Low-Density Lipoprotein Receptor-Related Protein 1 (LRP1) Is a Negative Regulator of Oligodendrocyte Progenitor Cell Differentiation in the Adult Mouse Brain.

Loic Auderset,Kaylene M Young,Renee E Pepper,Carlie L Cullen,Kimberley A Pitman,Bruce V Taylor,Lisa Foa

doi:10.3389/fcell.2020.564351

Abstract

Low-density lipoprotein receptor-related protein 1 (LRP1) is a large, endocytic cell surface receptor that is highly expressed by oligodendrocyte progenitor cells (OPCs) and LRP1 expression is rapidly downregulated as OPCs differentiate into oligodendrocytes (OLs). We report that the conditional deletion of Lrp1 from adult mouse OPCs (Pdgfrα-CreER :: Lrp1fl/fl) increases the number of newborn, mature myelinating OLs added to the corpus callosum and motor cortex. As these additional OLs extend a normal number of internodes that are of a normal length, Lrp1-deletion increases adult myelination. OPC proliferation is also elevated following Lrp1 deletion in vivo, however, this may be a secondary, homeostatic response to increased OPC differentiation, as our in vitro experiments show that LRP1 is a direct negative regulator of OPC differentiation, not proliferation. Deleting Lrp1 from adult OPCs also increases the number of newborn mature OLs added to the corpus callosum in response to cuprizone-induced demyelination. These data suggest that the selective blockade of LRP1 function on adult OPCs may enhance myelin repair in demyelinating diseases such as multiple sclerosis.

Highlights

Oligodendrocytes (OLs) myelinate the central nervous system (CNS) to facilitate the saltatory conduction of action potentials and provide essential metabolic support to axons
To determine the role that lipoprotein receptor-related protein 1 (LRP1) plays in regulating adult myelination, lipoprotein receptor related protein 1 (Lrp1) was conditionally deleted from oligodendrocyte progenitor cells (OPCs) in young adult mice
By performing immunohistochemistry to detect YFP, the OPC marker PDGFRα, and Breast Carcinoma Amplified Sequence 1 (BCAS1), a protein expressed by some OPCs and all premyelinating OLs (Fard et al, 2017; Ferreira et al, 2020), we found that the fraction of YFP+ cells that were mature OLs (YFP+ PDGFRα-neg BCAS1-neg) was increased in the corpus callosum of Lrp1-deleted mice compared to controls (Figures 9M–O)

Summary

Introduction

Oligodendrocytes (OLs) myelinate the central nervous system (CNS) to facilitate the saltatory conduction of action potentials and provide essential metabolic support to axons (reviewed by Pepper et al, 2018). Microarray (Cahoy et al, 2008) and RNA sequencing (Zhang et al, 2014; Hrvatin et al, 2018) experiments have uncovered a number of additional genes that are differentially expressed across OL development and have an unknown or partly characterized regulatory function in the OL lineage. One such gene is the low-density lipoprotein receptor related protein 1 (Lrp1)

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Results

Conclusion