Molecular Cell Biology | Neuroscience
The neuronal cytoskeleton in axon guidance
Axon extension, branching, and retraction are morphological changes that neurons have to execute to accomplish correct wiring of the nervous system during development and regeneration. These transformations are guided by extracellular signals which ultimately need to be translated into rearrangement of the neuronal cytoskeleton. We study mechanisms involved in the orchestrated reorganization of neuronal microtubules and actin filaments. Our approach combines gene ablation in...more
Axon extension, branching, and retraction are morphological changes that neurons have to execute to accomplish correct wiring of the nervous system during development and regeneration. These transformations are guided by extracellular signals which ultimately need to be translated into rearrangement of the neuronal cytoskeleton. We study mechanisms involved in the orchestrated reorganization of neuronal microtubules and actin filaments. Our approach combines gene ablation in the mouse with cell biological and molecular analyses in cultured neurons as well as biochemical and ultrastructural analysis.
One focus of our research is the role of microtubule-associated proteins of the MAP1 family. In the past we have shown that MAP1B is a component of a pathway that links calcium influx and activation of neuronal nitric oxide synthase to reconfiguration of axonal microtubules and thus might contribute to physiological and pathological effects of nitric oxide in the brain. We have since demonstrated that MAP1B is essential for signal transduction of several other repulsive axon guidance cues as well. These include semaphorin 3A and draxin which critically depend on MAP1B which in response to these extracellular cues is phosphorylated through a PI3 kinase-Akt-GSK-3beta pathway (Figure 1).
To complement our work in mice and primary neurons we investigate the ultrastructural details of the microtubule binding domain of MAP1 proteins. This domain is about 125 amino acids in length and intrinsically disordered. In collaboration with Robert Konrat (MFPL) we use nuclear magnetic resonance techniques to reveal structural changes in its interaction with microtubules.
Recently, we also engaged in a systems biological multi-scale, multi-parametric image analysis of microtubule dynamics in axonal growth cones of live primary neurons of wild-type and mutant mice. This study is aimed at determining whether growth cone behavior (migration, pausing, collapse and retraction) is associated with distinct sets of microtubule dynamic parameters (Figure 2). We measure about 80 parameters of microtubule dynamics and growth cone behavior in hundreds of migrating growth cones yielding tens of thousands of observations. We apply advanced statistical methods to determine if and how the behavior of individual growth cones (minutes time scale) is linked to microtubule dynamic parameters (seconds time scale).
Stroissnigg, Heike; Trancíková, Alzbeta; Descovich, Luise; Fuhrmann, Jakob; Kutschera, Waltraud; Kostan, Julius; Meixner, Arabella; Nothias, Fatiha; Propst, Friedrich (2007). S-nitrosylation of microtubule-associated protein 1B mediates nitric-oxide-induced axon retraction. NAT CELL BIOL. PMID: 17704770
Meli, Rajeshwari; Weisová, Petronela; Propst, Friedrich (2015). Repulsive axon guidance by Draxin is mediated by protein Kinase B (Akt), glycogen synthase kinase-3β (GSK-3β) and microtubule-associated protein 1B. PLOS ONE;10(3):e0119524. PMID: 25775433
Cheng, Long; Desai, Jigar; Miranda, Carlos J; Duncan, Jeremy S; Qiu, Weihong; Nugent, Alicia A; Kolpak, Adrianne L; Wu, Carrie C; Drokhlyansky, Eugene; Delisle, Michelle M; Chan, Wai-Man; Wei, Yan; Propst, Friedrich; Reck-Peterson, Samara L; Fritzsch, Bernd; Engle, Elizabeth C (2014). Human CFEOM1 mutations attenuate KIF21A autoinhibition and cause oculomotor axon stalling. NEURON;82(2):334-49. PMID: 24656932
Wings for Life Spinal Cord Research Foundation
Project: Parameters of microtubule dynamics as determinants of axon extension and retraction