MYR 8 : the first member of a novel myosin class is expressed during brain development

Abstract

Neuronal cell migration and cellular differentiation, major phases in the assembly process of the mammalian neocortex, involve considerable organelle and cellular motility. While the cytoskeletal organization of migrating neurons is well documented, and the involvement of the cytoskeleton in modulating intracellular membrane transport events during neuronal cell differentiation is well appreciated, identification of selective cytoskeletal components underlying these· processes is only beginning to emerge. Observations over the past two decades reveal that myosin motors are involved intimately in multiple actin-dependent membrane movements, including vesicular trafficking, organelle localization and organization, endocytosis, exocytosis, phagocytosis, lamellopodial extension, and the more classically defined functions such as cytokinesis, contractility, and cell motility or migration. Accordingly, our studies have been directed toward the identification and characterization of unconventional myosins that may participate in neuronal cell migration and/or differentiation events within the developing manlinalian brain. Our analyses identified two myosin isoforms that contribute to a novel unconventional myosin class. We have cloned, sequenced, and designated these myosin isoforms as myr Sa and Sb (S,. unconventional myosin from rat). Structurally, the head domain of myr & contains a large N-terminal extension composed of multiple ankyrin repeats similar to· myosin phosphatase. The motor domain is followed by a single putative light chain binding domain. The tail domain of myr Sa is comparatively short with a net positive charge, whereas the elongated tail domain of myr Sb bears an overall neutral charge and reveals several streches of poly-proline residues. Phylogenetic analysis indicates that myr 8 is sufficiently divergent from known myosins as to comprise a new class of myosins. Northern. analyses demonstrate that the myr 8 myosins are expressed predominantly in the nervous system, and are detected principally at developmental timeperiods. Indirect-immunofluorescent studies reveal a pattern of irmnunoreactivity within forming neuronal and astroglial cell processes located throughout the ·developing brain. Taken together these data suggest that this novel myosin may play a crucial role in membrane biogenetic events during neuronal and astroglial cell differentiation. Given the increasing identification of 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 in which this novel unconventional myosin may participate during neocortical development.