Regulation of neuron development & ciliary function by microtubule glutamylation

University Of Michigan At Ann Arbor, Ann Arbor MI

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Abstract

DESCRIPTION (provided by applicant): The long-term objective of this proposal is to investigate the role of tubulin post-translational modifications in microtubule functions. Microtubules play critical roles in cell division, intracellular trafficking, cell structure, and mitosis. Although all microtubules are polymerized from a common tubulin building block, cells create distinct microtubules for these different functions. How cells are able to generate heterogeneous microtubule populations has been a persistent question in cell biology and is important for understanding the molecular basis of diseases related to dysfunction of microtubule-based processes such as neurodegenerative diseases (e.g. Alzheimer and Huntington diseases), ciliopathies (e.g. Bardet-Bield syndrome and polycystic kidney disease), and cancer. Microtubules are subject to numerous post-translational modifications including acetylation, detyrosination, and glutamylation. It has been suggested that these modifications play a role in "marking" microtubule populations to create a "tubulin code" that directs specific cell functions, similar to how the histone code is thought to direct chromatin functions. We will test the hypothesis that tubulin glutamylation contributes to neuronal development and ciliary function through specific effects on kinesin-based transport. The recent discovery of the tubulin glutamylase properties of tubulin tyrosine ligase-like (TTLL) enzymes will enable us to modify microtubule glutamylation levels in cells. We will observe the direct effects of altered microtubule glutamylation on the development of primary hippocampal neurons and cilia sensory function in olfactory cells. We will investigate the effects of altered microtubule glutamylation on kinesin-based transport events in hippocampal neurons and olfactory cilia. We will determine how microtubule glutamylation affects kinesin motility properties at the single-molecule level. Taken together, these studies will provide a fundamental understanding of how microtubule post-translational modifications affect neuronal development and ciliary function through regulation of long-distance intracellular trafficking events. Intracellular trafficking and the proper distribution of structural and signaling proteins is critical for cellular functions such as neuronal transmission and ciliary beating. Disruption of intracellular trafficking leads to neurodegenerative diseases and ciliopathies. Yet an in-depth understanding of cellular transport processes is still lacking. This proposal aims to investigate how transport events are regulated and contribute to the development and function of neuronal cells and cilia in olfactory cells.