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DEANNA S. SMITH, Ph.D.
Hebbar, S, Guillotte, A, Mesngon, M, Zhou, Q, Wynshaw-Boris, A, Smith, Deanna S. (In Press) The APC+/min genotype sensitizes mice to the effect of Lis1 heterozygosity. Developmental Neuroscience.
Willis, DE, van Niekerk, EA Sasaki, Y, Mesngon, M, Merianda, TT, Williams, GG, Kendall, M, Deanna S. Smith, Bassell, GJ, Twiss, JL. (In Press) Extracellular stimuli specifically regulate localized levels of individual neuronal mRNAs. Journal of Cell Biology
Mesngon MT, Tarricone C, Hebbar S, Guillotte AM, Schmitt EW, Lanier L, Musacchio A, King SJ, Smith, Deanna, S. (2006). Regulation of cytoplasmic dynein ATPase by Lis1. J Neuroscience. 26(7):2132-9.
Smith
DS, Tsai LH. Cdk5 behind the wheel: a role in trafficking
and transport? Trends Cell Biol. 2002 Jan;12(1):28-36.
Review.
Cdk5, a serine/threonine kinase in the
cyclin-dependent kinase (Cdk) family, is an important
regulator of neuronal positioning during brain development.
Cdk5 might also play a role in synaptogenesis and
neurotransmission. Loss of Cdk5 in mice is perinatal lethal,
and overactive Cdk5 induces apoptosis in cultured cells,
indicating that strict regulation of kinase activity is
crucial. Indeed, activity depends on the stability of
activating partners, subcellular localization and the
phosphorylation state of the enzyme itself. Deregulated
kinase activity has been linked to neurodegenerative
diseases such as Alzheimer's disease (AD) and amyotrophic
lateral sclerosis (ALS). This review focuses on links
between Cdk5 activity and components of cytoskeletal,
membrane and adhesion systems that allow us to postulate a
role for Cdk5 in directing intracellular traffic in neurons.
Smith DS, Tsai L-H. Cdk5 on the brain.
2001 Cell Growth and Diff. 12, 277-283.
Mammalian brains are highly
compartmentalized into groups of functionally specialized
neurons. Cell migration and neurite outgrowth must be
tightly orchestrated to achieve this level of organization.
A small serine/threonine kinase that shows homology to
cyclin-dependent kinases (Cdks) has emerged as an important
regulator of neuronal migration. Cdk5, unlike other Cdks, is
not regulated by cyclins, and its activity is primarily
detected in postmitotic neurons in developing and adult
nervous systems. This review describes work indicating that
Cdk5 links extracellular signaling pathways and cytoskeletal/membrane
systems to direct neuronal migration, axon growth, and
possibly neurosecretion. Despite its importance, unchecked
Cdk5 activity is toxic to neurons, and may underlie some of
the pathologies associated with neurodegenerative disorders
such as Alzheimer’s disease and amyotrophic lateral
sclerosis.
Smith DS, Niethammer M, Ayala R, Zhou
Y, Gambello MJ, Wynshaw-Boris A, and Tsai L-H. Regulation of
cytoplasmic dynein behaviour and microtubule organization by
mammalian Lis1. 2000 Nature Cell Biology 2, 767-775.
Whereas total loss of Lis1 is lethal,
disruption of one allele of the Lis1 gene results in brain
abnormalities, indicating that developing neurons are
particularly sensitive to a reduction in Lis1 dosage. Here
we show that Lis1 is enriched in neurons relative to levels
in other cell types, and that Lis1 interacts with the
microtubule motor cytoplasmic dynein. Production of more
Lis1 in non-neuronal cells increases retrograde movement of
cytoplasmic dynein and leads to peripheral accumulation of
microtubules. These changes may reflect neuron-like dynein
behaviours induced by abundant Lis1. Lis1 deficiency
produces the opposite phenotype. Our results indicate that
abundance of Lis1 in neurons may stimulate specific dynein
functions that function in neuronal migration and axon
growth.
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