title: Collagen XIII secures pre- and postsynaptic integrity of the neuromuscular synapse.
abstract: Both transmembrane and extracellular cues, one of which is collagen XIII, regulate the formation and function of the neuromuscular synapse, and their absence results in myasthenia. We show that the phenotypical changes in collagen XIII knock-out mice are milder than symptoms in human patients, but the Col13a1-/- mice recapitulate major muscle findings of congenital myasthenic syndrome type 19 and serve as a disease model. In the lack of collagen XIII neuromuscular synapses do not reach full size, alignment, complexity and function resulting in reduced muscle strength. Collagen XIII is particularly important for the preterminal integrity, and when absent, destabilization of the motor nerves results in muscle regeneration and in atrophy especially in the case of slow muscle fibers. Collagen XIII was found to affect synaptic integrity through binding the ColQ tail of acetylcholine esterase. Although collagen XIII is a muscle-bound transmembrane molecule, it also undergoes ectodomain shedding to become a synaptic basal lamina component. We investigated the two forms' roles by novel Col13a1tm/tm mice in which ectodomain shedding is impaired. While postsynaptic maturation, terminal branching and neurotransmission was exaggerated in the Col13a1tm/tm mice, the transmembrane form's presence sufficed to prevent defects in transsynaptic adhesion, Schwann cell invagination/retraction, vesicle accumulation and acetylcholine receptor clustering and acetylcholinesterase dispersion seen in the Col13a1-/- mice, pointing to the transmembrane form as the major conductor of collagen XIII effects. Altogether, collagen XIII secures postsynaptic, synaptic and presynaptic integrity, and it is required for gaining and maintaining normal size, complexity and functional capacity of the neuromuscular synapse.
authors.affiliation: Center for Cell-Matrix Research, Biocenter Oulu, Faculty of Biochemistry and Molecular Medicine, University of Oulu, PO Box 5400, 90014 University of Oulu, Oulu, Finland.
authors.forename: Heli
authors.initials: H
authors.lastname: Härönen
authors.affiliation: Center for Cell-Matrix Research, Biocenter Oulu, Faculty of Biochemistry and Molecular Medicine, University of Oulu, PO Box 5400, 90014 University of Oulu, Oulu, Finland.
authors.forename: Zarin
authors.initials: Z
authors.lastname: Zainul
authors.affiliation: Center for Cell-Matrix Research, Biocenter Oulu, Faculty of Biochemistry and Molecular Medicine, University of Oulu, PO Box 5400, 90014 University of Oulu, Oulu, Finland.
authors.forename: Hongmin
authors.initials: H
authors.lastname: Tu
authors.affiliation: Department of Biotechnology and Molecular Medicine, A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, PO Box 1627, 70211 Kuopio, Finland.
authors.forename: Nikolay
authors.initials: N
authors.lastname: Naumenko
authors.affiliation: Biocenter Oulu Electron Microscopy Core Facility, University of Oulu, PO Box 5000, 90014 University of Oulu, Oulu, Finland.
authors.forename: Raija
authors.initials: R
authors.lastname: Sormunen
authors.affiliation: Biocenter Oulu Electron Microscopy Core Facility, University of Oulu, PO Box 5000, 90014 University of Oulu, Oulu, Finland.
authors.forename: Ilkka
authors.initials: I
authors.lastname: Miinalainen
authors.affiliation: Department of Neurobiology, A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, PO Box 1627, 70211 Kuopio, Finland.|Laboratory of Neurobiology, Department of Physiology, Kazan Federal University, 420008 Kazan, Russia.
authors.forename: Anastasia
authors.initials: A
authors.lastname: Shakirzyanova
authors.affiliation: Center for Cell-Matrix Research, Biocenter Oulu, Faculty of Biochemistry and Molecular Medicine, University of Oulu, PO Box 5400, 90014 University of Oulu, Oulu, Finland.
authors.forename: Tuomo
authors.initials: T
authors.lastname: Oikarainen
authors.affiliation: Department of Neurobiology, A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, PO Box 1627, 70211 Kuopio, Finland.
authors.forename: Azat
authors.initials: A
authors.lastname: Abdullin
authors.affiliation: Center for Cell-Matrix Research, Biocenter Oulu, Faculty of Biochemistry and Molecular Medicine, University of Oulu, PO Box 5400, 90014 University of Oulu, Oulu, Finland.
authors.forename: Paula
authors.initials: P
authors.lastname: Martin
authors.affiliation: Center for Cell-Matrix Research, Biocenter Oulu, Faculty of Biochemistry and Molecular Medicine, University of Oulu, PO Box 5400, 90014 University of Oulu, Oulu, Finland.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Santoleri
authors.affiliation: Department of Neurobiology, A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, PO Box 1627, 70211 Kuopio, Finland.
authors.forename: Jari
authors.initials: J
authors.lastname: Koistinaho
authors.affiliation: Department of Neurobiology, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Israel
authors.initials: I
authors.lastname: Silman
authors.affiliation: Department of Neurobiology, A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, PO Box 1627, 70211 Kuopio, Finland.|Laboratory of Neurobiology, Department of Physiology, Kazan Federal University, 420008 Kazan, Russia.
authors.forename: Rashid
authors.initials: R
authors.lastname: Giniatullin
authors.affiliation: Virginia Tech Carilion Research Institute, Roanoke, VA 24016, USA.|Department of Biological Sciences, Virginia Tech, Blacksburg, VA 24061, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Fox
authors.affiliation: Center for Cell-Matrix Research, Biocenter Oulu, Faculty of Biochemistry and Molecular Medicine, University of Oulu, PO Box 5400, 90014 University of Oulu, Oulu, Finland.
authors.forename: Anne
authors.initials: A
authors.lastname: Heikkinen
authors.affiliation: Center for Cell-Matrix Research, Biocenter Oulu, Faculty of Biochemistry and Molecular Medicine, University of Oulu, PO Box 5400, 90014 University of Oulu, Oulu, Finland.
authors.forename: Taina
authors.initials: T
authors.lastname: Pihlajaniemi
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism; D000818:Animals; D001485:Basement Membrane / Q000378:metabolism; D002448:Cell Adhesion / Q000502:physiology; D003094:Collagen / Q000378:metabolism; D024181:Collagen Type XIII / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009124:Muscle Proteins / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism; D009469:Neuromuscular Junction / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D011950:Receptors, Cholinergic / Q000378:metabolism; D013569:Synapses / Q000378:metabolism*; D009435:Synaptic Transmission
chemical_list: D024181:Collagen Type XIII; D009124:Muscle Proteins; D011950:Receptors, Cholinergic; D003094:Collagen; D020794:Receptor Protein-Tyrosine Kinases; D000110:Acetylcholinesterase