26-07-08(20:03:35)
Authors:
Mirjam Sibbe, Eckart Förster and Michael Frotscher
Institutions:
Institute of Anatomy and Cell Biology, University of Freiburg, Germany
Title of abstract : Reelin functions in hippocampal development by interacting with Notch1 signalling
Abstract text:
Reelin is required for the proper positioning of neurons in the cerebral cortex, cerebellum and hippocampus. In the reeler mutant mouse lacking Reelin, an ordered hippocampal radial glial scaffold does not develop and dentate granule cells fail to form a regular, densely packed cell layer. Reelin signalling via its receptors ApoER2 and VLDLR is known to involve several kinases finally leading to cytoskeletal changes involving tau phosphorylation. Our data suggest that cross-talk between Reelin and Notch plays a crucial role in normal hippocampal development. Upon activation, the intracellular domain (NICD) of the transmembrane Notch1 receptor is cleaved and translocates into the nucleus acting as a transcriptional activator. We found reduced protein levels of NICD in the hippocampus of young postnatal reeler mutant mice as well as decreased expression of brain lipid-binding protein (BLBP), a transcriptional target of Notch1 signalling. Furthermore, our data suggest that Reelin signalling interacts with Notch1 via the intracellular adaptor protein Disabled1, a key regulator in the Reelin signalling pathway. Moreover, inhibition of Notch cleavage induces a reeler-like phenotype in hippocampal slice cultures. We further investigated whether Reelin treatment in culture is capable of enhancing Notch-signalling. Our data point to a recruitment of Notch1 activity by Reelin signalling to form and stabilize the hippocampal radial glia scaffold.
(Supported by the Deutsche Forschungsgemeinschaft: SFB 505, TP A8)
