title: GEFT, A Rho family guanine nucleotide exchange factor, regulates lens differentiation through a Rac1-mediated mechanism.
abstract: The Rho-family of small GTPase specific guanine nucleotide exchange factor, GEFT, is expressed at high levels in adult human excitable tissues including the brain, heart, and skeletal muscle. Previously, we demonstrated that GEFT is specifically expressed in the adult mouse hippocampus and cerebellum, and that overexpression of this protein can result in neurite and dendrite remodeling. This finding prompted us to explore the expression of GEFT in other tissues, which share common developmental ancestry to the nervous system, specifically the ocular system. Using immunohistochemical analysis specific for GEFT protein expression, we observed the highest ocular expression of GEFT occurring in the neuroblastic layer and differentiating lens fibers of the late-stage mouse embryo, and in the postnatal corneal epithelium, lens epithelium, and throughout the retina. Exogenous expression of GEFT in N/N1003A rabbit lens epithelial cells induced lens fiber differentiation as reflected by cell elongation and lentoid formation, as well as a strong increase in β-crystallin and filensin expression. Moreover, transfection of lens epithelial cells with GEFT resulted in a Rac-1 mediated up-regulation of αA-, αB-, βB-, γC-, or γF-crystallin promoter activities that is in part dependent on the nuclear localization of Rac1. Furthermore, pharmacological inhibition of Rac1 blocked GEFT-induced N/N1003A lens fiber differentiation and βB-crystallin expression in ex vivo mouse lens explants. These results demonstrate for the first time a role for GEFT in lens cell differentiation and mouse eye development. Moreover, GEFT regulation of lens differentiation and eye development occurs through a Rac1-dependent mechanism.
authors.affiliation: Institute of Biosciences and Technology, and Department of Molecular and Cellular Medicine, Texas A&M University Health Science Center, Houston, USA.
authors.forename: D C
authors.initials: DC
authors.lastname: Mitchell
authors.forename: B A
authors.initials: BA
authors.lastname: Bryan
authors.forename: L
authors.initials: L
authors.lastname: Liu
authors.forename: X-H
authors.initials: XH
authors.lastname: Hu
authors.forename: X-Q
authors.initials: XQ
authors.lastname: Huang
authors.forename: W-K
authors.initials: WK
authors.lastname: Ji
authors.forename: P-C
authors.initials: PC
authors.lastname: Chen
authors.forename: W-F
authors.initials: WF
authors.lastname: Hu
authors.forename: J-P
authors.initials: JP
authors.lastname: Liu
authors.forename: J
authors.initials: J
authors.lastname: Zhang
authors.forename: M
authors.initials: M
authors.lastname: Liu
authors.forename: D W-C
authors.initials: DW
authors.lastname: Li
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002460:Cell Line; D003459:Crystallins / Q000235:genetics / Q000378:metabolism; D019573:Epithelium, Corneal / Q000166:cytology / Q000254:growth & development / Q000378:metabolism; D005136:Eye Proteins / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics* / Q000378:metabolism*; D007381:Intermediate Filament Proteins / Q000378:metabolism; D007908:Lens, Crystalline / Q000166:cytology* / Q000196:embryology* / Q000254:growth & development; D051379:Mice; D008810:Mice, Inbred C57BL; D009479:Neuropeptides / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011817:Rabbits; D012160:Retina / Q000166:cytology / Q000254:growth & development / Q000378:metabolism; D064067:Rho Guanine Nucleotide Exchange Factors; D015398:Signal Transduction; D015854:Up-Regulation; D020744:rac GTP-Binding Proteins / Q000378:metabolism*; D020830:rac1 GTP-Binding Protein
chemical_list: D003459:Crystallins; D005136:Eye Proteins; C577427:GEFT protein, mouse; D020662:Guanine Nucleotide Exchange Factors; D007381:Intermediate Filament Proteins; D009479:Neuropeptides; C484602:Rac1 protein, mouse; D064067:Rho Guanine Nucleotide Exchange Factors; C079098:filensin; D020744:rac GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein