The Intraflagellar Transport Protein Ift80 Is Essential for Photoreceptor Survival in a Zebrafish Model of Jeune Asphyxiating Thoracic Dystrophy

Hudak, Leah M.; Lunt, Shannon; Chang, Chi-Hsuan; Winkler, Ethan A.; Flammer, Halley; Lindsey, Michael; Perkins, Brian D.

doi:10.1167/iovs.09-4312

Cited by 42 publications

(37 citation statements)

References 51 publications

(74 reference statements)

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“…Consistent with such a role, cilia in Cep290 mutants had abnormal accumulations and reductions of various IFT and BBS proteins (34). Interactions between IFT and BBS proteins have been identified in C. elegans (59) and zebrafish retina (60). OSs continuously elongate as the outermost disks are engulfed by the RPE, explaining the importance of the ciliary axoneme to constantly supply new disk components.…”

Section: Figurementioning

confidence: 88%

Combining Cep290 and Mkks ciliopathy alleles in mice rescues sensory defects and restores ciliogenesis

Rachel¹,

May-Simera²,

Veleri³

et al. 2012

J. Clin. Invest.

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Cilia are highly specialized microtubule-based organelles that have pivotal roles in numerous biological processes, including transducing sensory signals. Defects in cilia biogenesis and transport cause pleiotropic human ciliopathies. Mutations in over 30 different genes can lead to cilia defects, and complex interactions exist among ciliopathy-associated proteins. Mutations of the centrosomal protein 290 kDa (CEP290) lead to distinct clinical manifestations, including Leber congenital amaurosis (LCA), a hereditary cause of blindness due to photoreceptor degeneration. Mice homozygous for a mutant Cep290 allele (Cep290 rd16 mice) exhibit LCA-like early-onset retinal degeneration that is caused by an in-frame deletion in the CEP290 protein. Here, we show that the domain deleted in the protein encoded by the Cep290 rd16 allele directly interacts with another ciliopathy protein, MKKS. MKKS mutations identified in patients with the ciliopathy BardetBiedl syndrome disrupted this interaction. In zebrafish embryos, combined subminimal knockdown of mkks and cep290 produced sensory defects in the eye and inner ear. Intriguingly, combinations of Cep290 rd16 and Mkks ko alleles in mice led to improved ciliogenesis and sensory functions compared with those of either mutant alone. We propose that altered association of CEP290 and MKKS affects the integrity of multiprotein complexes at the cilia transition zone and basal body. Amelioration of the sensory phenotypes caused by specific mutations in one protein by removal of an interacting domain/protein suggests a possible novel approach for treating human ciliopathies.

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Section: Figurementioning

confidence: 88%

Combining Cep290 and Mkks ciliopathy alleles in mice rescues sensory defects and restores ciliogenesis

Rachel¹,

May-Simera²,

Veleri³

et al. 2012

J. Clin. Invest.

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“…For example, a mutation in the IFT-A particle protein, IFT144 (also known as WDR19 ) is associated with retinal, renal, skeletal and other abnormalities known as Jeune and Sensenbrenner syndromes (Bredrup et al, 2011). A series of subsequent studies used the power of zebrafish genetics to demonstrate that mutations in multiple IFT components can all prevent proper outer segment formation (Bahadori et al, 2003; Davis et al, 2011; Hudak et al, 2010; Krock and Perkins, 2008; Omori et al, 2008; Sukumaran and Perkins, 2009; Tsujikawa and Malicki, 2004). …”

Section: Protein Sorting and Traffickingmentioning

confidence: 99%

Protein sorting, targeting and trafficking in photoreceptor cells

Pearring

Salinas

Baker

et al. 2013

Progress in Retinal and Eye Research

167

175

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Vision is the most fundamental of our senses initiated when photons are absorbed by the rod and cone photoreceptor neurons of the retina. At the distal end of each photoreceptor resides a lightsensing organelle, called the outer segment, which is a modified primary cilium highly enriched with proteins involved in visual signal transduction. At the proximal end, each photoreceptor has a synaptic terminal, which connects this cell to the downstream neurons for further processing of the visual information. Understanding the mechanisms involved in creating and maintaining functional compartmentalization of photoreceptor cells remains among the most fascinating topics in ocular cell biology. This review will discuss how photoreceptor compartmentalization is supported by protein sorting, targeting and trafficking, with an emphasis on the best-studied cases of outer segment-resident proteins.

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“…Defective IFT80 produces a zebrafish model of jeune thoracic asphyxiating dystrophy (Hudak et al, 2010). Mutations in IFT22 and IFT43 result in Sensenbrenner syndrome, a disorder featuring craniofacial abnormalities due to defects in Shh signaling (Arts et al, 2011; Walczak-Sztulpa et al, 2010).…”

Section: Diseases Of Abnormal Ciliary Formation and Maintenancementioning

confidence: 99%

Stages of ciliogenesis and regulation of ciliary length

Avasthi¹,

Marshall²

2012

Differentiation

190

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Cilia and flagella are highly conserved eukaryotic microtubule-based organelles that protrude from the surface of most mammalian cells. These structures require large protein complexes and motors for distal addition of tubulin and extension of the ciliary membrane. In order for ciliogenesis to occur, coordination of many processes must take place. An intricate concert of cell cycle regulation, vesicular trafficking, and ciliary extension must all play out with accurate timing to produce a cilium. Here, we review the stages of ciliogenesis as well as regulation of the length of the assembled cilium. Regulation of ciliogenesis during cell cycle progression centers on centrioles, from which cilia extend upon maturation into basal bodies. Centriole maturation involves a shift from roles in cell division to cilium nucleation via migration to the cell surface and docking at the plasma membrane. Docking is dependent on a variety of proteinaceous structures, termed distal appendages, acquired by the mother centriole. Ciliary elongation by the process of intraflagellar transport (IFT) ensues. Direct modification of ciliary structures, as well as modulation of signal transduction pathways, play a role in maintenance of the cilium. All of these stages are tightly regulated to produce a cilium of the right size at the right time. Finally, we discuss the implications of abnormal ciliogenesis and ciliary length control in human disease as well as some open questions.

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The Intraflagellar Transport Protein Ift80 Is Essential for Photoreceptor Survival in a Zebrafish Model of Jeune Asphyxiating Thoracic Dystrophy

Cited by 42 publications

References 51 publications

Combining Cep290 and Mkks ciliopathy alleles in mice rescues sensory defects and restores ciliogenesis

Combining Cep290 and Mkks ciliopathy alleles in mice rescues sensory defects and restores ciliogenesis

Protein sorting, targeting and trafficking in photoreceptor cells

Stages of ciliogenesis and regulation of ciliary length

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