Reelin signals through apolipoprotein E receptor 2 and Cdc42 to increase growth cone motility and filopodia formation.
Lipoprotein receptor signaling regulates the positioning and differentiation of postmitotic neurons during development and modulates neuronal plasticity in the mature brain. Depending on the contextual situation, the lipoprotein receptor ligand Reelin can have opposing effects on cortical neurons. We show that Reelin increases growth cone motility and filopodia formation, and identify the underlying signaling cascade. Reelin activates the Rho GTPase Cdc42, known for its role in neuronal morphogenesis and directed migration, in an apolipoprotein E receptor 2-, Disabled-1-, and phosphatidylinositol 3-kinase-dependent manner. We demonstrate that neuronal vesicle trafficking, a Cdc42-controlled process, is increased after Reelin treatment and further provide evidence that the peptidergic VIP/PACAP38 system and Reelin can functionally interact to promote axonal branching. In conclusion, Reelin-induced activation of Cdc42 contributes to the regulation of the cytoskeleton of individual responsive neurons and converges with other signaling cascades to orchestrate Rho GTPase activity and promote neuronal development. Our data link the observation that defects in Rho GTPases and Reelin signaling are responsible for developmental defects leading to neurological and psychiatric disorders.
Center for Neuroscience, Albert-Ludwigs-University, 79104 Freiburg, Germany.
Jost
J
Leemhuis
Elisabeth
E
Bouché
Michael
M
Frotscher
Frank
F
Henle
Lutz
L
Hein
Joachim
J
Herz
Dieter K
DK
Meyer
Marina
M
Pichler
Günter
G
Roth
Carsten
C
Schwan
Hans H
HH
Bock
D000818:Animals; D000831:Animals, Newborn; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics* / Q000502:physiology; D002465:Cell Movement / Q000235:genetics; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000196:embryology* / Q000378:metabolism / Q000502:physiology*; D016326:Extracellular Matrix Proteins / Q000235:genetics* / Q000502:physiology; D020439:Growth Cones / Q000378:metabolism* / Q000648:ultrastructure; D057809:HEK293 Cells; D006801:Humans; D026502:LDL-Receptor Related Proteins; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000502:physiology; D009924:Organ Culture Techniques; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000502:physiology; D011554:Pseudopodia / Q000235:genetics / Q000502:physiology* / Q000648:ultrastructure; D051381:Rats; D018110:Receptors, Lipoprotein / Q000235:genetics / Q000502:physiology*; D000091042:Reelin Protein; D012697:Serine Endopeptidases / Q000235:genetics* / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics; D020764:cdc42 GTP-Binding Protein / Q000235:genetics / Q000502:physiology*
D015816:Cell Adhesion Molecules, Neuronal; D016326:Extracellular Matrix Proteins; D026502:LDL-Receptor Related Proteins; D009419:Nerve Tissue Proteins; D019869:Phosphatidylinositol 3-Kinases; D018110:Receptors, Lipoprotein; D000091042:Reelin Protein; D012697:Serine Endopeptidases; D020764:cdc42 GTP-Binding Protein; C103773:Dab1 protein, mouse; C000717129:Reln protein, rat; C098773:low density lipoprotein receptor-related protein 8; C000717127:RELN protein, human; C000717128:Reln protein, mouse