Geneeskundige Stichting Koningin Elisabeth verslag - GSKE - FMRE

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50 Andre M. GOFFINET, MD, PhD Unité de Génétique du Développement Avenue E. Mounier, 73, Bte 7382 1200 Bruxelles T: +32-(0)2 764 7386 F: +32-(0)2 764 7430 Email: Andre.Goffinet@gede.ucl.ac.be Team at UCL: Nina IGNATOVA (PhD student, <strong>FMRE</strong>), Yves JOSSIN (PhD student, FRIA), Fadel TISSIR (PhD), Lanrun GUI (Bursary, UCL), Chuan-En WANG (Bursary, UCL) Collaborations at UCL: F. Lemaigre (HORM), C. Sindic (Neurology), M. Vikkula (BCHM) External collaborations: I. Bar, O. De Backer, A. Kuvbachieva, C. Lambert de Rouvroit (FUNDP, Namur) D. Blaas (Vienne), J. Herz (Dallas), G. Meyer (La Laguna), J. Nimpf (Vienne), JY Sire (Paris)
Genetic determinants of mouse brain development : The reelin signaling pathway. 1. Reelin and brain development. 1.1 Interactions between reelin and its receptors In 1999, together with the group of J. Herz (Dallas), we showed that two receptors of the lipoprotein receptor family, namely the very low density lipoprotein receptor VLDLR and apolipoprotein E receptor type 2 (ApoER2) are reelin receptor. In order to define better the region of the Reelin protein that is implicated in receptor binding, parts of the reelin cDNA were constructed and expressed in HEK297 cells. After verification that the proteins are secreted normally and thus presumably well folded, the supernatant from transfected cells is used as a ligand to interact with the extracellular part of VLDLR and ApoER2 produced in fusion with the Fc fragment of human IgG in a pull-down assay. Using this assay, we showed that the N-terminal part of Reelin, up to and including domains one, two, three and four is incapable of interacting with the receptors. On the other hand, a robust pull-down signal is obtained with a construction containing reelin domains 3-6 or domains 3-8. The terminal part of reelin (domains 7 and 8) do not bind. When smaller constructs are used, no binding is detected suggesting low affinity binding to several sites. When reelin is added to target neurons, the Dab1 adaptor is phosphorylated on tyrosine (Y). In order to assess whether reelin binding to VLDLR and ApoER2 is sufficient to explain the actions of reelin or whether engagement of another, thus far unknown receptor is required, we compared the binding of reelin constructs with their ability to generate Dab1 phosphorylation when added to primary neuronal cultures. There is a full correlation between the ability to bind to receptors and to stimulate Dab1 phosphorylation, suggesting that receptor binding is sufficient to activate the Dab1 part of the reelin signalling network. These studies will be part of the PhD thesis of Y. Jossin. Some of these results are in press (Jossin et al., 2002) and the others have been submitted. 1.2. Reelin in human brain development. In collaboration with G. Meyer (La Laguna), we undertook a study of expression of the Dab1 gene in the developing human brain. Both in situ hybridization and monoclonal antibodies against Dab1 were used. These monoclonal antiDab1 antibodies have been developed by C. Lambert and the production of new antibodies against VLDLR and ApoER2 are currently under way. These studies on human cortical development allowed us to define better the succession of events and to demonstrate that cortical plate cells express Dab1 as expected, but also that Dab1 (mRNA and protein) are quite strongly expressed in precursor cells in the ventricular zone. This has been confirmed by other laboratories in rodents and points to a role of the reelin pathway in the regulation of neural stem cells. Furthermore, Cajal-Retzius cells, the main producers of reelin were shown to express also Dab1, indicating the presence of an autocrine loop. These findings are in press (Meyer et al, In press). 51
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Selectivity of monkey V4 neurons fo
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Pathogenesis of cellular dysfunctio
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orphan receptor has also been demon
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to three DC stimuli, TNF-alpha, LPS
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mediated antinociception and a sign
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induces a shift of arachidonic acid
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M and Zajac JM. Pharmacological cha
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During last year, our laboratory ta
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PUBLICATIONS 2002 ARTICLES AVEC COM
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ALZHEIMER'S DISEASE Alzheimer disea
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including 2 stroke patients. Most p
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Nicastrin haplotype in AD Mutation
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ecessive demyelinating CMT (CMT4A)
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Mutation analysis of known genes an
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E4 in the temporal variant of front
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PRESENTATIONS AT MEETINGS Invited L
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Functional analysis of a gene for p
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References • Lage, H., Helmbach,
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The functional neuroanatomy of nami
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hybridization and immunohistochemis
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Geneeskundige Stichting Koningin Elisabeth verslag - GSKE - FMRE

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