title: Retinal degeneration and failure of photoreceptor outer segment formation in mice with targeted deletion of the Joubert syndrome gene, Ahi1.
abstract: Vertebrate photoreceptors have a modified cilium composed of a basal body, axoneme and outer segment. The outer segment includes stacked membrane discs, containing opsin and the signal transduction apparatus mediating phototransduction. In photoreceptors, two distinct classes of vesicles are trafficked. Synaptic vesicles are transported down the axon to the synapse, whereas opsin-containing vesicles are transported to the outer segment. The continuous replacement of the outer segments imposes a significant biosynthetic and trafficking burden on the photoreceptors. Here, we show that Ahi1, a gene that when mutated results in the neurodevelopmental disorder, Joubert syndrome (JBTS), is required for photoreceptor sensory cilia formation and the development of photoreceptor outer segments. In mice with a targeted deletion of Ahi1, photoreceptors undergo early degeneration. Whereas synaptic proteins are correctly trafficked, photoreceptor outer segment proteins fail to be transported appropriately or are significantly reduced in their expression levels (i.e., transducin and Rom1) in Ahi1(-/-) mice. We show that vesicular targeting defects in Ahi1(-/-) mice are cilium specific, and our evidence suggests that the defects are caused by a decrease in expression of the small GTPase Rab8a, a protein required for accurate polarized vesicular trafficking. Thus, our results suggest that Ahi1 plays a role in stabilizing the outer segment proteins, transducin and Rom1, and that Ahi1 is an important component of Rab8a-mediated vesicular trafficking in photoreceptors. The retinal degeneration observed in Ahi1(-/-) mice recapitulates aspects of the retinal phenotype observed in patients with JBTS and suggests the importance of Ahi1 in photoreceptor function.
authors.affiliation: Department of Biology, Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, New York 12180, USA.
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Westfall
authors.forename: Carlton
authors.initials: C
authors.lastname: Hoyt
authors.forename: Qin
authors.initials: Q
authors.lastname: Liu
authors.forename: Yi-Chun
authors.initials: YC
authors.lastname: Hsiao
authors.forename: Eric A
authors.initials: EA
authors.lastname: Pierce
authors.forename: Patrick S
authors.initials: PS
authors.lastname: Page-McCaw
authors.forename: Russell J
authors.initials: RJ
authors.lastname: Ferland
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport; D000818:Animals; D001927:Brain Diseases; D002923:Cilia / Q000378:metabolism; D005136:Eye Proteins / Q000378:metabolism; D044385:GTP-Binding Protein alpha Subunits / Q000378:metabolism; D017353:Gene Deletion; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D012160:Retina / Q000378:metabolism; D012162:Retinal Degeneration / Q000378:metabolism*; D055214:Retinal Photoreceptor Cell Outer Segment / Q000378:metabolism*; D013572:Synaptic Vesicles / Q000378:metabolism; D013577:Syndrome; D059470:Tetraspanins; D015293:Transducin / Q000378:metabolism; D020691:rab GTP-Binding Proteins / Q000378:metabolism
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; C465818:Ahi1 protein, mouse; D005136:Eye Proteins; D044385:GTP-Binding Protein alpha Subunits; C488949:Gnat1 protein, mouse; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; C546061:Rab8a protein, mouse; C081477:Rom1 protein, mouse; D059470:Tetraspanins; D015293:Transducin; D020691:rab GTP-Binding Proteins