ApoER2 and its ligand Reelin participate in neuronal migration during development. Upon receptor binding, Reelin induces the proteolytic processing of ApoER2 as well as the activation of signaling pathway, including small Rho GTPases. Besides its presence in the central nervous system (CNS), Reelin is also secreted by Schwann cells (SCs), the glial cells of the peripheral nervous system (PNS). Reelin deficient mice (reeler) show decreased axonal regeneration in the PNS; however neither the presence of ApoER2 nor the role of the Reelin signaling pathway in the PNS have been evaluated. Interestingly SC migration occurs during PNS development and during injury-induced regeneration and involves activation of small Rho GTPases. Thus, Reelin-ApoER2 might regulate SC migration during axon regeneration in the PNS. Here we demonstrate the presence of ApoER2 in PNS. After sciatic nerve injury Reelin was induced and its receptor ApoER2 was proteolytically processed. In vitro, SCs express both Reelin and ApoER2 and Reelin induces SC migration. To elucidate the molecular mechanism underlying Reelin-dependent SC migration, we examined the involvement of Rac1, a conspicuous small GTPase family member. FRET experiments revealed that Reelin activates Rac1 at the leading edge of SCs. In addition, Tiam1, a major Rac1-specific GEF was required for Reelin-induced SC migration. Moreover, Reelin-induced SC migration was decreased after suppression of the polarity protein PAR3, consistent with its association to Tiam1. Even more interesting, we demonstrated that PAR3 binds preferentially to the full-length cytoplasmic tail of ApoER2 corresponding to the splice-variant containing the exon 19 that encodes a proline-rich insert and that ApoER2 was required for SC migration. Our study reveals a novel function for Reelin/ApoER2 in PNS, inducing cell migration of SCs, a process relevant for PNS development and regeneration.
Bibliographical noteFunding Information:
We thank Dr. Joachim Herz (University of Texas Southwestern, USA) for kindly providing the HEK293 Reelin-producing cells. We also thank Dr. Kazunori Sango (Tokyo Metropolitan Institute of Medical Science, Japan) for providing IFRS1 Schwann cells. Dr. Lissette Leyton (Universidad de Chile, Chile) for giving us the rat specific PAR3 siRNA and Dr. Gregg G. Gundersen (Columbia University, USA) for providing the plasmid for PAK-CRIB fusion protein. This study was supported by the Fondo Nacional de Ciencia y Tecnología, FONDECYT of Chile , through Post-doctoral project 3130373 to CP, FONDECYT project 1150444 to MPM and by Millennium Nucleus in Regenerative Biology (MINREB) RC-120-003 to MPM, FAC and IJ.
© 2015 Elsevier Inc.
- Proteolytic processing
- Rho GTPases
- Schwann cells
- Sciatic nerve