Differential MAP kinases activation during semaphorin3A-induced repulsion or apoptosis of neural progenitor cells $ D. Bagnard, a, * ,1 N. Sainturet, b,1 D. Meyronet, b M. Perraut, a M. Miehe, a G. Roussel, a D. Aunis, a M.F. Belin, b and N. Thomasset b, * a INSERM U575, ‘‘Physiopathologie du Syste `me Nerveux’’, 67084 Strasbourg, France b INSERM U433, ‘‘Neurobiologie Expe ´rimentale et Physiopathologie’’, Faculte ´ de Me ´decine Lae ¨nnec, 69372 Lyon cedex 08, France Received 6 August 2003; revised 2 December 2003; accepted 12 December 2003 Semaphorins are multifunctional factors implicated in various developmental processes. Little is known about the intracellular pathways ensuring appropriate signal transduction that encode the diverse functions observed. In this study, we investigated whether mitogen-activated protein kinases (MAPK), which are key elements of signal transduction in eukaryotic cells, were activated during semaphorin 3A (Sema3A)-induced repulsion or apoptosis of neural progenitor cells. We found that selective recruitment of the ERK1/2 pathway occurred during Sema3A-induced neural progenitor cell repulsion, whereas p38 MAPK activation was necessary for induction of apoptosis. Moreover, we provide evidence for the involvement of vascular endothelial growth factor receptor 1 (VEGFR1) in the activation of ERK1/2. Additional experiments performed with native cerebellar progenitors confirmed such a selective recruitment of MAPK during Sema3A-dependent migration or apoptosis. Altogether, our results suggest a model to explain how a single factor can exert different functions for a given cell type by the selective recruitment of intracellular pathways. D 2004 Elsevier Inc. All rights reserved. Introduction The development of the nervous system requires precise coor- dination of the cellular and molecular events controlling cell fate. Cellular proliferation, migration, and elimination are tightly regu- lated by environmental signals, which show marked changes in spatial and temporal distribution in developing organisms. Among those, a family of secreted and transmembrane molecules called semaphorins have a wide range of functions (Tamagnone and Comoglio, 2000). Semaphorins were first described as guidance signals with both attractive (Bagnard et al., 1998; de Castro et al., 1999; Polleux et al., 2000) and repulsive (Bagnard et al., 1998; Luo et al., 1993; Messersmith et al., 1995; Puschel et al., 1995) properties for axons of several neuronal types during the embry- onic development of the nervous system, but are now known to be involved in cell migration (Bagnard et al., 2001; Eickholt et al., 1999; Soker et al., 1998), induction of apoptosis (Bagnard et al., 2001; Gagliardini and Fankhauser, 1999; Shirvan et al., 1999), nerve regeneration (Pasterkamp et al., 1998), and tumor progres- sion (Christensen et al., 1998; Roche et al., 1996). This functional diversity has been proposed to be related to the formation of receptor complexes ensuring appropriate signal transduction. In- deed, neuropilin-1 (NRP1) (Fujisawa and Kitsukawa, 1998; Kitsu- kawa et al., 1997), an adhesion molecule with a short intracellular domain lacking transduction capacity, is the semaphorin-binding subunit that can associate with different partners, such as plexins, the adhesion molecule L1, or vascular endothelial growth factor receptors (VEGFR) to transduce semaphorin signaling (Bagnard et al., 2001; Castellani et al., 2000; Gluzman-Poltorak et al., 2001; He and Tessier-Lavigne, 1997; Kolodkin et al., 1997; Soker et al., 2002; Takahashi et al., 1999; Whitaker et al., 2001). We previously demonstrated that VEGFR1 is required for Sema3A-triggered neural progenitor cell repulsion (Bagnard et al., 2001). Moreover, VEGFR is involved in the MAPK activation triggered by VEGF (Zachary and Gliki, 2001). Hence, we decided to investigate whether members of the MAPK superfamily were involved in Sema3A signaling for cell migration and apoptosis. In the present study, we show that neural progenitors of the DEV cell line express both ERK1/2 and p38 MAPK and that Sema3A triggers a differential activation of these MAPK. Selec- tive pharmacological inhibition of ERK1/2 during functional assays revealed that ERK1/2 activity, found to be VEGFR1 dependent, is required for Sema3A-induced cell repulsion. In contrast, pharmacological inactivation of p38 MAPK had no effect on Sema3A-induced cell repulsion, but prevented Sema3A-in- duced apoptosis. Taken together, our results demonstrate that activation of ERK1/2 and p38 MAPK by Sema3A provides a way for a same ligand to trigger different effects (repulsion/ apoptosis) in the same cell type. Additional experiments conducted 1044-7431/$ - see front matter D 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.mcn.2003.12.007 $ Supplementary data associated with this article can be found at doi:10.1016/S1044-7431(03)00396-8. * Corresponding authors. D. Bagnard is to be contacted at INSERM U575 Physiopathologie du Syste `me Nerveux, Centre de Neurochimie, 5 rue Blaise Pascal, 67084 Strasbourg, France. Fax: +33-38-8600806. N. Thomasset is to be contacted at INSERM U433 ‘‘Neurobiologie Expe ´rimentale et Physiopathologie’’, Faculte ´ de Me ´decine Lae ¨nnec, Rue Guillaume Paradin, 69372 Lyon cedex 08, France. E-mail addresses: bagnard@neurochem.u-strasbg.fr (D. Bagnard), thomasse@lyon.inserm.fr (N. Thomasset). 1 Both authors contributed equally to this article. Available online on ScienceDirect (www.sciencedirect.com.) www.elsevier.com/locate/ymcne Mol. Cell. Neurosci. 25 (2004) 722 – 731