title: Lgr5 Marks Post-Mitotic, Lineage Restricted Cerebellar Granule Neurons during Postnatal Development.
abstract: Wnt signaling regulates self-renewal and fate commitment of stem and progenitor cells in development and homeostasis. Leucine-rich repeat-containing G-protein coupled receptor 5 (Lgr5) is a co-receptor for Wnt signaling that marks highly proliferative stem and progenitor cells in many epithelial tissue types. Wnt signaling instructs neural developmental and homeostatic processes; however, Lgr5 expression in the developing and adult brain has not been characterized. Here we report that Lgr5 is expressed in the postnatal cerebellum during the maturation and synaptogenesis of cerebellar granule neurons (CGNs), processes controlled by Wnt signaling. Using a transgenic reporter mouse for in vivo Lgr5 expression analysis and lineage tracing, we reveal that Lgr5 specifically identified CGNs and was restricted temporally to the CGN maturation phase within the internal granule layer, but absent in the adult brain. Cells marked by Lgr5 were lineage restricted, post-mitotic and long-lived. The ligand for Lgr5, R-spondin, was secreted in a paracrine fashion that evolved during the maturation of CGNs, which coincided with the Lgr5 expression pattern. Our findings provide potential new insight into the critical regulation of Wnt signaling in the developing cerebellum and support a novel role for Lgr5 in the regulation of post-mitotic cells.
authors.affiliation: Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, United States of America; Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio, United States of America.
authors.forename: Tyler E
authors.initials: TE
authors.lastname: Miller
authors.affiliation: Sanford-Burnham Medical Research Institute, La Jolla, California, United States of America.
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, United States of America; Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio, United States of America.
authors.forename: Kumar
authors.initials: K
authors.lastname: Sukhdeo
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Kentucky, Lexington, Kentucky, United States of America.
authors.forename: Craig
authors.initials: C
authors.lastname: Horbinski
authors.affiliation: Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Cleveland, Ohio, United States of America.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Tesar
authors.affiliation: Sanford-Burnham Medical Research Institute, La Jolla, California, United States of America.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Wechsler-Reya
authors.affiliation: Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, United States of America; Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio, United States of America.
authors.forename: Jeremy N
authors.initials: JN
authors.lastname: Rich
mesh_terms: D000818:Animals; D019070:Cell Lineage; D049109:Cell Proliferation; D002531:Cerebellum / Q000166:cytology / Q000254:growth & development*; D004848:Epithelium / Q000254:growth & development; D051379:Mice; D008822:Mice, Transgenic; D008938:Mitosis; D058953:Neural Stem Cells / Q000378:metabolism*; D009474:Neurons / Q000166:cytology* / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D019699:Thrombospondins / Q000096:biosynthesis; D060449:Wnt Signaling Pathway / Q000502:physiology*
chemical_list: C493597:Lgr5 protein, mouse; C518903:RSPO1 protein, mouse; D043562:Receptors, G-Protein-Coupled; D019699:Thrombospondins