Local regulation of axonal stability by microtubules

• Applicant: Dr. Monika Leischner-Brill
• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells ; Developmental Neurobiology ; Cell Biology
• Term: since 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 450131873

In this proposal, I plan to investigate the signaling pathways and transcriptional programs related to the neurotransmission-dependent regulation of the microtubule cytoskeleton during synapse elimination. This fundamental process of neural development removes exuberant synapses in an activity-dependent manner, both in the central and peripheral nervous system. During the pruning phase, several equivalent inputs compete for the final exclusive innervation of a synapse. The loser retracts, while the winner stabilizes. The objectives outlined in this proposal build on my prior work, which is largely obtained under the predecessor funding of this grant. I found that spastin-mediated microtubule remodeling is a critical step during synapse elimination and subsequent maturation of the axon-glia unit. In an activity-dependent manner, this is driven by the posttranslational modification of tubulin, polyglutamylation. This pathway is important for both the central and peripheral nervous systems. Now, I will tackle exciting new research questions using various approaches from live imaging, translatome profiling, and genetic manipulations: (1) How do the retrograde signaling pathways instructing synaptic competition intersect with cytoskeletal remodeling and the underlying enzymatic regulation? (2) How does neurotransmission influence the overall transcriptional programs of cytoskeletal regulators that are permissive and required for local remodeling? From these questions emerge the specific hypotheses, which I will address in the following objectives of my grant: Objective ① - Characterize the local retrograde signals that regulate microtubule polyglutamylation and severing. Objective ② a - Explore the activity-based transcriptional control of microtubule stability. Objective ② b - Gene editing of candidates and analysis of functional consequences. Thus, in this follow-up project, I will explore axon remodeling and synapse elimination's cell biology, which are fundamental neurodevelopmental processes and have important parallels during axonopathic neurodegenerative diseases.

• DFG Programme: Research Grants