Abstract/Details

Roles of dynein and dynactin in cell migration and disease


2008 2008

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Abstract (summary)

The minus-end directed microtubule motor cytoplasmic dynein is critical for diverse cellular processes such as spindle formation and axonal transport. Here, roles for dynein in cell migration and neuronal disease were studied. Dynein has a role in driving the polarization of the microtubule cytoskeleton upon stimulation of fibroblast migration, and recent evidence suggests that dynein has a second role in motility after establishment of polarity. Here, the mechanism by which dynein contributes to directed migration was examined. Knockdown of dynein slows protrusion of the leading edge and causes defects in nuclear movements. Both forward movement of the nucleus, as well as stochastic movements that center the nucleus in the cell, are reduced in dynein knockdown cells. In control cells, wounding the monolayer stimulates a dramatic induction of nuclear rotations at the wound edge. These rotations are significantly inhibited in dynein knockdown cells. Surprisingly, nuclear rotations are not accompanied by rotation of the centrosome, which remains stably positioned between the nucleus and the leading edge. Together, these results suggest that dynein contributes to migration in two ways: (1) maintaining centrosome centrality by tethering microtubule ends at the cortex, and (2) maintaining nuclear centrality by asserting force directly on the nucleus. Although dynein is ubiquitously expressed with roles in migration as well as many other cell processes, a newly-identified G59S mutation in the p150Glued subunit of the dynein activator dynactin results in motor neuron degeneration in a human kindred. This mutation lowers the affinity of p150Glued for two key binding proteins, tubulin and EB1. Cell lines from patients are morphologically normal but show delayed recovery after nocodazole treatment, consistent with a subtle disruption of dynein/dynactin function. The G59S mutation disrupts the folding of the microtubule-binding domain, resulting in aggregation of the p150Glued protein, which is accompanied by an increase in cell death in a motor neuron cell line. Overexpression of the chaperone Hsp70 inhibits aggregate formation and prevents cell death. These data support a model in which a point mutation in p150Glued causes both loss of dynein/dynactin function and gain of toxic function, which together lead to motor neuron cell death.

Indexing (details)


Subject
Cellular biology
Classification
0379: Cellular biology
Identifier / keyword
Biological sciences; Cell migration; Dynactin; Dynein; Microtubules
Title
Roles of dynein and dynactin in cell migration and disease
Author
Levy, Jennifer Rachel
Number of pages
175
Publication year
2008
Degree date
2008
School code
0175
Source
DAI-B 69/04, Dissertation Abstracts International
Place of publication
Ann Arbor
Country of publication
United States
ISBN
9780549574293
Advisor
Holzbaur, Erika
University/institution
University of Pennsylvania
University location
United States -- Pennsylvania
Degree
Ph.D.
Source type
Dissertations & Theses
Language
English
Document type
Dissertation/Thesis
Dissertation/thesis number
3309468
ProQuest document ID
304492413
Copyright
Database copyright ProQuest LLC; ProQuest does not claim copyright in the individual underlying works.
Document URL
http://search.proquest.com/docview/304492413
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