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 Ϫ / Ϫ mice. We show that vesicular targeting defects in Ahi1 Ϫ/Ϫ 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 Ϫ/Ϫ mice recapitulates aspects of the retinal phenotype observed in patients with JBTS and suggests the importance of Ahi1 in photoreceptor function.

Strange as it may seem: the many links between Wnt signaling, planar cell polarity, and cilia: Figure 1.

“…One group (Lancaster et al 2009) reported that Jbn is not required for ciliogenesis, but another group (Hsiao et al 2009) reported that it is required. Both groups reported a role for Jbn in trafficking in the photoreceptor connecting cilium (Louie et al 2010;Westfall et al 2010). Taken together, these results might seem to indicate a positive, rather than negative, role for Jbn and cilia in Wnt signaling.…”

The Joubert Syndrome-associated Missense Mutation (V443D) in the Abelson-helper Integration Site 1 (AHI1) Protein Alters Its Localization and Protein-Protein Interactions

“…At the subcellular level, Ahi1 is found in the cytoplasm and at the basal bodies of primary cilia, and inhibition of Ahi1 expression blocks the formation of primary cilia (11). Moreover, Ahi1-deficient mice display retinal degeneration resulting from defective ciliary protein trafficking (12,13). These studies suggest a crucial role for Ahi1 in cilium formation and function.…”

The role of primary cilia in the development and disease of the retina

“…Ahi1 mutant mice either do not develop OS or develop abnormal OS leading to subsequent photoreceptor degeneration, associated with defects in vesicular trafficking of transducin, ROM1 and opsin with a decrease in Rab8 expression. 192,193 ahi1 morphant zebrafish develop abnormally shaped eyes with coloboma and defective retinal lamination.…”