Final Report Summary - AC BREAKS THE SPHERE (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.
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.