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Regulating Filopodial Dynamics Through Actin-Depolymerizing Factor

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Regulating Filopodial Dynamics Through Actin-Depolymerizing Factor Anatomical Science International (2004) 79, 173–183 SpecialBlackwell Publishing, Ltd. Review Based on a Presentation made at the 16th International Congress of the IFAA Regulating filopodial dynamics through actin-depolymerizing factor/cofilin Joseph Fass,1 Scott Gehler,2 Patrick Sarmiere,1 Paul Letourneau2 and James R. Bamburg1 1 Department of Biochemistry and Molecular Biology, Colorado State University, Fort Collins, Colorado and 2 Department of Neuroscience, University of Minnesota, Minneapolis, Minnesota, USA Abstract The regulation of filopodial dynamics by neurotrophins and other guidance cues plays an integral role in growth cone pathfinding. Filopodia are F-actin-based structures that explore the local environment, generate forces and play a role in growth cone translocation. Here, we review recent research showing that the actin-depolymerizing factor (ADF)/cofilin family of proteins mediates changes in the length and number of growth cone filopodia in response to brain-derived neurotrophic factor (BDNF). Although inhibition of myosin contractility also causes filopodial elongation, the elongation in response to BDNF does not occur through a myosin-dependent pathway. Active ADF/cofilin increases the rate of cycling between the monomer and polymer pools and is critical for the BDNF-induced changes. Thus, we discuss potential mechanisms by which ADF/cofilin may affect filopodial initiation and length change via its effects on F-actin dynamics in light of past research on actin and myosin function in growth cones. Key words: actin-depolymerizing factor, cofilin, filopodia, growth cone. Introduction processes; growth cone morphology and the behavior of its actin and microtubule cytoskeletal structures Neuronal growth cones rely on dynamic filopodia is modified downstream of guidance molecules to explore their surroundings, as well as for force (Gallo et al., 1997; Gallo & Letourneau, 2004; Zhou generation related to motility (Heidemann et al., & Cohan, 2004) and axonal collateral branching 1990). Filopodia are generally short (0.5 to several (following extensive filopodial sprouting) can result µm) membranous protrusions containing a core of from contact with beads coated with nerve growth colinear, bundled F-actin filaments, but also contain factor (NGF; Gallo & Letourneau, 1998). In addition, den- myosin and components of focal contacts (Bridgman dritic filopodia are precursors to dendritic spines, & Dailey, 1989; Steketee & Tosney, 2002). The F-actin post-synaptic structures whose diverse and dynamic in filopodial bundles is cross-linked with fascin (Cohan morphology is thought to underlie learning and mem- et al., 2001) and is very stable, having a half-life ory (Sala, 2002). Neurotrophins have been implicated more than 10-fold longer (approximately 25 min) in modulating the formation and morphology of both than lamellipodial F-actin (Mallavarapu & Mitchison, dendritic filopodia and spines (Shimada et al., 1998; 1999). Matsutani & Yamamoto, 2004). Furthermore, a point Regulation of filopodia in neurons is important mutation that impairs secretion of the neurotrophin for both growth cone guidance and neurite branch brain-derived neurotrophic factor (BDNF) is corre- formation, both of which determine the ultimate lated with hippocampal functional impairment in arborization and connectivity in the nervous system humans and animals and plasticity impairment in (Goodman & Shatz, 1993; Gallo & Letourneau, 1999). hippocampal cell culture models (Egan et al., 2003; Contact with guidance cues directs both of these Hariri et al., 2003), providing a potential link between filopodial regulation and adult cognitive function. Growth cone filopodia explore their local environ- Correspondence: James R. Bamburg, Department of ment via extension, waving and retraction. When Biochemistry & Molecular Biology, 1870 Campus Delivery, Colorado State University, Fort Collins, CO 80523-1870, USA. adhered at their tips, they can exert a pulling force Email: [email protected] (Heidemann et al., 1990; Smith, 1994; Suter et al., Presented at the 16th International Congress of the IFAA, held 1998; Suter & Forscher, 2000) that can either move at the International Conference Hall, Kyoto, 22–27 August 2004. attached objects (such as beads or other neurite Received 3 September 2004; accepted 13 September 2004. shafts) rearwards towards the growth cone or pull 174 J. Fass et al. material from the growth cone central region antero- of F-actin, active AC proteins can participate in gradely, resulting in engorgement of the filopodium enhancing the rate of cycling, or turnover, between and advance of the growth cone along the path of G- and F-actin in many systems (Carlier et al., 1997; the filopodium (Goldberg & Burmeister, 1986; Smith, Lappalainen & Drubin, 1997; Rosenblatt et al., 1997; 1994; Letourneau, 1996). Engorgement of a filopo- Theriot, 1997), including within neuronal growth cones dium into a neurite is a proposed mechanism for (Meberg & Bamburg, 2000). interactions with guidepost cells during grasshopper How might AC proteins be involved specifically in pioneer axon extension (Sabry et al., 1991) and has filopodial regulation? Recently, Gehler et al. (2004a) been observed during interactions between Aplysia demonstrated that BDNF signals in retinal ganglion growth cones and restrained (immobilized) Aplysia growth cones by inhibiting Rho GTPase. Working cell adhesion molecule (apCAM)-coated beads downstream of Rho, Gehler et al. have found that (Suter et al., 1998), as well as between chick sym- BDNF effects on filopodia are mediated through pathetic neuron growth cones and other cells or modulation of AC protein activity and, although myosin beads coated with polyornithine or laminin (Smith, II-dependent alterations in filopodia length can occur 1994). This filopodial behavior seems analogous to in these growth cones, BDNF does not work through the entire growth cone, in which there is an inverse modulating myosin II activity (Gehler et al., 2004b). relationship between retrograde flow and growth These experiments will be reviewed first and we will cone advance (Lin & Forscher, 1995). This relation- then address their potential implications for how AC ship has led to a model for forward motility whereby proteins may function in filopodial initiation, extension a cellular process will either be retracted at some and retraction. time after protrusion or adhere to some stable substrate, allowing the same forces that would have AC regulation of filopodia caused retraction to result in forward movement of more proximal cellular components. Generation of Gehler et al. previously demonstrated that BDNF pulling force is dependent upon motor proteins (for binding to the p75 neurotrophin receptor (p75NTR) a review, see Brown & Bridgman, 2004), presumably enhances filopodial length by decreasing the activity isoforms of myosin attached to actin filaments with of RhoA (Gehler et al., 2004a). Their results showed opposite orientations (Wylie et al., 1998; Bridgman that several neurotrophins (BDNF, nerve growth et al., 2001; Wylie & Chantler, 2001; Bridgman, factor (NGF), and neurotrophin (NT)-3) cause increases 2002; Brown & Bridgman, 2003b). However, it is as in filopodial length in chick retinal, dorsal root yet unclear which specific isoforms of myosin are ganglion (DRG) and ciliary growth cones (Gehler involved directly in filopodial retraction or, for that et al., 2004a). Furthermore, these length changes were matter, engorgement. mimicked and pre-empted by treatment with either Nevertheless, filopodial behavior is not simply of two p75-specific antibodies: CHEX and AB1554. the result of motor-based rearrangement of static Neurotrophin-induced filopodial length changes were actin structures. F-actin throughout the growth cone not observed in growth cones of p75–/– mouse retinal is constantly turning over, via polymerization at the or DRG neurons, yet these growth cones had longer leading edge, retrograde flow of F-actin and depo- filopodia, similar to neurotrophin-treated p75+/+ growth lymerization within the transitional zone (Forscher & cones, implicating unoccupied p75NTR in downregu- Smith, 1988; Lin & Forscher, 1995; Welnhofer et al., lation of filopodial length. Finally, both p75–/– and 1997; Schaefer et al., 2002). One of the major agents BDNF-treated neurons displayed reduced levels of responsible for this turnover is the actin-depolymerizing RhoA activity. More recent experiments have dis- factor (ADF)/cofilin (AC) family of proteins (reviewed sected the signaling downstream of Rho, beginning by Sarmiere & Bamburg, 2004). The AC proteins with the rho-associated coiled-coil kinase (ROCK), bind preferentially to F-actin on which the associated also called Rho kinase (ROK) or Rho-associated ATP has been hydrolyzed to ADP (Carlier et al., 1997) kinase (Gehler et al., 2004b). and promote both severing of filaments (Bamburg Rho-associated kinase is well characterized as et al., 1999; Ichetovkin et al., 2000, 2002) and depo- an upregulator of myosin II-dependent contractility lymerization from the pointed end. Once in the mon- in non-muscle cells (e.g. Hirose et al., 1998) that acts omer state, profilin induces a rapid exchange of through either direct activation of myosin light chain ATP for ADP on the G-actin and, because AC proteins kinase or inhibition of the phosphatase that removes preferentially bind ADP–actin monomers, they are the phosphate from the light chain (Amano et al., free to recycle to F-actin to repeat their dynamizing 1996; Kimura et al., 1996). In addition,
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