Keratinocyte migration in the developing eyelid requires LIMK2.
In vitro studies have identified LIMK2 as a key downstream effector of Rho GTPase-induced changes in cytoskeletal organization. LIMK2 is phosphorylated and activated by Rho associated coiled-coil kinases (ROCKs) in response to a variety of growth factors. The biochemical targets of LIMK2 belong to a family of actin binding proteins that are potent modulators of actin assembly and disassembly. Although numerous studies have suggested that LIMK2 regulates cell morphology and motility, evidence supportive of these functions in vivo has remained elusive. In this study, a knockout mouse was created that abolished LIMK2 biochemical activity resulting in a profound inhibition of epithelial sheet migration during eyelid development. In the absence of LIMK2, nascent eyelid keratinocytes differentiate and acquire a pre-migratory phenotype but the leading cells fail to nucleate filamentous actin and remain immobile causing an eyes open at birth (EOB) phenotype. The failed nucleation of actin was associated with significant reductions in phosphorylated cofilin, a major LIMK2 biochemical substrate and potent modulator of actin dynamics. These results demonstrate that LIMK2 activity is required for keratinocyte migration in the developing eyelid.
Lexicon Pharmaceuticals Incorporated, The Woodlands, TX, USA. drice@lexpharma.com
Dennis S
DS
Rice
Gwenn M
GM
Hansen
Feng
F
Liu
Mike J
MJ
Crist
Matthew M
MM
Newhouse
David
D
Potter
Nianhua
N
Xu
Alejandro
A
Abuin
Peter J
PJ
Vogel
Brian P
BP
Zambrowicz
D000199:Actins / Q000378:metabolism; D000818:Animals; D002465:Cell Movement / Q000235:genetics*; D005143:Eyelids / Q000166:cytology* / Q000196:embryology / Q000473:pathology; D005838:Genotype; D015603:Keratinocytes / Q000166:cytology*; D054461:Lim Kinases / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D010766:Phosphorylation
D000199:Actins; D054461:Lim Kinases; C095325:Limk2 protein, mouse