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Low density lipoprotein-related protein-2/megalin is expressed in oligodendrocytes in the mouse spinal cord white matter
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Genetisk utvecklingsbiologi.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap.
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2006 (Engelska)Ingår i: Journal of Neuroscience Research, ISSN 0360-4012, E-ISSN 1097-4547, Vol. 83, nr 5, s. 864-873Artikel i tidskrift (Refereegranskat) Published
Fritextbeskrivning
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.

Ort, förlag, år, upplaga, sidor
2006. Vol. 83, nr 5, s. 864-873
Nationell ämneskategori
Medicin och hälsovetenskap Neurovetenskaper
Forskningsämne
Neurovetenskap; Neurovetenskap
Identifikatorer
URN: urn:nbn:se:uu:diva-80225DOI: 10.1002/jnr.20774PubMedID: 16463279OAI: oai:DiVA.org:uu-80225DiVA, id: diva2:108139
Tillgänglig från: 2006-05-03 Skapad: 2006-05-03 Senast uppdaterad: 2018-01-13Bibliografiskt granskad
Ingår i avhandling
1. Clusterin and Megalin in The Spinal Cord
Öppna denna publikation i ny flik eller fönster >>Clusterin and Megalin in The Spinal Cord
2006 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
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.

Ort, förlag, år, upplaga, sidor
Uppsala: Acta Universitatis Upsaliensis, 2006. s. 58
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 208
Nyckelord
Neurosciences, nerve degeneration, hypoglossal nerve, chaperone, apolipoprotein, development, transcription factor, astrocyte, glial differentiation, myelin, cell signalling, Neurovetenskap
Identifikatorer
urn:nbn:se:uu:diva-7365 (URN)91-554-6739-3 (ISBN)
Disputation
2006-12-19, B22, Biomedical Centre (BMC), Husargatan 3, Uppsala, 13:15
Opponent
Handledare
Tillgänglig från: 2006-11-27 Skapad: 2006-11-27 Senast uppdaterad: 2013-05-23Bibliografiskt granskad
2. Megalin, an Endocytotic Receptor with Signalling Potential
Öppna denna publikation i ny flik eller fönster >>Megalin, an Endocytotic Receptor with Signalling Potential
2006 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
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.

Ort, förlag, år, upplaga, sidor
Uppsala: Acta Universitatis Upsaliensis, 2006. s. 60
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 116
Nyckelord
Biochemistry, Megalin, LRP-2, Postsynaptic density-95, Retinol-binding protein, Oligodendrocytes, Central nervous system, Biokemi
Nationell ämneskategori
Medicinsk bioteknologi (med inriktning mot cellbiologi (inklusive stamcellsbiologi), molekylärbiologi, mikrobiologi, biokemi eller biofarmaci)
Identifikatorer
urn:nbn:se:uu:diva-6585 (URN)91-554-6483-1 (ISBN)
Disputation
2006-03-31, B41, BMC, Uppsala, 13:15
Opponent
Handledare
Tillgänglig från: 2006-03-10 Skapad: 2006-03-10 Senast uppdaterad: 2013-05-23Bibliografiskt granskad

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