Aberrant actin cytoskeleton leads to accelerated proliferation of corneal epithelial cells in mice deficient for destrin (actin depolymerizing factor).
Corneal disease is the most common cause of bilateral blindness in the world. Visual loss in this condition is often due to changes in morphology and function of the corneal epithelial surface. Corneal disease-1 (corn1) and corn1(2J) are spontaneous mouse mutants that develop irregular thickening of the corneal epithelium, similar to that observed in human corneal surface disease. These autosomal-recessive mutations cause an increase in the rate of proliferation of the corneal epithelial cells. Here, we report that the phenotypes in both mutants are caused by mutations within the destrin gene (also known as actin-depolymerizing factor). By positional cloning, we identified a deletion encompassing the entire coding sequence of the destrin gene in corn1 mice, and a point mutation (Pro106Ser) in the coding sequence of destrin in corn1(2J) mice. In situ analysis showed that destrin is highly expressed in the corneal epithelium. Consistent with the cellular roles for destrin, an essential regulator of actin filament turnover that acts by severing and enhancing depolymerization of actin filament, we observed that the corn1 mutations increased the content of filamentous actin in corneal epithelial cells. Our results suggest an in vivo connection between remodeling of the actin cytoskeleton and the control of cell proliferation, and a new pathway through which an aberrant actin cytoskeleton can cause epithelial hyperproliferation.
Ikeda
Sakae
S
The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609, USA.
Cunningham
Leslie A
LA
Boggess
Dawnalyn
D
Hawes
Norman
N
Hobson
Craig D
CD
Sundberg
John P
JP
Naggert
Jürgen K
JK
Smith
Richard S
RS
Nishina
Patsy M
PM
D051339:Actin Depolymerizing Factors; D000199:Actins / Q000378:metabolism*; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D002455:Cell Division / Q000502:physiology*; D003315:Cornea / Q000378:metabolism*; D003598:Cytoskeletal Proteins; D003599:Cytoskeleton / Q000378:metabolism*; D051345:Destrin; D004848:Epithelium / Q000378:metabolism; D051379:Mice; D017384:Sequence Deletion
D051339:Actin Depolymerizing Factors; D000199:Actins; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; C495824:DSTN protein, human; D051345:Destrin; C495825:Dstn protein, mouse