Reelin induces the detachment of postnatal subventricular zone cells and the expression of the Egr-1 through Erk1/2 activation.
Reelin binds to very low-density lipoprotein receptor and apolipoprotein E receptor 2, thereby inducing mDab1 phosphorylation and activation of the phosphatidylinositide 3 kinase (PI3K) pathway. Here we demonstrate that Reelin activates the mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) pathway, which leads to the phosphorylation of Erk1/2 proteins. The inhibition of Src family kinases (SFK) blocked Reelin-dependent Erk1/2 activation. This was also shown in neuronal cultures from mDab1-deficient mice. Although rat sarcoma viral oncogene was weakly activated upon Reelin treatment, pharmacological inhibition of the PI3K pathway blocked Reelin-dependent ERK activation, which indicates cross talk between the ERK and PI3K pathways. We show that blockade of the ERK pathway does not prevent the chain migration of neurons from the subventricular zone (SVZ) but does inhibit the Reelin-dependent detachment of migrating neurons. We also show that Reelin induces the transcription of the early growth response 1 transcription factor. Our findings demonstrate that Reelin triggers ERK signaling in an SFK/mDab1- and PI3K-dependent manner and that ERK activation is required for Reelin-dependent transcriptional activation and the detachment of neurons migrating from the SVZ.
Simó
Sergi
S
Developmental Neurobiology and Regeneration Laboratory, Barcelona Science Park-IRB and Department of Cell Biology, University of Barcelona, E-08028 Barcelona, Spain.
Pujadas
Lluís
L
Segura
Miguel F
MF
La Torre
Anna
A
Del Río
Jose A
JA
Ureña
Jesús M
JM
Comella
Joan X
JX
Soriano
Eduardo
E
D000818:Animals; D000831:Animals, Newborn; D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology*; D015816:Cell Adhesion Molecules, Neuronal / Q000494:pharmacology*; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D002552:Cerebral Ventricles / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D051766:Early Growth Response Protein 1 / Q000378:metabolism*; D004789:Enzyme Activation; D016326:Extracellular Matrix Proteins / Q000494:pharmacology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects / Q000502:physiology; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D051379:Mice; D009419:Nerve Tissue Proteins / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D000091042:Reelin Protein; D012697:Serine Endopeptidases / Q000494:pharmacology*
D015816:Cell Adhesion Molecules, Neuronal; D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; D016326:Extracellular Matrix Proteins; D009419:Nerve Tissue Proteins; D000091042:Reelin Protein; C000717129:Reln protein, rat; D048049:Extracellular Signal-Regulated MAP Kinases; C000717128:Reln protein, mouse; D012697:Serine Endopeptidases