A LewisX Glycoprotein Screen Identifies the Low Density Lipoprotein Receptor-related Protein 1 (LRP1) as a Modulator of Oligodendrogenesis in Mice

Hennen, Eva; Safina, Dina; Haußmann, Ute; Wörsdörfer, Philipp; Edenhofer, Frank; Poetsch, Ansgar; Faissner, Andréas

doi:10.1074/jbc.m112.419812

Cited by 34 publications

(46 citation statements)

References 31 publications

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“…Our previous studies showed that LewisX glycosylated LRP1 is highly upregulated in the cortical plate (Hennen et al 2013). To investigate whether this is a unique phenomenon for the developing cortex or a more common feature of the developing CNS, we tested LRP1 and LeX expression in the spinal cord.…”

Section: Resultsmentioning

confidence: 99%

“…We previously demonstrated that cortical LRP1-deficient cells generate fewer O4-positive oligodendrocytes (Hennen et al 2013). Here we asked whether other stages of oligodendroglial development, including early PDGFRα-positive progenitors and mature MBP-positive oligodendrocytes, were also affected by the in vitro knockout.…”

Section: Resultsmentioning

confidence: 99%

“…Cre-recombinase transduction was performed as described previously (Hennen et al 2013) with minor changes. 5 days in vitro (DIV 5) cortical neurospheres and DIV 7 spinal cord neurospheres were dissociated with the help of 0.05% (v/v) trypsin-EDTA (Invitrogen, Karlsruhe, Germany), and 50,000 cortical or 40,000 spinal cord derived NSPCs were plated on 16-mm dishes (Nunc) pre-coated with 15 μg/ml polyornithine (Sigma-Aldrich) and 2 μg/ml laminin (BD Bioscience, Franklin Lakes, NJ, USA).…”

Section: Methodsmentioning

confidence: 99%

“…LRP1 is highly enriched in the developing cortex and LeX-glycosylated in the radial glia compartment (Hennen et al 2013). LRP1 is a large ubiquitously expressed cell membrane receptor which functions as a major cholesterol transporter, and interacts with a variety of ligands involved in cell signaling (Lillis et al 2008).…”

Section: Introductionmentioning

confidence: 99%

“…Recently, we reported that LRP1-deficient NSPCs generate less O4-positive cells compared to control cells (Hennen et al 2013). In the present study, we demonstrate that LRP1 expression and glycosylation in the developing spinal cord is similar to the pattern in the cortex.…”

Section: Introductionmentioning

confidence: 99%

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Low‐density lipoprotein receptor‐related protein 1 is a novel modulator of radial glia stem cell proliferation, survival, and differentiation

Safina

Schlitt

Romeo

et al. 2016

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The LDL family of receptors and its member LRP1 have classically been associated with a modulation of lipoprotein metabolism. Current studies, however, indicate diverse functions for this receptor in various aspects of cellular activities, including cell proliferation, migration, differentiation and survival. LRP1 is essential for normal neuronal function in the adult CNS, whereas the role of LRP1 in development remained unclear. Previously we have observed an upregulation of LewisX (LeX) glycosylated LRP1 in the stem cells of the developing cortex and demonstrated its importance for oligodendrocyte differentiation. In the current study we show that LeX-glycosylated LRP1 is also expressed in the stem cell compartment of the developing spinal cord and has broader functions in the developing CNS. We have investigated the basic properties of LRP1 conditional knockout on the neural stem/progenitor cells (NSPCs) from the cortex and the spinal cord, created by means of Cre-loxp mediated recombination in vitro. The functional status of LRP1-deficient cells has been studied using proliferation, differentiation and apoptosis assays. LRP1 deficient NSPCs from both CNS regions demonstrated altered differentiation profiles. Their differentiation capacity towards oligodendrocyte progenitor cells (OPCs), mature oligodendrocytes and neurons was reduced. In contrast, astrocyte differentiation was promoted. Moreover, LRP1 deletion had a negative effect on NSPCs proliferation and survival. Our observations suggest that LRP1 facilitates NSPCs differentiation via interaction with ApoE. Upon ApoE4 stimulation wild type NSPCs generated more oligodendrocytes, but LRP1 knockout cells showed no response. The effect of ApoE seems to be independent of cholesterol uptake, but is rather mediated by downstream MAPK and Akt activation.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Low‐density lipoprotein receptor‐related protein 1 is a novel modulator of radial glia stem cell proliferation, survival, and differentiation

Safina

Schlitt

Romeo

et al. 2016

Glia

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

Bres

Safina

Müller

et al. 2020

Glia

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The Alzheimer disease-associated multifunctional low-density lipoprotein receptorrelated protein-1 is expressed in the brain. Recent studies uncovered a role of this receptor for the appropriate functioning of neural stem cells, oligodendrocytes, and neurons. The constitutive knockout (KO) of the receptor is embryonically lethal. To unravel the receptors' role in the developing brain we generated a mouse mutant by specifically targeting radial glia stem cells of the dorsal telencephalon. The lowdensity lipoprotein receptor-related protein-1 lineage-restricted KO female and male mice, in contrast to available models, developed a severe neurological phenotype with generalized seizures during early postnatal development. The mechanism leading to a buildup of hyperexcitability and emergence of seizures was traced to a failure in adequate astrocyte development and deteriorated postsynaptic density integrity. The detected impairments in the astrocytic lineage: precocious maturation, reactive gliosis, abolished tissue plasminogen activator uptake, and loss of functionality emphasize the importance of this glial cell type for synaptic signaling in the developing brain. Together, the obtained results highlight the relevance of astrocytic lowdensity lipoprotein receptor-related protein-1 for glutamatergic signaling in the

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Modulation of Neural Stem Cell Expressed Extracellular Matrix (ECM) by Targeting Glycosyltransferases

Hennen

Faissner

2014

Extracellular Matrix

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A LewisX Glycoprotein Screen Identifies the Low Density Lipoprotein Receptor-related Protein 1 (LRP1) as a Modulator of Oligodendrogenesis in Mice

Cited by 34 publications

References 31 publications

Low‐density lipoprotein receptor‐related protein 1 is a novel modulator of radial glia stem cell proliferation, survival, and differentiation

Low‐density lipoprotein receptor‐related protein 1 is a novel modulator of radial glia stem cell proliferation, survival, and differentiation

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

Modulation of Neural Stem Cell Expressed Extracellular Matrix (ECM) by Targeting Glycosyltransferases

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