title: Megalin mediates the influence of sonic hedgehog on oligodendrocyte precursor cell migration and proliferation during development.
abstract: Oligodendrocyte precursor cells (OPCs) of the optic nerve are generated in the preoptic area, from where they migrate to colonize it entirely. Sonic hedgehog (Shh) induces the proliferation of these cells as well as influencing their migration, acting through its canonical receptor (Ptc-1). However, the multiligand receptor megalin (or LRP-2) is also involved in Shh-induced OPC proliferation and migration, and thus, we have evaluated the relevance of this interaction. During the stages at which Shh influences OPC development, we found megalin to be selectively expressed by optic nerve astrocytes, whereas Ptc-1 and Gli1 were found in OPCs. Indeed, this pattern of expression paralleled the rostral-caudal expression of the three Shh-related molecules during the time course of plp-dm20(+) -OPC colonization. The blockage of megalin partially abolished OPC chemoattraction and fully impaired Shh-induced proliferation. Using in vitro co-cultures of dissociated optic nerve cells, we demonstrated that Shh was internalized by astrocytes via megalin, and sufficient Shh was subsequently released to produce the biological effects on OPCs observed in the nerve. Together, these data indicate that at least part of the influence of Shh on OPCs is mediated by megalin during optic nerve development, and that astrocytes expressing megalin transiently capture Shh to present it to OPCs and/or to control the gradient of this molecule during development.
authors.affiliation: Grupo de Neurobiología del Desarrollo-GNDe, Unidad de Neurología Experimental, Hospital Nacional de Parapléjicos, Finca La Peraleda s/n, Toledo, Spain.
authors.forename: María Cristina
authors.initials: MC
authors.lastname: Ortega
authors.forename: Olivier
authors.initials: O
authors.lastname: Cases
authors.forename: Paloma
authors.initials: P
authors.lastname: Merchán
authors.forename: Renata
authors.initials: R
authors.lastname: Kozyraki
authors.forename: Diego
authors.initials: D
authors.lastname: Clemente
authors.forename: Fernando
authors.initials: F
authors.lastname: de Castro
mesh_terms: D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D001253:Astrocytes / Q000502:physiology; D001973:Bromodeoxyuridine / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002633:Chemotaxis / Q000502:physiology; D018920:Coculture Techniques / Q000379:methods; D006224:Cricetinae; D003412:Cricetulus; D003561:Cytarabine / Q000494:pharmacology; D004622:Embryo, Mammalian; D053595:Embryonic Stem Cells / Q000187:drug effects / Q000502:physiology; D005089:Exocytosis / Q000502:physiology; D005123:Eye / Q000196:embryology / Q000378:metabolism; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D005732:Gangliosides / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism*; D007166:Immunosuppressive Agents / Q000494:pharmacology; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism; D026561:Low Density Lipoprotein Receptor-Related Protein-2 / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D018991:Myelin Proteolipid Protein / Q000378:metabolism; D009836:Oligodendroglia / Q000187:drug effects / Q000502:physiology*; D009900:Optic Nerve / Q000166:cytology / Q000196:embryology; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D011956:Receptors, Cell Surface / Q000378:metabolism; D014162:Transfection; D014746:Vimentin / Q000378:metabolism; D000071676:Zinc Finger Protein GLI1
chemical_list: D000906:Antibodies; D005732:Gangliosides; C498520:Gli1 protein, mouse; D005904:Glial Fibrillary Acidic Protein; D053823:Hedgehog Proteins; D007166:Immunosuppressive Agents; D051741:Kruppel-Like Transcription Factors; D026561:Low Density Lipoprotein Receptor-Related Protein-2; D018991:Myelin Proteolipid Protein; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; C047516:Plp1 protein, mouse; C000606240:Ptch1 protein, mouse; D011956:Receptors, Cell Surface; C465570:Shh protein, mouse; D014746:Vimentin; D000071676:Zinc Finger Protein GLI1; C062875:ganglioside A2B5; D003561:Cytarabine; D016222:Fibroblast Growth Factor 2; D049452:Green Fluorescent Proteins; D001973:Bromodeoxyuridine