Activation of ezrin/radixin/moesin mediates attractive growth cone guidance through regulation of growth cone actin and adhesion receptors

• Published in: The Journal of neuroscience Vol. 32; no. 1; pp. 282 - 296
• Main Authors: Marsick, Bonnie M, San Miguel-Ruiz, Jose E, Letourneau, Paul C
• Format: Journal Article
• Language: English
• Published: United States Society for Neuroscience 04.01.2012
• Subjects: Actins - metabolism; Animals; Chick Embryo; Chickens; Cytoskeletal Proteins - antagonists & inhibitors; Cytoskeletal Proteins - genetics; Cytoskeletal Proteins - metabolism; Female; Ganglia, Spinal - cytology; Ganglia, Spinal - embryology; Growth Cones - drug effects; Growth Cones - metabolism; Growth Cones - ultrastructure; Male; Membrane Proteins - antagonists & inhibitors; Membrane Proteins - genetics; Membrane Proteins - metabolism; Microfilament Proteins - antagonists & inhibitors; Microfilament Proteins - genetics; Microfilament Proteins - metabolism; Primary Cell Culture; Sensory Receptor Cells - cytology; Sensory Receptor Cells - drug effects; Sensory Receptor Cells - metabolism
• ISSN: 0270-6474; 1529-2401
• DOI: 10.1523/jneurosci.4794-11.2012

The development of a functioning neural network relies on responses of axonal growth cones to molecular guidance cues that are encountered en route to their target tissue. Nerve growth factor (NGF) and neurotrophin-3 serve as attractive cues for chick embryo sensory growth cones in vitro and in vivo, but little is known about the actin-binding proteins necessary to mediate this response. The evolutionarily conserved ezrin/radixin/moesin (ERM) family of proteins can tether actin filaments to the cell membrane when phosphorylated at a conserved threonine residue. Here we show that acute neurotrophin stimulation rapidly increases active phospho-ERM levels in chick sensory neuron growth cone filopodia, coincident with an increase in filopodial L1 and β-integrin. Disrupting ERM function with a dominant-negative construct (DN-ERM) results in smaller and less motile growth cones with disorganized actin filaments. Previously, we found that NGF treatment increases actin-depolymerizing factor (ADF)/cofilin activity and growth cone F-actin (Marsick et al., 2010). Here, we show this F-actin increase, as well as attractive turning to NGF, is blocked when ERM function is disrupted despite normal activation of ADF/cofilin. We further show that DN-ERM expression disrupts leading edge localization of active ADF/cofilin and free F-actin barbed ends. Moreover, filopodial phospho-ERM levels are increased by incorporation of active ADF/cofilin and reduced by knockdown of L1CAM.Together, these data suggest that ERM proteins organize actin filaments in sensory neuron growth cones and are crucial for neurotrophin-induced remodeling of F-actin and redistribution of adhesion receptors.