Lack of collagen XV impairs peripheral nerve maturation and, when combined with laminin-411 deficiency, leads to basement membrane abnormalities and sensorimotor dysfunction.
Although the Schwann cell basement membrane (BM) is required for normal Schwann cell terminal differentiation, the role of BM-associated collagens in peripheral nerve maturation is poorly understood. Collagen XV is a BM zone component strongly expressed in peripheral nerves, and we show that its absence in mice leads to loosely packed axons in C-fibers and polyaxonal myelination. The simultaneous lack of collagen XV and another peripheral nerve component affecting myelination, laminin α4, leads to severely impaired radial sorting and myelination, and the maturation of the nerve is permanently compromised, contrasting with the slow repair observed in Lama4-/- single knock-out mice. Moreover, the Col15a1-/-;Lama4-/- double knock-out (DKO) mice initially lack C-fibers and, even over 1 year of age have only a few, abnormal C-fibers. The Lama4-/- knock-out results in motor and tactile sensory impairment, which is exacerbated by a simultaneous Col15a1-/- knock-out, whereas sensitivity to heat-induced pain is increased in the DKO mice. Lack of collagen XV results in slower sensory nerve conduction, whereas the Lama4-/- and DKO mice exhibit increased sensory nerve action potentials and decreased compound muscle action potentials; x-ray diffraction revealed less mature myelin in the sciatic nerves of the latter than in controls. Ultrastructural analyses revealed changes in the Schwann cell BM in all three mutants, ranging from severe (DKO) to nearly normal (Col15a1-/-). Collagen XV thus contributes to peripheral nerve maturation and C-fiber formation, and its simultaneous deletion from neural BM zones with laminin α4 leads to a DKO phenotype distinct from those of both single knock-outs.
Rasi
Karolina
K
Oulu Center for Cell-Matrix Research, Biocenter Oulu, Department of Medical Biochemistry and Molecular Biology, University of Oulu, and Department of Clinical Neurophysiology, Oulu University Hospital, FIN-90221 Oulu, Finland.
Hurskainen
Merja
M
Kallio
Mika
M
Stavén
Saara
S
Sormunen
Raija
R
Heape
Anthony M
AM
Avila
Robin L
RL
Kirschner
Daniel
D
Muona
Anu
A
Tolonen
Uolevi
U
Tanila
Heikki
H
Huhtala
Pirkko
P
Soininen
Raija
R
Pihlajaniemi
Taina
T
D000200:Action Potentials / Q000502:physiology; D000818:Animals; D001369:Axons / Q000502:physiology / Q000648:ultrastructure; D001485:Basement Membrane / Q000502:physiology* / Q000648:ultrastructure; D001522:Behavior, Animal / Q000502:physiology; D003094:Collagen / Q000235:genetics* / Q000502:physiology*; D004594:Electrophysiology; D004797:Enzyme-Linked Immunosorbent Assay; D007797:Laminin / Q000235:genetics* / Q000502:physiology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D016253:Microscopy, Immunoelectron; D009046:Motor Neurons / Q000502:physiology; D009186:Myelin Sheath / Q000502:physiology; D036421:Nerve Fibers, Unmyelinated / Q000502:physiology; D009431:Neural Conduction / Q000502:physiology; D010525:Peripheral Nerves / Q000502:physiology* / Q000648:ultrastructure; D010812:Physical Stimulation; D012018:Reflex / Q000502:physiology; D011984:Sensory Receptor Cells / Q000502:physiology; D012684:Sensory Thresholds / Q000502:physiology; D020886:Somatosensory Disorders / Q000235:genetics* / Q000503:physiopathology; D014961:X-Ray Diffraction
C501370:Lama4 protein, mouse; D007797:Laminin; C553732:collagen XV, mouse; D003094:Collagen