Reelin and cyclin-dependent kinase 5-dependent signals cooperate in regulating neuronal migration and synaptic transmission.
Neuronal migration and positioning in the developing brain require the coordinated interaction of multiple cellular signaling pathways. The extracellular signaling molecule Reelin and the cytoplasmic serine/threonine kinase Cdk5 (cyclin-dependent kinase 5) are both required for normal neuronal positioning, lamination of the neocortex, and foliation of the cerebellum. They also modulate synaptic transmission in the adult brain. It is not known, however, to what extent Cdk5 participates in Reelin signaling and whether both pathways interact on the genetic or biochemical level. We have used genetically altered mice to generate compound functional defects of Reelin and Cdk5 signaling. Differential neurohistochemical staging combined with the biochemical analysis of Reelin- and Cdk5-dependent signaling in primary embryonic neurons and electrophysiology in hippocampal slices reveals evidence for genetic and functional interaction between both pathways. Inhibition of Reelin or Cdk5 signaling had no discernible biochemical effect on each other. Taken together, these findings suggest that both pathways function together in a parallel, rather than a simple, linear manner to coordinate neuronal migration and neurotransmission in the developing and mature brain.
Beffert
Uwe
U
Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9046, USA.
Weeber
Edwin J
EJ
Morfini
Gerardo
G
Ko
Jane
J
Brady
Scott T
ST
Tsai
Li-Huei
LH
Sweatt
J David
JD
Herz
Joachim
J
D000818:Animals; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics / Q000378:metabolism*; D002465:Cell Movement / Q000235:genetics / Q000502:physiology*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000473:pathology; D051360:Cyclin-Dependent Kinase 5; D018844:Cyclin-Dependent Kinases / Q000235:genetics / Q000378:metabolism*; D004392:Dwarfism / Q000235:genetics; D004789:Enzyme Activation / Q000187:drug effects / Q000235:genetics; D019706:Excitatory Postsynaptic Potentials / Q000235:genetics / Q000502:physiology; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism*; D006624:Hippocampus / Q000196:embryology / Q000473:pathology / Q000502:physiology; D006801:Humans; D026502:LDL-Receptor Related Proteins; D017774:Long-Term Potentiation / Q000235:genetics; D051379:Mice; D008818:Mice, Neurologic Mutants; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000235:genetics; D009473:Neuronal Plasticity / Q000235:genetics / Q000502:physiology; D009474:Neurons / Q000473:pathology / Q000502:physiology*; D010766:Phosphorylation; D018110:Receptors, Lipoprotein / Q000172:deficiency / Q000235:genetics; D000091042:Reelin Protein; D012697:Serine Endopeptidases; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D015996:Survival Rate; D009435:Synaptic Transmission / Q000235:genetics / Q000502:physiology*
D015816:Cell Adhesion Molecules, Neuronal; D016326:Extracellular Matrix Proteins; D026502:LDL-Receptor Related Proteins; D009419:Nerve Tissue Proteins; D018110:Receptors, Lipoprotein; D000091042:Reelin Protein; C098773:low density lipoprotein receptor-related protein 8; C089495:neuronal Cdk5 activator (p25-p35); D051360:Cyclin-Dependent Kinase 5; C495905:CDK5 protein, human; C495906:Cdk5 protein, mouse; D018844:Cyclin-Dependent Kinases; C000717127:RELN protein, human; C000717128:Reln protein, mouse; D012697:Serine Endopeptidases