Discovering how neurons form and maintain the membrane-associated periodic skeleton in vivo

• Applicant: Dr. Oliver Vinzenz Glomb
• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells ; Cell Biology
• Term: from 2021 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 465611822

A fundamental question in neuronal cell biology is how axons maintain their structural integrity. Recently, a periodic lattice of actin rings connected by spectrin tetramers was shown to scaffold the axonal membrane and promote mechanical resilience. This function is strongly supported by mutations in spectrin which lead to axon breakage and brain atrophy in patients. While the main components of the MPS (Membrane-associated Periodic Skeleton) have been identified, the molecular mechanisms governing its assembly and maintenance remain unknown.Here, I propose to uncover these mechanisms and their regulation in vivo by establishing C. elegans as a genetically tractable model of MPS expansion and turnover. An in vivo system enables to study MPS dynamics not only as the axon navigates to its target in early development, but also during subsequent organismal growth which stretches the axon to its final size, accounting for most of the mature axon length, or during adulthood and aging. I will develop a unique set of temporally controlled probes to identify sites of MPS expansion and measure its turnover kinetics at endogenous levels in live animals, within a single neuron integrated into its native circuit. Leveraging these probes and the stereotypic development and connectivity of the C. elegans nervous system will allow me to determine how physiological cues such as animal growth-rate, extracellular signals and synapse-location modulate MPS dynamics. Finally, I will use unbiased forward genetics to identify key regulators of MPS lattice formation and elucidate their roles using my probes and super-resolution microscopy. These studies will pioneer roads to understanding mechanisms of MPS formation and turnover and uncover how their regulation maintains axonal integrity during growth and throughout life.

• DFG Programme: WBP Fellowship
• International Connection: USA
• Host: Professor Shaul Yogev, Ph.D.