title: Loss ofIkbkapCauses Slow, Progressive Retinal Degeneration in a Mouse Model of Familial Dysautonomia.
abstract: Familial dysautonomia (FD) is an autosomal recessive congenital neuropathy that is caused by a mutation in the gene for inhibitor of kappa B kinase complex-associated protein (IKBKAP). Although FD patients suffer from multiple neuropathies, a major debilitation that affects their quality of life is progressive blindness. To determine the requirement forIkbkapin the developing and adult retina, we generatedIkbkapconditional knockout (CKO) mice using aTUBA1apromoter-Cre (Tα1-Cre). In the retina,Tα1-Creexpression is detected predominantly in retinal ganglion cells (RGCs). At 6 months, significant loss of RGCs had occurred in the CKO retinas, with the greatest loss in the temporal retina, which is the same spatial phenotype observed in FD, Leber hereditary optic neuropathy, and dominant optic atrophy. Interestingly, the melanopsin-positive RGCs were resistant to degeneration. By 9 months, signs of photoreceptor degeneration were observed, which later progressed to panretinal degeneration, including RGC and photoreceptor loss, optic nerve thinning, Müller glial activation, and disruption of layers. Taking these results together, we conclude that althoughIkbkapis not required for normal development of RGCs, its loss causes a slow, progressive RGC degeneration most severely in the temporal retina, which is later followed by indirect photoreceptor loss and complete retinal disorganization. This mouse model of FD is not only useful for identifying the mechanisms mediating retinal degeneration, but also provides a model system in which to attempt to test therapeutics that may mitigate the loss of vision in FD patients.
authors.affiliation: Department of Cell Biology and Neuroscience, Montana State University , Bozeman, MT 59717.
authors.forename: Yumi
authors.initials: Y
authors.lastname: Ueki
authors.affiliation: Department of Cell and Developmental Biology, University of Colorado School of Medicine , Aurora, CO 80045.
authors.forename: Grisela
authors.initials: G
authors.lastname: Ramirez
authors.affiliation: Department of Cell and Developmental Biology, University of Colorado School of Medicine , Aurora, CO 80045.
authors.forename: Ernesto
authors.identifier: 0000-0002-1142-8980
authors.initials: E
authors.lastname: Salcedo
authors.affiliation: Department of Cell and Developmental Biology, University of Colorado School of Medicine , Aurora, CO 80045.
authors.forename: Maureen E
authors.identifier: 0000-0002-2159-5301
authors.initials: ME
authors.lastname: Stabio
authors.affiliation: Department of Cell Biology and Neuroscience, Montana State University , Bozeman, MT 59717.
authors.forename: Frances
authors.identifier: 0000-0002-2064-8678
authors.initials: F
authors.lastname: Lefcort
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D018450:Disease Progression; D004402:Dysautonomia, Familial / Q000378:metabolism* / Q000473:pathology; D005260:Female; D055786:Gene Knockout Techniques; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D018345:Mice, Knockout; D009457:Neuroglia / Q000378:metabolism / Q000473:pathology; D009900:Optic Nerve / Q000378:metabolism / Q000473:pathology; D009902:Optic Neuritis / Q000378:metabolism / Q000473:pathology; D020419:Photoreceptor Cells, Vertebrate / Q000378:metabolism / Q000473:pathology; D012162:Retinal Degeneration / Q000378:metabolism* / Q000473:pathology; D012165:Retinal Ganglion Cells / Q000378:metabolism / Q000473:pathology; D017299:Rod Opsins / Q000378:metabolism; D013997:Time Factors; D000099210:Melanopsin
chemical_list: D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D017299:Rod Opsins; D000099210:Melanopsin; C491968:Ikbkap protein, mouse
keywords: IKAP/Elp1; Ikbkap; familial dysautonomia; retinal degeneration; retinal ganglion cell