Linked Life Data

19109949

Source:http://linkedlifedata.com/resource/pubmed/id/19109949

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
3
pubmed:dateCreated
2009-3-13
pubmed:abstractText
Despite the magnitude of the problem, no effective treatments exist to prevent retinal ganglion cell (RGC) death and optic nerve degeneration from occurring in diseases affecting the human eye. Animal models currently available for developing treatment strategies suffer from cumbersome procedures required to induce RGC death or rely on mutations that induce defects in developing retinas rather than in mature retinas of adults. Our objective was to develop a robust genetically engineered adult mouse model for RGC loss and optic nerve degeneration based on genetic ablation. To achieve this, we took advantage of Pou4f2 (Brn3b), a gene activated immediately as RGCs begin to differentiate and expressed throughout life. We generated adult mice whose genomes harbored a conditional Pou4f2 allele containing a floxed-lacZ-stop-diphtheria toxin A cassette and a CAGG-Cre-ER transgene. In this bigenic model, Cre recombinase is fused to a modified estrogen nuclear receptor in which the estrogen-binding domain binds preferentially to the estrogen agonist tamoxifen rather than to endogenous estradiol. Upon binding to the estrogen-binding domain, tamoxifen derepresses Cre recombinase, leading to the efficient genomic deletion of the floxed-lacZ-stop DNA sequence and expression of diphtheria toxin A. Tamoxifen administered to adult mice at different ages by intraperitoneal injection led to rapid RGC loss, reactive gliosis, progressive degradation of the optic nerve over a period of several months, and visual impairment. Perhaps more reflective of human disease, partial loss of RGCs was achieved by modulating the tamoxifen treatment. Especially relevant for RGC death and optic nerve degeneration in human retinal pathologies, RGC-ablated retinas maintained their structural integrity, and other retinal neurons and their connections in the inner and outer plexiform layers appeared unaffected by RGC ablation. These events are hallmarks of progressive optic nerve degeneration observed in human retinal pathologies and demonstrate the validity of this model for use in developing stem cell therapies for replacing dead RGCs with healthy ones.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Mar
pubmed:issn
1096-0007
pubmed:author
pubmed:issnType
Electronic
pubmed:volume
88
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
542-52
pubmed:meshHeading
pubmed-meshheading:19109949-Animals, pubmed-meshheading:19109949-Cell Death, pubmed-meshheading:19109949-Diphtheria Toxin, pubmed-meshheading:19109949-Disease Models, Animal, pubmed-meshheading:19109949-Disease Progression, pubmed-meshheading:19109949-Dose-Response Relationship, Drug, pubmed-meshheading:19109949-Gene Deletion, pubmed-meshheading:19109949-Gliosis, pubmed-meshheading:19109949-Homeodomain Proteins, pubmed-meshheading:19109949-Mice, pubmed-meshheading:19109949-Mice, Inbred C57BL, pubmed-meshheading:19109949-Mice, Transgenic, pubmed-meshheading:19109949-Nerve Degeneration, pubmed-meshheading:19109949-Optic Nerve, pubmed-meshheading:19109949-Optic Nerve Diseases, pubmed-meshheading:19109949-Peptide Fragments, pubmed-meshheading:19109949-Retina, pubmed-meshheading:19109949-Retinal Ganglion Cells, pubmed-meshheading:19109949-Tamoxifen, pubmed-meshheading:19109949-Transcription Factor Brn-3B, pubmed-meshheading:19109949-Visual Acuity
pubmed:year
2009
pubmed:articleTitle
Retinal ganglion cell death and optic nerve degeneration by genetic ablation in adult mice.
pubmed:affiliation
Department of Biochemistry and Molecular Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural