Semaphorin 3A–Vascular Endothelial Growth Factor-165 Balance Mediates Migration and Apoptosis of Neural Progenitor Cells by the Recruitment of Shared Receptor

Abstract

The dynamic and coordinated interaction between cells and their microenvironment controls cell migration, proliferation, and apoptosis, mediated by different cell surface molecules. We have studied the response of a neuroectodermal progenitor cell line, Dev, to a guidance molecule, semaphorin 3A (Sema3A), described previously as a repellent-collapsing signal for axons, and we have shown that Sema3A acts as a repellent guidance cue for migrating progenitor cells and, on prolonged application, induces apoptosis. Both repulsion and induction of cell death are mediated by neuropilin-1, the ligand-binding component of the Sema3A receptor. The vascular endothelial growth factor, VEGF165, antagonizes Sema3A-induced apoptosis and promotes cell survival, migration, and proliferation. Surprisingly, repulsion by Sema3A also depends on expression of VEGFR1, a VEGF165 receptor, expressed in Dev cells. Moreover, we found that these repulsive effects of Sema3A require tyrosine kinase activity, which can be attributed to VEGFR1. These results indicate that the balance between guidance molecules and angiogenic factors can modulate the migration, apoptosis (or survival), and proliferation of neural progenitor cells through shared receptors.

Cranial expression of class 3 secreted semaphorins and their neuropilin receptors

“…This effect is apparently not mediated by Sema3A (Ohta et al, 1999;Shepherd et al, 1996); therefore, it would be interesting to see whether Sema3D can repel RGCs. In addition to chemorepulsion, Sema3A has been shown to promote apoptosis, including that of RGCs (Bagnard et al, 2001;Shirvan et al, 2002). This is an important process in the developing lens (Jean et al, 1998) to which Sema3A may, …”

“…Between them, they regulate the formation of neuronal networks in many regions of the CNS, including the hippocampus, cerebral cortex, and olfactory system (Chedotal et al, 1998;Polleux et al, 1998;Schwarting et al, 2000;Pozas et al, 2001;Cloutier et al, 2002;Walz et al, 2002;Taniguchi et al, 2003). In addition to directing growth cone movements, they regulate the migration of cells, including neural crest and neuronal progenitor cells (Song et al, 1998;Eickholt et al, 1999;Bagnard et al, 2001;Kawasaki et al, 2002) and, thus, may play a role in shaping anatomic structures. Recent studies have demonstrated that Semas may also act as chemoattractants (Bagnard et al, 1998;de Castro et al, 1999;Polleux et al, 2000).…”

Pulmonary Epithelial Neuropilin-1 Deletion Enhances Development of Cigarette Smoke–induced Emphysema

“…Nrp1 may modulate the balance between VEGF and Sema3 signaling to alter cell proliferation and death in nonepithelial cell types (17,26). Both Nrp1 ligands, VEGF, and Sema3A, have independently been shown to contribute to alveolar septation (24,(27)(28)(29)(30) and vascular patterning (23,27,31), and human (32,33), animal (34)(35)(36)(37), and in vitro (38) studies support a possible role for VEGF in protection from acute lung injury and preservation of alveolar cell survival (39).…”

“…In the nervous system, Nrp1 mediates semaphorin-induced axonal growth cone collapse (7,11) and is required for semaphorinmediated neuronal (16) and neural progenitor cell apoptosis (17). In endothelium, Nrp1 enhances VEGF-mediated phosphorylation and signaling via VEGFR2 (18)(19)(20) and enhances VEGF-induced endothelial permeability (18), chemotaxis (18,19), proliferation, and cell survival (19).…”

Des signaux mortels qui contrôlent la taille du cerveau

“…Ainsi, il est tentant de spéculer que des changements évolutifs du contrôle de la mort cellulaire neurale feraient partie des facteurs ayant permis l'émergence d'un cerveau de plus grande taille dans notre espèce. Les éphrines sont loin d'être les seuls facteurs de guidage impliqués dans les mécanismes de mort cellulaire : ainsi, les nétrines et leurs récepteurs, les sémapho-rines, la molécule RGM (repulsive guidance molecule) ont également été impliqués dans le contrôle de la mort cellulaire [8][9][10][11]. Dans les plupart des cas, cependant, l'apoptose induite résulte de l'absence de stimulation des récepteurs par leurs ligands, selon le concept de récepteur de dépendance [10].…”