Analysis of transgenic mouse models for the role of polysialic acid and NCAM during brain development

• Applicant: Professor Dr. Herbert Hildebrandt
• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells
• Term: from 2010 to 2014
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 160524507

Glycosylation with the sugar polymer polysialic acid (polySia) drastically alters the binding properties of the neural cell adhesion molecule NCAM. Mice that are unable to synthesize polySia lack major brain axon tracts. These defects, however, can be rescued by additional ablation of the polySia carrier protein NCAM. Thus, to guarantee normal development, polySia seems to prevent NCAM interactions during critical time windows. The objective of this project is to resolve the molecular and cellular mechanisms leading to the brain wiring defects that appear in polySia-deficient mice. Analysis will be performed on the mamillothalamic tract, a large axonal bundle originating in the mammillary body, a hypothalamic nucleus. Due to its homogeneous structure and accessibility this axon tract is particularly suited for the kind of experiments planned. In a first step, its embryonic development in the wild-type and in mouse lines with different NCAM- and polysialyltransferase-equipment will be characterized. In utero electroporation will then be used to induce expression of different NCAM isoforms and different NCAM modules in the mammillary body of polySia- and NCAM-negative mice. Developmental defects induced by this treatment will allow drawing conclusions on the NCAM-interactions relevant for axonal pathfinding. Complementary, the potential contribution of known NCAM-mediated signaling pathways to axonal growth of polySia-deficient hypothalamic neurons will be studied in explant cultures. These approaches allow for the first time to analyze, how the control of NCAM interactions by polySia directs brain development.

• DFG Programme: Research Grants
• Participating Person: Dr. Gonzalo Alvarez-Bolado