uu.seUppsala University Publications
Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Low density lipoprotein-related protein-2/megalin is expressed in oligodendrocytes in the mouse spinal cord white matter
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
Show others and affiliations
2006 (English)In: Journal of Neuroscience Research, ISSN 0360-4012, E-ISSN 1097-4547, Vol. 83, no 5, 864-873 p.Article in journal (Refereed) Published
Description
Abstract [en]

Lipoprotein receptor-related protein-2 (LRP2)/megalin is a member of the low density lipoprotein receptor (LDLR) family, and is essential in absorptive epithelia for endocytosis of lipoproteins, low molecular weight proteins, cholesterol and vitamins, as well as in cellular signaling. Previous studies have shown megalin expression in ependymal cells and choroid plexus. We have investigated megalin expression in the spinal cord of postnatal mice with immunohistochemistry and immunoblot. Antibodies recognizing either the cytoplasmic tail (MM6) or the extracellular domain (E11) of megalin labeled oligodendrocytes in the spinal cord white matter, in parallel with myelination. MM6 antibodies, predominantly labeled the nuclei, whereas E11 antibodies labeled the cytoplasm of these cells. MM6 antibodies labeled also nuclei of oligodendrocytes cultured from embryonic mouse spinal cord. Immunoblots of spinal cord showed intact megalin, as well as its carboxyterminal fragment, the part remaining after shedding of the extracellular domain of megalin. Megalin-immunoreactive oligodendrocytes also expressed presenilin 1, an enzyme responsible for gamma-secretase mediated endodomain cleavage. These findings show that spinal cord oligodendrocytes are phenotypically different from those in the brain, and indicate that megalin translocates signals from the cell membrane to the nucleus of oligodendrocytes during the formation and maintenance of myelin of long spinal cord pathways.

Place, publisher, year, edition, pages
2006. Vol. 83, no 5, 864-873 p.
National Category
Medical and Health Sciences Neurosciences
Research subject
Neuroscience; Neuroscience
Identifiers
URN: urn:nbn:se:uu:diva-80225DOI: 10.1002/jnr.20774PubMedID: 16463279OAI: oai:DiVA.org:uu-80225DiVA: diva2:108139
Available from: 2006-05-03 Created: 2006-05-03 Last updated: 2017-12-14Bibliographically approved
In thesis
1. Clusterin and Megalin in The Spinal Cord
Open this publication in new window or tab >>Clusterin and Megalin in The Spinal Cord
2006 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Nerve injury induces up-regulation of the chaperone protein clusterin in affected neurons and adjacent astrocytes but the functional significance of this response is unclear. We find that motor neuron survival is significantly greater in clusterin(+/+) compared to (-/-) mice. These results suggest that endogenous expression of clusterin is neuroprotective after nerve injury. However, motor neuron survival in clusterin overexpressing mice was not different from that in wildtype mice. In contrast, treatment of neuronal cultures with clusterin-TAT recombinant protein is neuroprotective, including a positive effect on neuronal network complexity.

Since extracellular clusterin complexes are endocytosed after binding to various receptors, we examined the expression of known clusterin binding receptors in the spinal cord. We find that megalin is expressed in the nuclei of two cell populations in the mouse spinal cord: i) oligodendrocytes in late postnatal and adult spinal cord white matter, and ii) transiently (E11-15) in a population of immature astrocytes in the dorsal spinal cord. We find no correlation between clusterin and megalin in the intact or injured spinal cord. However, intranuclear localization of megalin, suggesting signalling properties, is supported by the co-localization with γ-secretase, the enzyme responsible for endodomain cleavage of megalin. Megalin deficient mice display a pronounced deformation of the dorsal part of spinal cord, an almost complete absence of oligodendroglial progenitor cells, and a marked reduction in the population of mature astrocytes at later prenatal developmental stages.

