Myosin X and its motorless isoform differentially modulate dendritic spine development by regulating trafficking and retention of vasodilator-stimulated phosphoprotein

Abstract

SummaryMyosin X (Myo10) is an unconventional myosin with two known isoforms: full-length (FL)-Myo10 that has motor activity, and a recently identified brain-expressed isoform, headless (Hdl)-Myo10, which lacks most of the motor domain. FL-Myo10 is involved in the regulation of filopodia formation in non-neuronal cells; however, the biological function of Hdl-Myo10 remains largely unknown. Here, we show that FL-and Hdl-Myo10 have important, but distinct, roles in the development of dendritic spines and synapses in hippocampal neurons. FL-Myo10 induces formation of dendritic filopodia and modulates filopodia dynamics by trafficking the actin-binding protein vasodilator-stimulated phosphoprotein (VASP) to the tips of filopodia. By contrast, Hdl-Myo10 acts on dendritic spines to enhance spine and synaptic density as well as spine head expansion by increasing the retention of VASP in spines. Thus, this study demonstrates a novel biological function for Hdl-Myo10 and an important new role for both Myo10 isoforms in the development of dendritic spines and synapses.

Dopamine transporter is enriched in filopodia and induces filopodia formation

“…5A), although a significant amount of immunofluorescence staining remained in the perinuclear areas of the cells. Since “headless” splicing form of MyoX (Lin et al, 2013) was not detected in PAE cells, the intracellular immunofluorescence in siRNA transfected cells is likely due to non-specific antibody binding. Analysis of multiple 3D images of YFP-HA-DAT and RFP-HA-DAT expressing cells showed that many MyoX-depleted cells were devoted of both peripheral and dorsal filopodia containing DAT (Fig.…”

“…Membrane bending by an I-BAR-domain-containing IRSp53 protein together with actin polymerization regulated by cdc42 are thought to be involved in the initial stages of filopodia formation, although cdc42 is not necessary for all types of filopodia (Mattila and Lappalainen, 2008; Sigal et al, 2007; Yang et al, 2009). VASP was proposed to regulate actin polymerization at the barbed ends of actin filaments to allow the extension of the filopodium, and it was proposed that MyoX is responsible for the delivery of VASP to the filopodium tip complex (Lin et al, 2013; Tokuo and Ikebe, 2004). However, formation of DAT-enriched filopodia did not absolutely require VASP and MyoX.…”

“…It is possible that the function of MyoX in growth cones is different from its function as an organizer of the filopodia tip complex. It is also possible that a headless form of MyoX (Lin et al, 2013) is predominantly expressed in postnatal DA neurons. Finally, limitations in the specificity of MyoX antibodies (all commercially available antibodies were tested) may have prevented the detection of MyoX at the filopodia tips in DA neurons.…”

Tracking the Fragile X Mental Retardation Protein in a Highly Ordered Neuronal RiboNucleoParticles Population: A Link between Stalled Polyribosomes and RNA Granules

“…Myo5a is required for the transport of FMRP mRNP [ 63 ] and associates with mRNP present in peripheral axons [ 64 ]. Myosin 10 is a motor involved in the formation of filopodia and development of dendritic spines and synapses in hippocampal neurons [ 65 ]. These data suggest that individual granules may be carried by different motors cooperating for their transport in the neuronal arborization [ 66 , 67 ].…”

The myosin X motor is optimized for movement on actin bundles

“…In fact, the motor activity of myosin X dimers even without the cargo-binding domain is sufficient for the initiation of filopodia 4 . Its unique ability to form these actin outgrowths allows myosin X to perform such functions as driving neuron extensions 2 5 6 , tumor invasion 7 8 9 10 11 , wound healing 9 and a subset of pathogen infections 9 . Thus, understanding the unique adaptations of this myosin class that enable its unique functions will provide fundamental insights into important cellular processes.…”