# Molecular Mechanisms of Semaphorin/Plexin-mediated Cytoskeletal Reorganization

> **NIH NIH R01** · UT SOUTHWESTERN MEDICAL CENTER · 2020 · $354,375

## Abstract

The goals of this project are to decipher the mechanisms that regulate the actin and microtubule cytoskeletons,
the structures underlying neural cell behaviors including morphology, polarity, adhesion, process elongation,
motility, navigation, connectivity, and plasticity. To change their size, shape, and connectivity, neurons require
actin and tubulin proteins to assemble together into long polymers (F-actin and microtubules, respectively) –
and numerous extracellular stimuli have now been identified that alter the assembly and organization of these
cytoskeletal structures. Yet, we still know little of how these extracellular cues exert their precise effects on the
cytoskeleton. To better understand these mechanisms, my lab has been focusing on one of the largest families
of extracellular cues, the Semaphorins (Semas) – which alter neuronal behaviors by eliciting destabilizing
effects on both F-actin and microtubules. Our strategy has been to use model organisms and screening
approaches to search for proteins that work in the signal transduction cascade utilized by Semas and their
Plexin receptors. Among the proteins that we have identified, is a new family of intracellular proteins called the
MICALs that are required for Sema/Plexin signal transduction. Now, work in my lab during the previous funding
cycle of this R01 has revealed that the MICALs employ a previously unknown Redox signaling system to
control the actin cytoskeleton. Namely, we have found that Mical is a novel F-actin disassembly factor – and
our results reveal that Sema/Plexin-mediated reorganizations of the actin cytoskeleton can be precisely
achieved in space and time through activation of Mical. We have also found that the MICALs belong to a class
of oxidoreductase (Redox) enzymes and that Mical employs its Redox enzymatic activity to alter the properties
of F-actin. Our work has gone on to identify that Mical uses F-actin as a direct substrate and post-
translationally oxidizes conserved amino acids on actin, simultaneously dismantling F-actin and decreasing
polymerization. Moreover, we find that this Sema/Plex/Mical-mediated Redox regulation of actin is reversible
(by a protein called SelR/MsrB) – and that this specific reversible Redox actin regulatory system directs
multiple different biological processes in neuronal and non-neuronal tissues. Therefore, I hypothesize that
Sema/Plexin guidance cues utilize a reversible Redox signaling mechanism composed of Mical and SelR to
directly and spatiotemporally coordinate cytoskeletal remodeling to drive cellular form and function. I propose
to test this hypothesis by following-up on several lines of preliminary observations that illuminate critical
molecular mechanisms of Sema/Plexin/Mical-mediated cytoskeletal reorganization including 1) specific types
of F-actin/networks of F-actin that are most responsive to Sema/Plex/Mical effects, 2) molecular interactions
that allow Sema/Plexins to coordinate the disassembly of the actin and...

## Key facts

- **NIH application ID:** 9864108
- **Project number:** 5R01NS073968-08
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** JONATHAN R TERMAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $354,375
- **Award type:** 5
- **Project period:** 2011-02-15 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9864108

## Citation

> US National Institutes of Health, RePORTER application 9864108, Molecular Mechanisms of Semaphorin/Plexin-mediated Cytoskeletal Reorganization (5R01NS073968-08). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9864108. Licensed CC0.

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