The role of cholesterol in neuronal development and function

• Applicant: Dr. Gesine Saher
• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells
• Term: from 2010 to 2015
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 171963272

Cholesterol is an essential component of cell membranes in vertebrates. Polarized cells such as neurons harbor membrane subdomains with particular cholesterol demands, i.e. growth cones, axons, dendrites, and synapses. Hence, it is important to understand the underlying mechanisms that lead to cholesterol enrichment in these specialized membranes and the cellular functions that require these cholesterol-rich membranes. Several in vitro studies characterize cholesterol-rich membranes e.g. membrane lipid rafts in many aspects of cellular function. However, little is known about their role in an entire organism.We found that cholesterol can act as a major regulator of the formation of such specialized membranes: Cholesterol is rate-limiting for the formation of myelin membranes by oligodendrocytes and Schwann cells. The inactivation of cholesterol biosynthesis in all neural progenitors suggested the possibility that particularly principal neurons in the developing neocortex require cell autonomous cholesterol synthesis. Using the tools of conditional gene inactivation, we will generate conditional mouse mutants that lack cholesterol biosynthesis in newly committed principal neurons of the neocortex.To define the role of cholesterol in neuronal development and function, we will address the following questions. (1) Is cell autonomous cholesterol synthesis required for neuronal survival and differentiation? (2) What are the mechanisms by which cholesterol enables neurite outgrowth? (3) Which particular step in synapse formation, function, and maintenance is dependent on cholesterol? Using our conditional mutants we will apply techniques of cell and molecular biology, biochemical analyses, electrophysiology, and transcriptomics.

• DFG Programme: Research Grants