Loss of glial fibrillary acidic protein (GFAP) impairs Schwann cell proliferation and delays nerve regeneration after damage.
Axonal loss causes disabling and permanent deficits in many peripheral neuropathies, and may result from inefficient nerve regeneration due to a defective relationship between Schwann cells, axons and the extracellular matrix. These interactions are mediated by surface receptors and transduced by cytoskeletal molecules. We investigated whether peripheral nerve regeneration is perturbed in mice that lack glial fibrillary acidic protein (GFAP), a Schwann-cell-specific cytoskeleton constituent upregulated after damage. Peripheral nerves develop and function normally in GFAP-null mice. However, axonal regeneration after damage was delayed. Mutant Schwann cells maintained the ability to dedifferentiate but showed defective proliferation, a key event for successful nerve regeneration. We also showed that GFAP and the other Schwann-cell-intermediate filament vimentin physically interact in two distinct signaling pathways involved in proliferation and nerve regeneration. GFAP binds integrin alphavbeta8, which initiates mitotic signals soon after damage by interacting with fibrin. Consistently, ERK phosphorylation was reduced in crushed GFAP-null nerves. Vimentin instead binds integrin alpha5beta1, which regulates proliferation and differentiation later in regeneration, and may compensate for the absence of GFAP in mutant mice. GFAP might contribute to form macro-complexes to initiate mitogenic and differentiating signaling for efficient nerve regeneration.
Triolo
Daniela
D
Neuropathology Unit, San Raffaele Scientific Institute, Via Olgettina 60, 20132 Milan, Italy.
Dina
Giorgia
G
Lorenzetti
Isabella
I
Malaguti
Mariachiara
M
Morana
Paolo
P
Del Carro
Ubaldo
U
Comi
Giancarlo
G
Messing
Albee
A
Quattrini
Angelo
A
Previtali
Stefano C
SC
D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D049109:Cell Proliferation; D003599:Cytoskeleton / Q000378:metabolism; D005109:Extracellular Matrix / Q000737:chemistry; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics* / Q000502:physiology*; D016023:Integrins / Q000378:metabolism; D007382:Intermediate Filaments / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009409:Nerve Crush / Q000534:rehabilitation; D009416:Nerve Regeneration / Q000235:genetics*; D009474:Neurons / Q000166:cytology / Q000502:physiology; D017933:Peripheral Nervous System / Q000254:growth & development; D012583:Schwann Cells / Q000502:physiology*; D012584:Sciatic Nerve / Q000293:injuries; D014746:Vimentin / Q000378:metabolism
D005904:Glial Fibrillary Acidic Protein; D016023:Integrins; D014746:Vimentin