AC BREAKS THE SPHERE · The physiological role of ADF/cofilin in neuronal development
FP7 — People (Marie Curie Actions)
- Duration
- 2009-04-01 → 2011-03-31
- EU contribution
- €170,418
- Participants
- 1
- Scheme
- MC-IIF
Lines connect the coordinator with its partners.
Results in brief
The physiological role of ADF/cofilin in neuronal development
Summary: Neuritogenesis is a decisive event in neuronal morphogenesis as the transformation of spherical cells into neurons with multiple extensions underlies the later development of axons and dendrites in mature neuronal networks. In this project we demonstrate that increased actin dynamics underlie neurite initiation and that ADF/cofilin (AC) proteins are crucial, physiologically-relevant players regulating actin organisation and dynamics during neuritogenesis. The genetic ablation of AC proteins results in neurons that fail to form neurites with increased F-actin levels, disordered actin filament orientation and irregular looping microtubules. Furthermore, AC knockout (KO) neurons display an immobilisation of F-actin retrograde flow, indicating that AC proteins are key determinants of actin turnover. The F-actin severing activity of AC proteins is pinpointed as the essential activity for neuritogenesis. In vivo, the ablation of ADF/cofilin resulting in severe brain abnormalities including cortical hypoplasia, hydrocephaly and a marked decrease in axonal tract formation. We propose that AC mediated actin filament severing underpins actin turnover and reorganisation in neurons, which may open up intracellular space and guide the protrusion of bundled microtubules, the backbone of neurites. This project thus fulfilled most of its primary objectives and was an overall sucess. Attached document is a manuscript in preparation for publication. Please do not disseminate.
Data: CORDIS, © European Union
Project objective
Beginning life as simple symmetric spheres, neurons undergo a complicated morphogenesis until they become integrated in functional neuronal networks. A neurons development involves migration, neuritogenesis, polarization, and axon guidance. Each of these processes relies heavily on the reorganization of the underlying cytoskeleton. From cultured neurons and invertebrates, progress has been made in identifying signalling proteins that modulate the cytoskeleton during different stages of neuronal development. Despite the progress, questions remain regarding the physiological relevance of these molecules during neuronal development in mammals. ADF/cofilin proteins (AC proteins) have been implicated in regulating actin during various phases of neuronal development. Here, we outline our plans to study the role of AC proteins during in vivo development and in regulating actin dynamics during neurite formation using the brain-specific double knockout of ADF/Cofilin in mice. These studies will provide a greater understanding of the specific role of AC proteins during neuronal development and reveal how the organization and kinetics of actin changes during neurite formation and growth. Specifically, this work will: 1) characterize the developmental consequences of AC ablation in vivo, ex vivo and in culture, 2) determine what changes occur to the actin cytoskeleton with and without AC proteins during neuritogenesis, and 3) determine the genetic relationships of AC proteins during neurite formation. The proposed work will entail a multi-directional transfer of knowledge in advancing the conceptual understanding of neuronal development and in sharing technical expertise to and from the proposed fellow, the host institution, and the European Neuroscience community at large. The work is highly significant because it will elucidate mechanisms underlying brain development, an important issue at the intersection of cell and developmental biology and neurobiology.
Original text from CORDIS.
Participants
- MAX-PLANCK-GESELLSCHAFT ZUR FORDERUNG DER WISSENSCHAFTEN EV · MUNCHENCoordinatorGermany
Links
Data: CORDIS, © European Union