【Seminar】April 12 @D015 Miss. Jelena Katic

Speaker: Miss. Jelena Katic

Center for Molecular Neurobiology Hamburg>>http://www.uke.de/english/general/international-affairs/index.html

Title:

Functional interplay between the adhesion molecule CHL1 and sonic hedgehog signaling pathway during development of cerebellum

Abstract:

Several L1-related adhesion molecules, expressed in a well-coordinated temporospatial pattern during development, are important for fine tuning of specific cerebellar circuitries. CHL1, the close homologue of L1, is abundantly expressed in the developing and adult cerebellum and required for normal cerebellar cytoarchitecture. Constitutive ablation of CHL1 in mice caused significant loss of Purkinje and granule cells in the adult cerebellum. We identify CHL1 as a novel ligand of patched-1, a receptor for hedgehog morphogens and a repressor of the hedgehog signal transducer smoothened. A sequence stretch in the extracellular CHL1 domain shows similarity to sonic hedgehog sequences and mediates the binding of CHL1 to the first extracellular loop of patched. CHL1 interacts with patched, activates smoothened and promotes cell survival in cultures of cerebellar neurons. In the organotypic cerebellar slice culture CHL1 inhibits apoptosis of Purkinje and granule cells via smoothened-, RhoA- and RhoA kinase-dependent signal transduction pathways. In histological sections from 10- and 14-day-old CHL1-deficient mice enhanced apoptosis of granule cells was observed, indicating that CHL1 contributes to programmed cell death of granule cells during the second postnatal week of cerebellar development. Our results indicate that CHL1 activates of RhoA and RhoA-associated kinase via patched and smoothened-dependent signal transduction pathways; triggering these pathways contributes to cell survival during postnatal cerebellar development.