Reeler/Disabled-like disruption of neuronal migration in knockout mice lacking the VLDL receptor and ApoE receptor 2.
Layering of neurons in the cerebral cortex and cerebellum requires Reelin, an extracellular matrix protein, and mammalian Disabled (mDab1), a cytosolic protein that activates tyrosine kinases. Here, we report the requirement for two other proteins, cell surface receptors termed very low density lipoprotein receptor (VLDLR) and apolipoprotein E receptor 2 (ApoER2). Both receptors can bind mDab1 on their cytoplasmic tails and are expressed in cortical and cerebellar layers adjacent to layers that express Reelin. mDab1 expression is upregulated in knockout mice that lack both VLDLR and ApoER2. Inversion of cortical layers and absence of cerebellar foliation in these animals precisely mimic the phenotype of mice lacking Reelin or mDab1. These findings suggest that VLDLR and ApoER2 participate in transmitting the extracellular Reelin signal to intracellular signaling processes initiated by mDab1.
Trommsdorff
M
M
Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas 75235-9046, USA.
Gotthardt
M
M
Hiesberger
T
T
Shelton
J
J
Stockinger
W
W
Nimpf
J
J
Hammer
R E
RE
Richardson
J A
JA
Herz
J
J
D000595:Amino Acid Sequence; D000818:Animals; D015816:Cell Adhesion Molecules, Neuronal / Q000378:metabolism*; D002460:Cell Line; D002465:Cell Movement / Q000502:physiology; D002540:Cerebral Cortex / Q000378:metabolism / Q000473:pathology; D003712:Dendrites / Q000502:physiology*; D016326:Extracellular Matrix Proteins / Q000378:metabolism*; D005260:Female; D026502:LDL-Receptor Related Proteins; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D011689:Purkinje Cells / Q000502:physiology*; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D018110:Receptors, Lipoprotein / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D000091042:Reelin Protein; D012697:Serine Endopeptidases; D015854:Up-Regulation
D015816:Cell Adhesion Molecules, Neuronal; C103773:Dab1 protein, mouse; D016326:Extracellular Matrix Proteins; D026502:LDL-Receptor Related Proteins; D009419:Nerve Tissue Proteins; D011973:Receptors, LDL; D018110:Receptors, Lipoprotein; D011993:Recombinant Fusion Proteins; D000091042:Reelin Protein; C036053:VLDL receptor; C098773:low density lipoprotein receptor-related protein 8; C000717128:Reln protein, mouse; D012697:Serine Endopeptidases