DESCRIPTION (provided by applicant): One of the basic principles of cerebral cortical development is that its constituent neurons are generated in proliferative zones that are located at a distance from their positions in the adult brain. The intervening process of radially-directed neuronal cell migration involves dislocation of postmitotic neurons from other cellular elements in the proliferative zone and active movement of these undifferentiated neurons along a scaffolding of radial glial cell fibers. Extensive imaging studies, both in vitro and in vivo, reveal that migrating neuronal cells display two phases of directed movement: outgrowth of the leading process and nuclear/somal translocation. Each aspect of movement is accompanied by extensive rearrangement of the cytoskeleton. Subsequent differentiation of dendritic and axonal processes also rely upon reorganization of the cytoskeleton. Significantly, independent genetic cloning studies have implicated deficiencies in the regulation of both actin and microtubule dynamics to impaired neuronal cell migration. Myosins comprise a superfamily of proteins that use the energy obtained from the hydrolysis of adenosine triphosphate (ATP) to generate directed mechanical force along the actin cytoskeleton. Myosins have been implicated in a wide spectrum of intracellular processes, in addition to the more classically defined functions such as cytokinesis, muscle contractility, and cell locomotion. As a step toward understanding the process of neuronal cell locomotion, we undertook studies directed toward the identification and characterization of unconventional myosins that could participate in neuronal cell migration and/or differentiation events within the developing mammalian brain. Our analyses identified a novel unconventional myosin, which we cloned, sequenced, and designated myr 8 (8th unconventional myosin from rat). Myr 8 is expressed predominantly in the nervous system and is detected principally at developmental timeperiods. Structurally, the head domain of myr 8 contains a large N-terminal extension composed of multiple ankyrin repeats, which we have implicated in the binding of protein phosphatase catalytic subunits PP1a and PP1g. The motor domain is followed by a single light chain binding domain. The tail domain comprises two splice variants, neither of which are predicted to display extensive a-helical coiled-coil structure. Phylogenetic analysis indicates that myr 8 is sufficiently divergent from known myosins as to comprise a new class of myosins, class XVI. Given the increasing identification and significance of neuronal migration disorders and other neurological dysfunctions that arise as a consequence of defective myosins, as well as from other cytoskeletal components, it is essential to unravel the selective roles that this novel unconventional myosin may play during brain development.
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