title: Identification of a lectin causing the degeneration of neuronal processes using engineered embryonic stem cells.
abstract: Unlike the mechanisms involved in the death of neuronal cell bodies, those causing the elimination of processes are not well understood owing to the lack of suitable experimental systems. As the neurotrophin receptor p75(NTR) is known to restrict the growth of neuronal processes, we engineered mouse embryonic stem (ES) cells to express an Ngfr (p75(NTR)) cDNA under the control of the Mapt locus (the gene encoding tau), which begins to be active when ES cell-derived progenitors start elongating processes. This caused a progressive, synchronous degeneration of all processes, and a prospective proteomic analysis showed increased levels of the sugar-binding protein galectin-1 in the p75(NTR)-engineered cells. Function-blocking galectin-1 antibodies prevented the degeneration of processes, and recombinant galectin-1 caused the processes of wild-type neurons to degenerate first, followed by the cell bodies. In vivo, the application of a glutamate receptor agonist, a maneuver known to upregulate p75(NTR), led to an increase in the amount of galectin-1 and to the degeneration of neurons and their processes in a galectin-1-dependent fashion. Section of the sciatic nerve also rapidly upregulated levels of p75(NTR) and galectin-1 in terminal Schwann cells, and the elimination of nerve endings was delayed at the neuromuscular junction of mice lacking Lgals1 (the gene encoding galectin-1). These results indicate that galectin-1 actively participates in the elimination of neuronal processes after lesion, and that engineered ES cells are a useful tool for studying relevant aspects of neuronal degeneration that have been hitherto difficult to analyze.
authors.affiliation: Biozentrum, University of Basel, Klingelbergstrasse 50/70, CH-4056 Basel, Switzerland.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Plachta
authors.forename: Christine
authors.initials: C
authors.lastname: Annaheim
authors.forename: Stephanie
authors.initials: S
authors.lastname: Bissière
authors.forename: Shuo
authors.initials: S
authors.lastname: Lin
authors.forename: Markus
authors.initials: M
authors.lastname: Rüegg
authors.forename: Sjouke
authors.initials: S
authors.lastname: Hoving
authors.forename: Dieter
authors.initials: D
authors.lastname: Müller
authors.forename: Françoise
authors.initials: F
authors.lastname: Poirier
authors.forename: Miriam
authors.initials: M
authors.lastname: Bibel
authors.forename: Yves-Alain
authors.initials: YA
authors.lastname: Barde
mesh_terms: D000818:Animals; D000906:Antibodies / Q000627:therapeutic use; D019771:Axotomy / Q000379:methods; D002227:Carbazoles / Q000494:pharmacology; D016923:Cell Death; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004622:Embryo, Mammalian; D037483:Galectin 1 / Q000276:immunology; D005786:Gene Expression Regulation / Q000502:physiology; D007211:Indoles / Q000494:pharmacology; D007785:Lactose / Q000494:pharmacology; D051379:Mice; D009410:Nerve Degeneration / Q000139:chemically induced* / Q000628:therapy*; D018696:Neuroprotective Agents / Q000494:pharmacology; D015202:Protein Engineering / Q000379:methods*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020800:Receptor, Nerve Growth Factor / Q000096:biosynthesis / Q000627:therapeutic use; D033581:Stem Cell Transplantation / Q000379:methods; D013234:Stem Cells / Q000502:physiology*; D016875:tau Proteins / Q000096:biosynthesis
chemical_list: D000906:Antibodies; D002227:Carbazoles; D037483:Galectin 1; D007211:Indoles; C489131:Mapt protein, rat; D018696:Neuroprotective Agents; D020800:Receptor, Nerve Growth Factor; D016875:tau Proteins; C106592:3,9-bis((ethylthio)methyl)-K-252a; D007785:Lactose