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Megalin deficiency induces critical changes in early glial development in mouse spinal cord
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuroanatomy.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuroanatomy.
2008 (English)In: NeuroReport, ISSN 0959-4965, E-ISSN 1473-558X, Vol. 19, no 5, 559-563 p.Article in journal (Refereed) Published
Abstract [en]

Low density lipoprotein receptor-related protein, megalin, is a multifunctional lipoproptein receptor expressed by absorptive epithelia for endocytosis of numerous ligands. Megalin is widely expressed during embryonic life and is essential for development of the nervous system as evidenced by severe forebrain abnormalities in megalin (-/-). Here, we investigated the influence of megalin deficiency on prenatal spinal cord development in mice. In contrast to wild-type mice, cells expressing Olig2 and NG2, that is, oligodendroglial precursor cells, are absent from embryonic stage E16 in megalin (-/-) mice. At the end of prenatal development, there is a failure in vertebral development, and the number of astrocytes are markedly reduced in megalin (-/-) mice. These findings indicate that megalin is essential in astro-oligodendroglial interactions during development of the spinal cord.

Place, publisher, year, edition, pages
2008. Vol. 19, no 5, 559-563 p.
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-95214DOI: 10.1097/WNR.0b013e3282f94267ISI: 000254372100010PubMedID: 18388738OAI: oai:DiVA.org:uu-95214DiVA: diva2:169342
Available from: 2006-11-27 Created: 2006-11-27 Last updated: 2011-11-17Bibliographically 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.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 208
Neurosciences, nerve degeneration, hypoglossal nerve, chaperone, apolipoprotein, development, transcription factor, astrocyte, glial differentiation, myelin, cell signalling, Neurovetenskap
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
Available from: 2006-11-27 Created: 2006-11-27 Last updated: 2013-05-23Bibliographically approved

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