Taken together, our findings indicate that megalin is a novel signalling molecule for distinct populations of glial cells in the pre- and postnatal spinal cord. The functional role(s) of megalin is unknown. However, its expression patterns and cellular localization suggest that megalin regulates differentiation of oligodendrocytes and astrocytes in the prenatal spinal cord, as well as the function of myelinating oligodendrocytes in the postnatal spinal cord.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2006. 58 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 208
Keyword
Neurosciences, nerve degeneration, hypoglossal nerve, chaperone, apolipoprotein, development, transcription factor, astrocyte, glial differentiation, myelin, cell signalling, Neurovetenskap
Identifiers
urn:nbn:se:uu:diva-7365 (URN)91-554-6739-3 (ISBN)
Public defence
2006-12-19, B22, Biomedical Centre (BMC), Husargatan 3, Uppsala, 13:15
Opponent
Supervisors
Available from: 2006-11-27 Created: 2006-11-27 Last updated: 2013-05-23Bibliographically approved
2. Megalin, an Endocytotic Receptor with Signalling Potential
Open this publication in new window or tab >>Megalin, an Endocytotic Receptor with Signalling Potential
2006 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Megalin is an endocytotic receptor belonging to the low-density lipoprotein family. It has often been viewed only as merely a scavenger receptor of absorptive and secretory epithelia. Recent work has revealed that the megalin intracellular domain contains several motifs potentially binding proteins involved in signal transduction.

To find potential intracellular proteins binding to megalin, a yeast two-hybrid screening was initiated with the intracellular tail of megalin as the bait. A partial clone encoding the scaffolding protein postsynaptic protein 95 (PSD-95) was found to bind to megalin with its second PDZ-domain. Co-localization experiments in HEK-293 cells and kidney, placenta and parathyroid tissue confirmed this interaction. The PSD-95 related proteins PSD-93 and SAP102 were also confirmed to bind megalin with their PDZ2-domains, but the corresponding domain from SAP97 did not bind. Mutation analysis revealed that an amino acid residue change Ala to Thr was the cause of this.

Megalin has within the central nervous system (CNS) been shown to be expressed only in the ependymal cells and choroid plexus. Nothing has been known about megalin expression in the spinal cord. To study spatio-temporal expression of megalin in the spinal cord, extensive staining of prenatal and postnatal mouse spinal cord was undertaken. Megalin expression was found in the dorsal part of the embryonic spinal cord. Most of these cells also expressed vimentin, suggesting that megalin has a role in the normal development of astrocytes. In the postnatal mouse, megalin seems to be expressed in oligodendrocytes only in the spinal cord white matter, and co-incident with myelination. This suggests that megalin is involved in the formation and maintenance of myelin along long spinal pathways. Megalin staining was clearly seen in the nucleus of these cells, indicating that megalin works in a notch-like signalling pathway.

Uptake of retinol to the retina pigment epithelium (RPE) has long been thought to be a diffusion process. Staining for megalin in RPE revealed strong expression, and uptake experiments with 3H-retinol bound to retinol-binding protein and blocking with the LDL-receptor family specific antagonist receptor-associated protein (RAP) showed that megalin is a receptor for uptake of retinol to the RPE.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2006. 60 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 116
Keyword
Biochemistry, Megalin, LRP-2, Postsynaptic density-95, Retinol-binding protein, Oligodendrocytes, Central nervous system, Biokemi
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:uu:diva-6585 (URN)91-554-6483-1 (ISBN)
Public defence
2006-03-31, B41, BMC, Uppsala, 13:15
Opponent
Supervisors
Available from: 2006-03-10 Created: 2006-03-10 Last updated: 2013-05-23Bibliographically approved

Open Access in DiVA

No full text

Other links

Publisher's full textPubMed

Authority records BETA

Aldskogius, Håkan

Search in DiVA

By author/editor
Larsson, MårtenAldskogius, Håkan
By organisation
Department of NeuroscienceDepartment of Medical Biochemistry and MicrobiologyDevelopmental GeneticsNeuroanatomy
In the same journal
Journal of Neuroscience Research
Medical and Health SciencesNeurosciences

Search outside of DiVA

GoogleGoogle Scholar

doi
pubmed
urn-nbn

Altmetric score

doi
pubmed
urn-nbn
Total: 597 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf