# Probing Microtubule Function in Neuronal Development

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2021 · $358,428

## Abstract

Neurons are the most morphologically complex cell type in multicellular organisms, and this complexity is
intricately linked to the complexity of nervous system information processing. Thus, impairments in neuronal
morphogenesis invariably result in alterations of nervous system function and often debilitating neurological
disease. Precise control of microtubule cytoskeleton organization is central to most if not all aspects of neuron
development and function ranging from the migration of newborn neurons, cycles of neurite elongation,
retraction and branching to growth cone guidance and synapse formation. This importance of neuronal
microtubules is reflected in the wide range of neurodevelopmental and neurodegenerative diseases linked to
genetic defects in proteins associated with the microtubule cytoskeleton. Human genetics and modern
sequencing techniques identified numerous mutations in related genes associated with frequently severe
cortical malformations. These include both mutations of tubulin genes themselves – so-named tubulinopathies
– as well as mutations in neuronal microtubule-associated proteins that often have a similar range of
neurodevelopmental phenotypes. While it is generally assumed that these mutations disrupt the developmental
migration of immature neurons through the developing cortex, we do not understand the rules governing
MT function in neuromorphogenesis at a mechanistic level. In this application, we propose to use emerging
human induced pluripotent stem cell (iPSC) technology in combination with state-of-the-art genome
engineering and our established expertise in quantitative microscopy to model and dissect the neuronal cell
biology of tubulinopathy-like diseases and the function of dynamic MTs in neuromorphogenesis. In Aim 1, we
focus on DCX and tubulin mutations that cause cortical malformations, and we will analyze how DCX controls
neuronal microtubule dynamics and mechanics, and neuronal morphogenesis based on our recent data that
DCX binds microtubules in a unique geometry-dependent way. In Aim 2, we employ novel optogenetics to
control protein interactions with growing microtubule plus ends with second and micrometer precision to map
how microtubule plus end complexes contribute to neuronal development dynamics. We believe that
quantitative and rigorous understanding of the principles that govern MT function in neuronal development and
what goes wrong in neurodevelopmental disease will have tangible and important outcomes for human health,
and can lay the foundation for future therapeutic approaches.

## Key facts

- **NIH application ID:** 10116503
- **Project number:** 5R01NS107480-04
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Torsten Wittmann
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $358,428
- **Award type:** 5
- **Project period:** 2018-06-15 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10116503

## Citation

> US National Institutes of Health, RePORTER application 10116503, Probing Microtubule Function in Neuronal Development (5R01NS107480-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10116503. Licensed CC0.

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