 is ubiquitously expressed, but strongly enriched in the liver, lung, blood vessels, and in the central nervous system (CNS). There, it is expressed by neurons, microglia, immature oligodendrocytes, and astrocytes ( May et al, 2004 ; Liu et al, 2010 ; Boucher and Herz, 2011 ; Auderset et al, 2016 ; Schäfer et al, 2019 ). LRP1 is critical for development, proved by the constitutive knockout causing embryonic lethality ( Herz et al, 1993 ).…”