During development neurons form an elaborate, branching system of protrusions.
Precise control over the correct development of neuronal protrusions is essential for
normal brain development and higher brain function. Even subtle defects in their
development or stability can lead to neuronal degeneration, dementias or psychosis.
Current treatments for such disorders are based on fragmented and incomplete
information. In order to improve current treatments, a better, more complete
understanding of the underlying biological systems is required.
This project focuses on the neuronal cytoskeleton during development. We focus
on the role of two major components: the microtubule and actin cytoskeleton.
Through the concerted action of many molecular machines, these components are
constantly remodeled throughout brain development, maintenance and repair. To
gain a better understanding about the mechanisms by which the neuronal
cytoskeleton is regulated and organized in neurons, and how this affects the
neuronal shape, we are using a multidisciplinary approach including high-content
screening and time-lapse microscopy. Via perturbation of individual regulators and
detailed quantitative microscopic analysis, we ultimately aim to build a computational
model of the neuronal cytoskeleton, which will guide further experimentation and our
understanding of the underlying mechanisms in neuronal development.
Figure
1:
The
neuronal
cytoskeleton during the initiation
of a protrusion. The two major
cytoskeletal systems: microtubules
(green) and actin (red) form fibrous
structures that play key roles in
neuronal morphogenesis.
Movie 1: Dynamic interactions between the
actin (red) and microtubule (green) cytoskeleton
systems in neuronal cells. Various modes of
interactions between the two cytoskeletal systems
are visualized via variants of the green fluorescent
protein and live cell video-microscopy.
AVI high / AVI low / QT high / QT low
People involved in the project:
Leif Dehmelt – principal investigator
Julia Arens – PhD student
Silke Gandor – PhD student
Magda Krejczy – graduate assistent
Anja Biesemann – master student
Verena Hannak – master student
Pia Jeggle – master student
Relevant Publications:
Halpain S, Calabrese B, and Dehmelt L. Actin Cytoskeleton in Growth Cones, Nerve
Terminals, and Dendritic Spines. New Encyclopedia for Neuroscience, (Ed. Larry Squire) (in
press).
Dehmelt L, Halpain S. (2007): Neurite Outgrowth: A Flick of the Wrist. Curr Biol 17:R611R614
Dehmelt L, Nalbant P, Steffen W, Halpain S. (2006): A Microtubule-Based, DyneinDependent Force Induces Local Cell Protrusions: Implications for Neurite Initiation. Brain Cell
Biology 35:39-56
Halpain S, Dehmelt L. (2006): The MAP1 family of microtubule-associated proteins.
Genome Biology ;7:224.
Dehmelt L, Halpain S. (2005): MAP2/tau family proteins. Genome Biology 6:204
Roger B, Al-Bassam J, Dehmelt L, Milligan RA, Halpain S. (2004): MAP2c, but not tau, binds
and bundles F-actin via its microtubule binding domain. Curr Biol 14:363-71 (featured in
N&V, Nature Cell Biology 6:390)
Dehmelt L, Halpain S. (2004): Actin and microtubules in neurite initiation: are MAPs the
missing link? J Neurobiol 58:18-33
Dehmelt L, Smart FM, Ozer RS, Halpain S (2003): The role of microtubule-associated
protein 2c in the reorganization of microtubules and lamellipodia during neurite initiation. J
Neurosci 23:9479-90 (cover illustration)