Cortical development in the presenilin-1 null mutant mouse fails after splitting of the preplate and is not due to a failure of reelin-dependent signaling.
Cortical development is disrupted in presenilin-1 null mutant (Psen1-/-) mice. Prior studies have commented on similarities between Psen1-/- and reeler mice. Reelin induces phosphorylation of Dab1 and activates the phosphatidylinositol 3-kinase (PI3K)/Akt pathway. Psen1 is known to modulate PI3K/Akt signaling and both known reelin receptors (apoER2 and VLDLR) are substrates for Psen1 associated gamma-secretase activity. The purpose of this study was to determine whether reelin signaling is disrupted in Psen1-/- mice. We show that, while Dab1 is hypophosphorylated late in cortical development in Psen1-/- mice, it is normally phosphorylated at earlier ages and reelin signaling is intact in Psen1-/- primary neuronal cultures. gamma-secretase activity was also not required for reelin-induced phosphorylation of Dab1. Unlike reeler mice the preplate splits in Psen1-/- brain. Thus cortical development in Psen1-/- mice fails only after splitting of the preplate and is not due to an intrinsic failure of reelin signaling.
De Gasperi
Rita
R
Research and Development James J. Peters Department of Veterans Affairs Medical Center, Bronx, New York 10468, USA.
Gama Sosa
Miguel A
MA
Wen
Paul H
PH
Li
Jingjun
J
Perez
Gissel M
GM
Curran
Tom
T
Elder
Gregory A
GA
D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D015816:Cell Adhesion Molecules, Neuronal / Q000378:metabolism*; D002460:Cell Line; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000196:embryology* / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D053764:Presenilin-1 / Q000235:genetics / Q000502:physiology*; D000091042:Reelin Protein; D012697:Serine Endopeptidases / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*
D053829:Amyloid Precursor Protein Secretases; D015816:Cell Adhesion Molecules, Neuronal; D016326:Extracellular Matrix Proteins; D009419:Nerve Tissue Proteins; D019869:Phosphatidylinositol 3-Kinases; D053764:Presenilin-1; D000091042:Reelin Protein; D012697:Serine Endopeptidases; C103773:Dab1 protein, mouse; C000717127:RELN protein, human; C000717128:Reln protein, mouse