Molecular Mechanisms of Neuronal Cell Migration

Project: Research project

Project Details


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.
StatusNot started


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