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The Chemokine CX3CL1 Reduces Migration and Increases Adhesion of Neurons with Mechanisms Dependent on the ₁ Integrin Subunit¹

Clotilde Lauro^2,*, Myriam Catalano^2,*,, Flavia Trettel^*,, Fabrizio Mainiero, Maria Teresa Ciotti^¶, Fabrizio Eusebi^*,, and Cristina Limatola^3,*,,

^* Istituto Pasteur-Fondazione Cenci Bolognetti and Dipartimento di Fisiologia Umana e Farmacologia, Centro di Eccellenza, Università La Sapienza, Rome, Italy; Neuromed, Pozzilli, Italy; Istituto di Medicina e Scienza dello Sport, Comitato Olimpico Nazionale Italiano, Rome, Italy; Dipartimento di Medicina Sperimentale e Patologia, Università La Sapienza, Rome, Italy; and ^¶ Istituto di Neurobiologia, Consiglio Nazionale delle Ricerche, Rome, Italy

Fractalkine/CX3CL1 and its specific receptor CX3CR1 are constitutively expressed in several regions of the CNS and are reported to mediate neuron-microglial interaction, synaptic transmission, and neuronal protection from toxic insults. CX3CL1 is released both by neuronal and astrocytic cells, whereas CX3CR1 is mainly expressed by microglial cells and neurons. Microglial cells efficiently migrate in response to CX3CL1, whereas no evidence is reported to date on CX3CL1-induced neuronal migration. For this reason, we have investigated in vitro the effects of CX3CL1 on basal migration of neurons and of the microglial and astrocytic populations, all these cells being obtained from the hippocampus and the cerebellum of newborn rats. We report that CX3CL1 stimulates microglial cell migration but efficiently reduces basal neuronal movement, regardless of the brain source. The effect of CX3CL1 is pertussis toxin (PTX) sensitive and PI3K dependent on hippocampal neurons, while it is PTX sensitive, PI3K dependent, and ERK dependent on cerebellar granules. Interestingly, CX3CL1 also increases neuron adhesion to the extracellular matrix component laminin, with mechanisms dependent on PTX-sensitive G proteins, and on the ERK and PI3K pathways. Both the reduction of migration and the increase of neuron adhesion require the activation of the ₁ and ₆ integrin subunits with the exception of cerebellar neuron migration, which is only dependent on the ₁ subunit. More importantly, in neurons, CX3CL1/CXCL12 cotreatment abolished the effect mediated by a single chemokine on chemotaxis and adhesion. In conclusion, our findings indicate that CX3CL1 reduces neuronal migration by increasing cell adhesion through integrin-dependent mechanisms in hippocampal and cerebellar neurons.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by grants from the Ministero dell’Università e della Ricerca (to F.E. and C.Li.).

² C.La. and M.C. contributed equally.

³ Address correspondence and reprint requests to Dr. Cristina Limatola, Dipartimento di Fisiologia Umana e Farmacologia, Università La Sapienza, I-00185 Rome, Italy. E-mail address: cristina.limatola{at}uniroma1.it

⁴ Abbreviations used in this paper: PTX, pertussis toxin; CGN, cerebellar granule neuron.

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