Neuritogenesis: the prion protein controls β1 integrin signaling activity.
Cytoskeleton modifications are required for neuronal stem cells to acquire neuronal polarization. Little is known, however, about mechanisms that orchestrate cytoskeleton remodeling along neuritogenesis. Here, we show that the silencing of the cellular prion protein (PrP(C)) impairs the initial sprouting of neurites upon induction of differentiation of the 1C11 neuroectodermal cell line, indicating that PrP(C) is necessary to neuritogenesis. Such PrP(C) function relies on its capacity to negatively regulate the clustering, activation, and signaling activity of β1 integrins at the plasma membrane. β1 Integrin aggregation caused by PrP(C) depletion triggers overactivation of the RhoA-Rho kinase-LIMK-cofilin pathway, which, in turn, alters the turnover of focal adhesions, increases the stability of actin microfilaments, and in fine impairs neurite formation. Inhibition of Rho kinases is sufficient to compensate for the lack of PrP(C) and to restore neurite sprouting. We also observe an increased secretion of fibronectin in the surrounding milieu of PrP(C)-depleted 1C11 cells, which likely self-sustains β1 integrin signaling overactivation and contributes to neuritogenesis defect. Our overall data reveal that PrP(C) contributes to the acquisition of neuronal polarization by modulating β1 integrin activity, cell interaction with fibronectin, and cytoskeleton dynamics.
Institut National Santé et de la Recherche Médicale (INSERM), Unité Mixte de Recherche en Santé (UMR-S) 747, Paris, France.
Damien
D
Loubet
Caroline
C
Dakowski
Mathéa
M
Pietri
Elodie
E
Pradines
Sophie
S
Bernard
Jacques
J
Callebert
Hector
H
Ardila-Osorio
Sophie
S
Mouillet-Richard
Jean-Marie
JM
Launay
Odile
O
Kellermann
Benoit
B
Schneider
D051339:Actin Depolymerizing Factors / Q000378:metabolism; D000199:Actins / Q000378:metabolism; D000818:Animals; D001483:Base Sequence; D002454:Cell Differentiation; D002460:Cell Line; D016764:Cell Polarity; D003599:Cytoskeleton / Q000378:metabolism; D005353:Fibronectins / Q000378:metabolism; D019012:Integrin beta1 / Q000378:metabolism*; D054461:Lim Kinases / Q000378:metabolism; D051379:Mice; D058953:Neural Stem Cells / Q000166:cytology / Q000378:metabolism; D016501:Neurites / Q000378:metabolism*; D055495:Neurogenesis / Q000502:physiology*; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D018621:PrPC Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction; D020741:rho GTP-Binding Proteins / Q000378:metabolism; D054460:rho-Associated Kinases / Q000378:metabolism; D020742:rhoA GTP-Binding Protein
D051339:Actin Depolymerizing Factors; D000199:Actins; D005353:Fibronectins; D019012:Integrin beta1; D018621:PrPC Proteins; D034741:RNA, Small Interfering; D054461:Lim Kinases; D054460:rho-Associated Kinases; C526380:RhoA protein, mouse; D020741:rho GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein