Inhibition of SRC family kinases and non-classical protein kinases C induce a reeler-like malformation of cortical plate development.
During development, most cortical neurons migrate to the cortical plate (CP) radially. CP development is abnormal in reeler and other mutant mice with defective Reelin signaling. Reelin is secreted by Cajal-Retzius cells and binds to the very low density lipoprotein receptor and apolipoprotein E receptor type 2 receptors on the surface of CP cells, inducing tyrosine phosphorylation of the intracellular Dab1 adapter. As with Reelin receptors, the identification of Reelin signaling partners is hampered by genetic redundancy. Using a new in vitro embryonic slice culture system, we demonstrate that chemical inhibitors of Src family kinases and Abl, but not inhibitors of Abl alone, generate a reeler-like malformation and that inhibitors of protein kinases C induce a malformation of cortical development that is also reminiscent of reeler. Our observations demonstrate a key role for these enzymes in radial migration to the cortical plate, possibly via interference with Reelin signaling.
University of Louvain Medical School, Developmental Genetics Unit, GEDE 7382, B1200 Brussels, Belgium.
Yves
Y
Jossin
Masuhara
M
Ogawa
Christine
C
Metin
Fadel
F
Tissir
André M
AM
Goffinet
D000818:Animals; D001973:Bromodeoxyuridine; D002540:Cerebral Cortex / Q000002:abnormalities* / Q000201:enzymology / Q000473:pathology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D066298:In Vitro Techniques; D051379:Mice; D008807:Mice, Inbred BALB C; D008818:Mice, Neurologic Mutants; D009421:Nervous System Malformations / Q000201:enzymology* / Q000473:pathology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D016315:Proto-Oncogene Proteins c-abl / Q000037:antagonists & inhibitors; D000091042:Reelin Protein; D015398:Signal Transduction / Q000187:drug effects; D019061:src-Family Kinases / Q000037:antagonists & inhibitors*
D004791:Enzyme Inhibitors; D000091042:Reelin Protein; D016315:Proto-Oncogene Proteins c-abl; D019061:src-Family Kinases; D011493:Protein Kinase C; C000717128:Reln protein, mouse; D001973:Bromodeoxyuridine