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First published online September 20, 2006
doi: 10.1242/10.1242/jcs.03168

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Loss of glial fibrillary acidic protein (GFAP) impairs Schwann cell proliferation and delays nerve regeneration after damage

¹ Neuropathology Unit, San Raffaele Scientific Institute, Via Olgettina 60, 20132 Milan, Italy
² Department of Neurology and INSPE, San Raffaele Scientific Institute, Via Olgettina 60, 20132 Milan, Italy
³ Neurophysiology Unit, San Raffaele Scientific Institute, Via Olgettina 60, 20132 Milan, Italy
⁴ Università Vita-Salute San Raffaele, 20132 Milan, Italy
⁵ Waisman Center and Department of Comparative Biosciences, University of Wisconsin-Madison, Madison, WI 53706, USA

^* Author for correspondence (e-mail: previtali.stefano{at}hsr.it)

Accepted 14 July 2006

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 vß8, 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 5ß1, 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.

Key words: Cytoskeleton, Transgenic mice, Extracellular matrix, Nerve regeneration, Adhesion

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