Muscle-derived collagen XIII regulates maturation of the skeletal neuromuscular junction.
Formation, maturation, stabilization, and functional efficacy of the neuromuscular junction (NMJ) are orchestrated by transsynaptic and autocrine signals embedded within the synaptic cleft. Here, we demonstrate that collagen XIII, a nonfibrillar transmembrane collagen, is another such signal. We show that collagen XIII is expressed by muscle and its ectodomain can be proteolytically shed into the extracellular matrix. The collagen XIII protein was found present in the postsynaptic membrane and synaptic basement membrane. To identify a role for collagen XIII at the NMJ, mice were generated lacking this collagen. Morphological and ultrastructural analysis of the NMJ revealed incomplete adhesion of presynaptic and postsynaptic specializations in collagen XIII-deficient mice of both genders. Strikingly, Schwann cells erroneously enwrapped nerve terminals and invaginated into the synaptic cleft, resulting in a decreased contact surface for neurotransmission. Consistent with morphological findings, electrophysiological studies indicated both postsynaptic and presynaptic defects in Col13a1(-/-) mice, such as decreased amplitude of postsynaptic potentials, diminished probabilities of spontaneous release and reduced readily releasable neurotransmitter pool. To identify the role of collagen XIII at the NMJ, shed ectodomain of collagen XIII was applied to cultured myotubes, and it was found to advance acetylcholine receptor (AChR) cluster maturation. Together with the delay in AChR cluster development observed in collagen XIII-deficient mutants in vivo, these results suggest that collagen XIII plays an autocrine role in postsynaptic maturation of the NMJ. Altogether, the results presented here reveal that collagen XIII is a novel muscle-derived cue necessary for the maturation and function of the vertebrate NMJ.
Latvanlehto
Anne
A
Oulu Center for Cell-Matrix Research, and Department of Medical Biochemistry and Molecular Biology, 90014 University of Oulu, Finland.
Fox
Michael A
MA
Sormunen
Raija
R
Tu
Hongmin
H
Oikarainen
Tuomo
T
Koski
Anu
A
Naumenko
Nikolay
N
Shakirzyanova
Anastasia
A
Kallio
Mika
M
Ilves
Mika
M
Giniatullin
Rashid
R
Sanes
Joshua R
JR
Pihlajaniemi
Taina
T
D000818:Animals; D019898:Autocrine Communication / Q000235:genetics / Q000502:physiology; D002460:Cell Line; D002478:Cells, Cultured; D024181:Collagen Type XIII / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000235:genetics / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008818:Mice, Neurologic Mutants; D018482:Muscle, Skeletal / Q000254:growth & development* / Q000294:innervation* / Q000502:physiology; D009469:Neuromuscular Junction / Q000235:genetics / Q000254:growth & development* / Q000378:metabolism; D013570:Synaptic Membranes / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D009435:Synaptic Transmission / Q000235:genetics / Q000502:physiology
D024181:Collagen Type XIII