title: LRP2 Acts as SHH Clearance Receptor to Protect the Retinal Margin from Mitogenic Stimuli.
abstract: During forebrain development, LRP2 promotes morphogen signaling as an auxiliary SHH receptor. However, in the developing retina, LRP2 assumes the opposing function, mediating endocytic clearance of SHH and antagonizing morphogen action. LRP2-mediated clearance prevents spread of SHH activity from the central retina into the retinal margin to protect quiescent progenitor cells in this niche from mitogenic stimuli. Loss of LRP2 in mice increases the sensitivity of the retinal margin for SHH, causing expansion of the retinal progenitor cell pool and hyperproliferation of this tissue. Our findings document the ability of LRP2 to act, in a context-dependent manner, as activator or inhibitor of the SHH pathway. Our current findings uncovered LRP2 activity as the molecular mechanism imposing quiescence of the retinal margin in the mammalian eye and suggest SHH-induced proliferation of the retinal margin as cause of the large eye phenotype observed in mouse models and patients with LRP2 defects.
authors.affiliation: Max-Delbrueck-Center for Molecular Medicine, 13125 Berlin, Germany. Electronic address: annabel.christ@mdc-berlin.de.
authors.forename: Annabel
authors.initials: A
authors.lastname: Christ
authors.affiliation: Max-Delbrueck-Center for Molecular Medicine, 13125 Berlin, Germany.
authors.forename: Anna
authors.initials: A
authors.lastname: Christa
authors.affiliation: Max-Delbrueck-Center for Molecular Medicine, 13125 Berlin, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Klippert
authors.affiliation: Small Animal Clinic, Free University Berlin, 14163 Berlin, Germany.
authors.forename: J Corinna
authors.initials: JC
authors.lastname: Eule
authors.affiliation: Institute for Vegetative Anatomy, Charité University Medicine Berlin, 10117 Berlin, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Bachmann
authors.affiliation: Toronto Western Research Institute, University Health Network, Toronto, ON M5T 2S8, Canada.
authors.forename: Valerie A
authors.initials: VA
authors.lastname: Wallace
authors.affiliation: Max-Delbrueck-Center for Molecular Medicine, 13125 Berlin, Germany.
authors.forename: Annette
authors.initials: A
authors.lastname: Hammes
authors.affiliation: Max-Delbrueck-Center for Molecular Medicine, 13125 Berlin, Germany. Electronic address: willnow@mdc-berlin.de.
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Willnow
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D004622:Embryo, Mammalian / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005260:Female; D018507:Gene Expression Regulation, Developmental; D053823:Hedgehog Proteins / Q000378:metabolism*; D006801:Humans; D006871:Hydrophthalmos / Q000378:metabolism / Q000473:pathology*; D007124:Immunoenzyme Techniques; D017403:In Situ Hybridization; D026561:Low Density Lipoprotein Receptor-Related Protein-2 / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008934:Mitogens / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D012160:Retina / Q000187:drug effects / Q000196:embryology / Q000378:metabolism / Q000473:pathology*; D015398:Signal Transduction / Q000187:drug effects; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism
chemical_list: D053823:Hedgehog Proteins; D026561:Low Density Lipoprotein Receptor-Related Protein-2; C055127:Lrp2 protein, mouse; D008934:Mitogens; C465570:Shh protein, mouse