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Dissecting a Rho GTPase spatio-temporal signaling network regulating growth cone motility, neurite and axonal outgrowth

English title Dissecting a Rho GTPase spatio-temporal signaling network regulating growth cone motility, neurite and axonal outgrowth
Applicant Pertz Olivier
Number 173462
Funding scheme Bilateral programmes
Research institution Departement Biomedizin Universität Basel
Institution of higher education University of Berne - BE
Main discipline Cellular Biology, Cytology
Start/End 01.11.2017 - 31.12.2020
Approved amount 259'554.00
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Keywords (6)

Neurite outgrowth; computer vision; axonal specification; Live cell imaging; signaling; Rho GTPase

Lay Summary (French)

Lead
Dissection d'un reseau de signalisation complexe regulant la croissance neuronale
Lay summary

 

Les neurones produisent les connections neuronales qui branchent le cerveau adulte, ainsi que le systeme nerveux peripheral. Ces connections neuronales sont endomagees dans des pathologies comme la maladie d’Alzheimer, ou apres la section accidentelle de la moelle epiniere. Il y a donc un considerable interet a comprendre la biologie fondamentale qui permet de faire repousser ces connections neuronales endommagees pour intervenir therapeutiquement. La croissance de ces connections neuronales est possible grace a une structure motile appellee le cone de croissance. Les forces mecaniques qui permettent la motilite du cone de croissance sont genereee grace la polymerization de l’actine, un composant du cytosquelette. Notre laboratoire a recemment montre comment un reseau complexe de dizaines de molecules de signalisation differentes parvient a positioner la polymerization le l’actine au bon moment, au bon endroit, pour favoriser une croissance neuronale optimale. Un important concept, qui faute de technologies adequates, a ete jusqu’a maintenant ignore, est que ce reseau de signalisation est beaucoup plus complexe que ce qui etait precedemment accepte. L’hypothese de ce projet est qu’une connaissance plus elaboree de la complexite de ce reseau de signalisation peut offrir une plus grande variete de modalities experimentales pour manipuler la croissance neuronale. Dans ce projet, nous allons donc explorer de nouveaux aspect de ce reseau de signalisation. Dans un second temps, nous allons essayer de manipuler different composants du reseau de signalization pour favoriser la croissance de ces connections neuronales.

Direct link to Lay Summary Last update: 03.10.2017

Responsible applicant and co-applicants

Employees

Name Institute

Collaboration

Group / person Country
Types of collaboration
INIMEC-CONICET Argentina (South America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Gaudenz Danuser/ UT Southwestern Dallas United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
FEBS 2018: Biology and pathology of cytoskeleton: the crossroads of three cytoskeletal systems 20-24/09/2018 Prague Poster Saptio-temporal Rho GTPase signaling during neurite outgrowth 10.09.2018 Prague, Czech Republic Pertz Olivier; Heydasch Max;


Knowledge transfer events

Active participation

Title Type of contribution Date Place Persons involved
Quantbio 2019 Summer School Workshop 15.09.2019 Fiesch, Switzerland Heydasch Max; Pertz Olivier;
6th SCRM Annual Student retreat 30. August 2019 Poster 30.08.2019 Bern, Switzerland Heydasch Max;
6th SCRM Annual Student retreat Poster 30.08.2019 Bern, Switzerland Heydasch Max;


Associated projects

Number Title Start Funding scheme
163061 Mapping Rho GTPase signaling networks through acute, dynamic stimulation of spatio-temporal signaling fluxes. 01.04.2016 Project funding (Div. I-III)
185376 Decoding and Re-Encoding Receptor Tyrosine Kinase/Fate Decision Signaling 01.06.2019 Project funding (Div. I-III)

Abstract

Rho GTPases are key signaling molecules that spatio-temporally regulate cytoskeletal dynamics. Classic models state that the three canonical Rho GTPases regulate specific cytoskeletal structures such as filopodia (Cdc42), lamellipodia (Rac1) and stress fibers (RhoA). In neuronal cells, this has led to a classic model in which Rac1 and Cdc42 signaling is required for growth cone extension/advance, while RhoA regulates acto-myosin-based contractility necessary for growth cone collapse. However, recent developments in biosensor technology to visualize Rho GTPase activation dynamics with unprecedented spatio-temporal resolution have revealed a much more complex picture. The Pertz laboratory has recently shown that RhoA is not only activated during growth cone collapse, as previously expected, but also at the tip of filopodial F-actin bundles during growth cone extension. Further, our unpublished results indicate that Cdc42 activity is present throughout growth cone filopodia, while Rac1 activity occurs in growth cone lamellipodial veils. These results indicate a much more complex regulation of Rho GTPase signaling during growth cone motility than previously anticipated, with the three Rho GTPases being activated at precise, distinct subcellular locations. This most likely serves to regulate specific cytoskeletal polymers that fine tune growth cone motility and neurite/axonal outgrowth. Further, this is consistent with the existence of a highly complex Rho GTPase network controlling neurite outgrowth, that we have recently identified using a large scale perturbation screenBy pooling expertise present in the lab of both applicants, we will now explore this unexpected spatio-temporal signaling complexity, both in a simple neuroblastoma cell system, as well as in primary neurons. We will tackle two interlinked questions: 1. Which are the molecular players (GEFs, GAPs and interacting proteins) that shape and dynamically maintain a specific spatio-temporal Rho GTPase activation pattern ? Based on a priori knowledge from our perturbation screen, we will identify the molecular network that generates different RhoA and Cdc42 activation domains within growth cones (measured using FRET-based biosensors). 2. What is the function of each Rho GTPase with respect to cytoskeletal regulation in response to neurite/axonal outgrowth? We will perturb previously identified molecular components of this network to manipulate RhoA and Cdc42 activation patterns, and evaluate their downstream cytoskeletal outputs. This is expected to give important clues about the specific function of each Rho GTPase in filopodium and lamellipodium formation, as well as growth cone cytoskeletal organization. Ultimately, we will use this knowledge to manipulate filopodial/lamellipodial dynamics to promote axonal regeneration. Understanding these complex spatio-temporal Rho GTPase signaling networks at multiple time and length scales (e.g. growth cone motility versus neurite/axonal outgrowth) therefore might have the potential to point to novel leads for the treatment of axonal regeneration after injury.
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