Intraflagellar Transport Genes Are Essential for Differentiation and Survival of Vertebrate Sensory Neurons

Abstract

Cilia play diverse roles in vertebrate and invertebrate sensory neurons. We show that a mutation of the zebrafish oval (ovl) locus affects a component of the ciliary transport (IFT) mechanism, the IFT88 polypeptide. In mutant retina, cilia are generated but not maintained, producing the absence of photoreceptor outer segments. A loss of cilia also occurs in auditory hair cells and olfactory sensory neurons. In all three sense organs, cilia defects are followed by degeneration of sensory cells. Similar phenotypes are induced by the absence of the IFT complex B polypeptides, ift52 and ift57, but not by the loss of complex A protein, ift140. The degeneration of mutant photoreceptor cells is caused, at least partially, by the ectopic accumulation of opsins. These studies reveal an essential role for IFT genes in vertebrate sensory neurons and implicate the molecular components of intraflagellar transport in degenerative disorders of these cells.

The zebrafish eye—a paradigm for investigating human ocular genetics

“…The zebrafish photoreceptor mutant oval (ovl) which encodes the cilium gene, IFT88 displays loss of outer segments due to mislocalised visual pigment and cilia dysfunction, similar to the mislocalisation observed in human photoreceptor cell death caused by RP, suggesting that ectopic phototransduction may have an important role in photoreceptor cell death. 82 Usher syndrome (USH) is an autosomal recessive genetic disease characterised by combined hearing and vision loss and occasionally balance problems. USH is classified into three subtypes according to clinical severity and symptoms; Usher type 1 (USH1) presents as severe to profound congenital sensorineural deafness and vestibular areflexia with onset of RP within the first decade of life; type 2 (USH2) patients show moderate to severe hearing loss, normal vestibular function and pre-/post-pubertal onset of RP; and type 3 (USH3) patients have progressive hearing loss, sporadic vestibular dysfunction, and variable onset of RP.…”

Zebrafish: A model system for the study of eye genetics

“…Mutations in intraflagellar transport protein loci, known to be associated with proper function of the connecting cilium in photoreceptor cells have also been recovered. Mutation in the oval gene, which encodes an intraflagellar transport protein, leads to photoreceptor cell dysgenesis as well as defects in other sensory receptor cells (Tsujikawa and Malicki, 2004). This provides just one example of a number of genetic models to study the basic cell biology of intraflagellar transport in vertebrate cells as well as providing additional models for diseases of the visual system.…”

Cilium-generated signaling and cilia-related disorders

“…Although a direct molecular connection has not been established between regulation of flagellar length and IFT or between initiation of flagellar assembly/disassembly and IFT, it will be surprising indeed if elements of the IFT machinery are not targets of the length-regulating MAP kinase 29 or of the disassembly-regulating aurora kinase. 31 A ciliary synthesis: linking IFT, PKD, and sensory transduction Although Chlamydomonas continues to be an excellent model system for elucidating ciliary assembly mechanisms and providing new ideas on IFT and the properties of cilia and flagella, studies on the cilia of the nematode worm Caenorhabditis elegans, 23 Drosophila, [37][38][39] Tetrahymena, 40 zebrafish, 41,42 and mouse 43 also are making fundamental contributions (reviewed in Rosenbaum and Witman 20 and Scholey 23 ). The discovery of IFT ultimately led, albeit through a somewhat circuitous route, to a partial solution to the riddle of why some PCD patients exhibited polycystic kidney disorders and to a fuller appreciation of the role of cilia in sensory transduction events beyond those of light, sound, and odorant perception.…”